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The investigators would like to conduct a double blind placebo-controlled prospective study  to show the impact of a treatment combining a specific cognitive rehabilitation program and  acetylcholinesterase inhibitors on executive function of young patients 3 months after a  first symptomatic stroke. The secondary objectives will be to assess cognitive changes  performance (executive but also non trained functions such as memory) before and after  treatments and treatment effect on activity of daily living and on quality of life.  The main objective of this study is to show the impact of this combined treatment on brain  activation maps in VCI-ND patients in the post-acute phase (3 months) after a stroke.  Treatment effect will be assessed by functional MRI (fMRI) while patients will be performing  a specific executive task.  The investigators hypothesize that the specific rehabilitation associated with  acetylcholinestrase inhibitors treatment will focalize cerebral activation observed in fMRI,  improve executive functions specifically, improve non trained cognitive functions  (generalization effect). Recent studies, including the investigators', have shown that neuropsychological alteration  is frequent and underestimated after stroke (Vascular Cognitive Impairment (VCI). VCI-No  Dementia (VCI-ND) is characterized by a mild cognitive alteration in relation to a  cerebrovascular lesion, diagnosed by a neuropsychological assessment, and without major  alteration in the activities of daily living, but that can represent an issue in return to  work for young patients. Some studies demonstrated that cognitive rehabilitation or  pharmacological intervention may to improve patients' cognition and social functioning.  The investigators hypothesize that a combination of pharmacological and cognitive  rehabilitation treatments is beneficial on executive but also other cognitive function in  VCI-ND patients  Therefore the investigators would like to conduct a double blind placebo-controlled  prospective study to show the impact of a treatment combining a specific cognitive  rehabilitation program and acetylcholinesterase inhibitors on executive function of young  patients 3 months after a first symptomatic stroke. The secondary objectives will be to  assess cognitive changes performance (executive but also non trained functions such as  memory) before and after treatments and treatment effect on activity of daily living and on  quality of life.  The main objective of this study is to show the impact of this combined treatment on brain  activation maps in VCI-ND patients in the post-acute phase (3 months) after a stroke.  Treatment effect will be assessed by functional MRI (fMRI) while patients will be performing  a specific executive task.  The investigators hypothesize that the specific rehabilitation associated with  acetylcholinestrase inhibitors treatment will focalize cerebral activation observed in fMRI,  improve executive functions specifically, improve non trained cognitive functions  (generalization effect). Inclusion Criteria:  -  Written consent form signed by the patient,  -  Patient must be affiliated with a social security system,  -  Age: 35-70,  -  First symptomatic stroke,  -  Brain ischemic lesion on MRI DWI consistent with a recent ischemic stroke,  -  Absence of cognitive decline before the stroke,  -  Detailed cognitive complaint of patient or the environment,  -  Patients with a cognitive impairment (VCI-ND criteria: impairment in at least one  cognitive domain with a score below 2 standard deviation according to clinical norms  in at least two cognitive functions exploring this domain. VCI-ND was diagnosed in the  absence of dementia according to the DSM IV,  -  Absence of hospitalization for cardiovascular disease from the acute phase of the  qualifying event,  -  NIHSS < 6,  -  mRs < 4,  -  Absence of aphasia, apraxia and neglect severe,  -  Patients not previously treated with cholinesterase inhibitors or memantine centrally  acting regardless of the duration of treatment and date of prescription,  -  Visual skills, auditory and oral or written expression sufficient to achieve adequate  neuropsychological tests,  -  Women of childbearing potential must be using contraception and a pregnancy test will  be conducted at the screening visit. Exclusion Criteria:  -  Subjects with contraindication to MRI (a pacemaker or a defibrillator, an implanted  material activated by an electrical, magnetic or mechanical carriers of hemostatic  clips of intracerebral aneurysms or carotid arteries, bearing orthopedic implants,  claustrophobia),  -  Preexisting cognitive decline,  -  VCI-ND criteria not fulfilled,  -  Patients previously treated with cholinesterase inhibitors or memantine centrally  acting regardless of the duration of treatment and date of prescription,  -  Known allergy or intolerance to cholinesterase inhibitors or their excipients,  -  Depression,  -  General Health scalable,  -  Progressive neurological disease causing cognitive impairment,  -  Clinically significant endocrine disease,  -  Patients with urinary retention or who have recently had surgery at the bladder,  -  Patients with rare hereditary problems of fructose intolerance, malabsorption of  glucose and galactose or sucrase-isomaltase insufficiency should not take this  medicine,  -  Patient with severe hepatic impairment,  -  Patient with severe renal impairment,  -  Patients with both hepatic and renal significant,  -  Patients with sick sinus disorder or other supraventricular cardiac conduction or in  those receiving concomitant drugs significantly slowing heart rate, such as digoxin  and beta blockers or in patients with uncorrected electrolyte disorders,  -  Period immediately post-myocardial infarction, recent-onset atrial fibrillation,  bundle branch block second degree or higher degree, unstable angina or congestive  heart failure, especially NYHA group III-IV,  -  Patients with gastrointestinal obstruction or recent surgery in gastrointestinal,  -  Patients receiving other cholinomimetic agents (such as ambenonium, donepezil,  neostigmine, pyridostigmine, rivastigmine and pilocarpine) administered systemically,  -  Breast feeding women,  -  Alcohol abuse,  -  Substance abuse,  -  Psychiatric condition scalable,  -  Patients who will have surgery during the study participation,  -  Known or suspected pregnancy, confirmed by a urine pregnancy test. This test will be  done prior to randomization if a woman of childbearing age without oral contraception  is included in the study, if a pregnancy is declared during the participation in the  study, the blind will be removed and the patient will be directed towards a  specialist,  -  Patient can not stop all treatment prohibited for this project at least 2 months  before inclusion,  -  French language level insufficient to properly participate in neuropsychological  assessment,  -  Transient ischemic stroke,  -  Subarachnoid hemorrhage or intraparenchymal,  -  Patient under protection of law or under another protection.

This is a single site, non-randomized, open-label, long-term safety and efficacy follow-up  Phase 1 study for subjects who have been treated with CARv3-TEAM-E T cells in clinical Study  DF/HCC IRB #20-532 (the main study), that evaluated the safety and efficacy of CARv3-TEAM-E T  cells in subjects with newly diagnosed or recurrent glioblastoma This is a single site, non-randomized, open-label, long-term safety and efficacy follow-up  Phase 1 study for subjects who have been treated with CARv3-TEAM-E T cells in clinical Study  DF/HCC IRB #20-532 (the main study), that evaluated the safety and efficacy of CARv3-TEAM-E T  cells in subjects with newly diagnosed or recurrent glioblastoma.  CARv3-TEAM-E drug product is defined as autologous T lymphocytes transduced with a CAR  lentiviral vector encoding a chimeric antigen receptor targeting human EGFRvIII antigen and a  T cell engaging antibody molecule (TEAM) targeting wildtype EGFR. CARv3-TEAM-E T cells are  administered in subjects up to six times in main Study #20-532.  No investigational treatment will be administered in this study.  The United States Food and Drug Administration (FDA, 2018) recommend long-term follow-up for  subjects treated with gene therapy drug products to monitor for selected adverse events (AEs)  and the durability of clinical response.  After the subjects in the parent study has been completed (24 months after CARv3-TEAM-E T  cells infusion, or <24 months after CARv3-TEAM-E infusion if subject discontinues due to  disease progression or any other reason), subjects will be asked to participate in a  long-term follow-up study. Inclusion Criteria:  - Subjects will be asked to participate leading up to the last Study #20-532 visit.  Subjects meeting the following criteria are eligible for study participation:  -  Provision of voluntary written informed consent by subject  -  CARv3-TEAM-E T cells were administered in DF/HCC IRB Study #20-532  -  Able to comply with study requirements Exclusion Criteria:  -  Subjects meeting the following criteria are to be excluded from study participation:  -  Subject has disease progression AND has 2 consecutive VCN measurements at least 1  month apart, at least 6 months after drug product infusion where testing demonstrates  undetectable VCN (<0.0003 vector copies per diploid genome) in peripheral blood cells.  -  Withdrew consent to Study #20-532.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive electro-physical  modality used for several pain conditions including labor pain control. Despite several years  of research, there is still no agreement within the literature regarding the selection of  TENS parameters. It is aimed to investigate TENS1 alternating between 4 to 100 Hz compared to  sham-TENS.  The present study aims to evaluate TENS in combination with cardiotocography (CTG).  The combination of TENS with CTG in a feedback-loop has not been reported in any studies  before. Midwives and the study investigator will ask parturients, who are admitted to the labor ward  at Region Hospital Herning satisfying the inclusion and exclusion criteria, whether they are  interested in attending the experimental session.  The study will be conducted as soon as the subject is admitted at the labor ward. The study  will only be conducted during early and active labor and not during the birth of the baby.  The subject in this study includes the package of a parturient and her neonate (after birth)  as we also obtain data about the neonate. Hereby, two consent forms will be obtained. As this  study is a non-invasive study, it is decided to have at least the consent of one parent.  The investigator will fill out a screening questionnaire about the laboring parturient in  cooperation with the subject and the midwife, including screening questions related to  inclusion and exclusion criteria before the experimental session starts.  The study will last approximately one hour and will be conducted during laboring  circumstances. KT (Kenoja Thuvarakan) will carry out the experiment, and she will be present  in the delivery room during the whole session.  The study includes several outcomes, including subjective and semi-objective pain measures.  The primary outcome is VAS (0-10 cm scale), while secondary outcomes include PPT and  satisfaction questionnaire (only at the end of the study). The subjects will be asked before,  and immediately after the experimental exposure about the outcomes (VAS and PPT). The  subjects will be exposed to one of the two combinations of TENS stimulation (low-to-high and  high alternating frequency), which will be compared to sham-TENS. Inclusion Criteria:  -  Singleton pregnancy  -  Vertex presentation  -  Speak, read and understand Danish Exclusion Criteria:  -  Gestational age < 37+0 weeks  -  Gestational age > to 41+6 weeks  -  High-risk pregnancies (including risk factors: eclampsia, pre-eclampsia, diabetes,  gestational diabetes, hypertension (above 140/90), and hypotension (below 90/60),  Intrauterine growth restriction (IUGR), polyhydramnious, and oligohydramnious).  -  Pre-gestational body mass index (BMI) above 40 kg/m2  -  Use of fetal scalp-electrode during the experiment  -  Use of pacemakers and other electronic implants  -  Severe arrhythmia  -  Present musculoskeletal illnesses (including myopathy and arthritis).  -  Chronic pain within last 6 months (Pelvic girdle pain (PGP) to a mild degree (VAS 0-6  cm) is accepted in the experiment. Severe degree (VAS 6-10 cm) (e.g. bedridden or  difficulty walking) especially within 24 hours before birth is excluded).  -  Present/previous neurologic illnesses (including epilepsy, migraine, and sclerosis).  -  Present medicated mental disorders (including dementia, personality disorders,  bipolar, ADHD, and anxiety).  -  Dermatological disorders (including skin allergy, tattoos or scars on the locations of  electrodes)  -  Use of other long-acting pain relief before the experiment (including Epidural,  Morphine less than 16 hours before experiment), Acupuncture, Paracetamol (less than 8  hours before experiment), Cocktail (less than 8 hours before experiment), nitrous  oxide (less than one hour before experiment), sterile water injection (less than two  hours before experiment).  -  Use of TENS 48 hours before the trial  -  Drug addiction defined as the use of cannabis, opioids or other drugs.  -  Smokers  -  Lack of ability to cooperate

-  cooperation of an International team with many years of experience in surgical  management of lymphedema  -  description of an effective surgical strategy to treat cancer-related lymphedema, a high  incidence pathology  -  the combination of LVA and liposuction guarantees long lasting results Cancer-related lymphedema represents one of the major complications of cancer treatment,  especially for breast and gynecologic cancers. Moreover, it has high impact on cancer  survivors and healthcare systems. Lymphedema management still remains challenging. The better  understanding of lymphedema physiopathology as well as the development of sophisticated  surgical and diagnostic techniques have led to effective strategies to address lymphedema  patients but, despite the considerable interest in international literature, no consensus  exist. The combination of LVA and liposuction may represent an effective strategy in treating  patients with cancer-related lymphedema, in order to reach a significant decrease in volume  and reduction of lymphangitis rate as well as stable results in time. In addition, it has the  aim of being minimally invasive and well tolerated by patients Inclusion Criteria:  -  free from cancer disease Exclusion Criteria:  - persistence of the neoplastic pathology  - patients affected by primary lymphedema

Fluid status and congestion can be determined by the CPM wearable device and correlates with  invasive measures, non-invasive measures and biochemical markers of congestion and changes in  congestion. HF is associated with frequent and lengthy hospitalisations. These hospitalisations are  usually as a result of congestion. The signs of congestion that can be recognised by  physicians or health care professionals such as lung crackles or worsening of peripheral  oedema are often seen at a late stage before an intervention can be made to prevent overt  decompensation and admission to hospital. Recognising changes in excess fluid status either  before a patient becomes unwell or during decongestion treatment is highly desirable so that  timely treatment can be started or so that treatment can be adjusted based on an individual's  response to therapy. The ability to assess patients by applying a single, non-invasive device  would potentially provide a useful tool for assessing a patient's congestion levels and allow  patients with progressive deterioration to be identified earlier. Inclusion Criteria:  Written informed consent  -  Male or female over18 years of age Cohort A  -  Meet European Society of Cardiology 1 (ESC) criteria for diagnosis of HF  -  Undergoing clinically-indicated RHC Cohort B  -  Established on haemodialysis for >90 days  -  Undergoing haemodialysis with target volume removal ≥1.5 litres fluid Cohort C  -  Meet ESC criteria for diagnosis of HF including heart failure  -  Requiring treatment with intravenous (IV) diuretics Training Cohort  -  Meet ESC criteria for diagnosis of HF including heart failure  -  Requiring treatment with intravenous (IV) diuretics Exclusion Criteria:  -  Unable to consent to inclusion in study due to cognitive impairment  -  Allergies or skin sensitivities to silicone-based adhesive  -  Skin breakdown or dermatological condition on the left chest or breast areas or chest  wall deformity where the device is placed  -  Pregnancy or breast-feeding  -  Conditions that may confound congestion assessments  -  COVID-19 infection.

This is a prospective, multi-center observational survey study to uncover how antibiotic  differences can influence utilization decisions. The purpose is to assess the trade-offs  between drug side effects and infection prevention that patients are willing to make when  taking prophylactic antibiotics. Misuse of antibiotics or non-adherence to prescribed  regimens is a public health issue that may be due to a variety of reasons including unclear  instructions, symptom improvement and adverse events Subjects will be healthcare providers  (physician or nurse) and individuals 18+ years of age in the dermatologic surgery waiting  area (including patients and accompanying individuals). Participants will complete a  conjoint.ly survey and choose between treatment (antibiotic vs no antibiotic) scenarios. This is a prospective, multi-center observational survey study to uncover how antibiotic  differences can influence utilization decisions. The purpose is to assess the trade-offs  between drug side effects and infection prevention that patients are willing to make when  taking prophylactic antibiotics. Misuse of antibiotics or non-adherence to prescribed  regimens is a public health issue that may be due to a variety of reasons including unclear  instructions, symptom improvement and adverse events Subjects will be healthcare providers  (physician or nurse) and individuals 18+ years of age in the dermatologic surgery waiting  area (including patients and accompanying individuals). Participants will complete a  conjoint.ly survey and choose between treatment (antibiotic vs no antibiotic) scenarios.  Adults in the dermatologic surgery department waiting room with age greater than or equal to  18 years (this includes both patients and accompanying individuals (family members, friends,  caregivers)) and healthcare providers in dermatologic surgery. A member of the study team  will approach patients in the Perelman Dermatology Clinic to determine if they meet inclusion  criteria and educate them about the study using the verbal script. If interested, patients  will receive a link to the online survey, which will contain an informed consent page.  Dermatology healthcare providers will be identified in clinic or from academic center staff  directories. Individuals meeting inclusion criteria will also be recruited from the  dermatologic surgery waiting rooms of other collaborating institutions (Penn State Health,  University of Missouri Health Care, Indiana University Health, University of Minnesota,  Oregon Health & Science University, Washington University in St. Louis, UT Southwestern, UC  Davis and Ohio State University) once approved by their IRB.  All data will be collected and stored in a secured password-protected conjoint.ly account  managed by the Penn Dermatologic Surgery Clinical Research Team. Collaborating institutions  will not have access to the survey responses. Data analysis: Multivariate random parameters  logit will be used to estimate preference weights for each attribute level. These preference  weights will be used to estimate the maximum acceptable risk of various side effects that  subjects would be willing to accept in exchange for infection prevention. Collaborating  researchers from other institutions will not be involved in data analysis. Inclusion Criteria:  -  Age ≥ 18 years  -  Individual in the dermatologic surgery waiting room: patient, caregiver, family member  or accompanying individual to patient receiving dermatologic surgery service, or  dermatology healthcare provider Exclusion Criteria:   -  Age less than 18 years.

This trial is a single-arm, multicenter phase Ib/II clinical study to evaluate the efficacy  and safety of Docetaxel for Injection (Albumin-bound) combined with Nivolumab and the  pharmacokinetic characteristics of Docetaxel in patients with recurrent or metastatic SCCHN  who are positive for PD-L1 expression and have progressed on or after platinum-based therapy. This study will be conducted in two stages (phase Ib and phase II). Phase Ib: To explore the  safety and tolerability of Docetaxel for Injection (Albumin-bound) (75 mg/m^2 and 100 mg/m^2)  combined with Nivolumab 360 mg. Dose exploration will be started at low dose and proceed in  turn.  Phase II: According to the recommended phase II dose (RP2D) determined in the phase Ib study,  a phase II study of Docetaxel for Injection (Albumin-bound) combined with Nivolumab will be  conducted to observe the efficacy of the combination regimen, with ORR as the primary study  endpoint. Simon's optimal 2-stage design will be adopted for phase II study.  All patients in Phase Ib and Phase II will be treated with Docetaxel for Injection  (Albumin-bound) combined with Nivolumab until participants meet the criteria for termination  or withdrawal criteria, for a maximum of 2 years Inclusion Criteria:  1. Age ≥ 18 years old and voluntarily signed the informed consent form.  2. Patients with histologically or cytologically confirmed SCCHN (primary tumor located  in the oral cavity, oropharynx, larynx or hypopharynx), with positive PD-L1  expression, and who are not suitable for local radical therapy.  3. Patients with platinum-based regimen failure, defined as:  1. . Recurrent or metastatic SCCHN with disease progression during or after  platinum-based therapy;  2. . Locally advanced head and neck carcinoma with recurrence or metastasis within 6  months after platinum-based therapy in previous multimodal therapy.  4. Previous or qualified tumor tissue samples are available for testing PD-L1.  5. Patients with oropharyngeal carcinoma should provide previous HPVp16  immunohistochemical test results, or eligible tumor tissue samples for testing HPV  status.  6. At least one measurable lesion confirmed by CT or MRI according to RECISTv1.1  (previously irradiated, progressive disease or tumor persistence ≥ 3 months after  radiotherapy can be considered as measurable lesions).  7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.  8. Life expectancy ≥ 3 months.  9. Main organ function meets the following criteria within 7 days before treatment (no  medical supportive treatments such as blood component transfusion, human granulocyte  colony-stimulating factor (G-CSF), thrombopoietin (TPO), interleukin-11, and  erythropoietin (EPO) within 2 weeks before administration of the investigational  product).  Absolute neutrophil count ≥1.5×10^9/L Platelets ≥90×10^9/L Hb≥90 g/L or ≥5.6 mmol/L  Serum creatinine ≤ 1.5×ULN or creatinine clearance rate ≥ 40 mL/min Total bilirubin  ≤1.0×ULN (≤ 1.5 × ULN for patients with liver metastasis or liver cancer); Alanine  aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN ( ≤ 2.5 × ULN  for patients with liver metastasis or liver cancer); Activated Partial Thromboplastin  Time (APTT) ≤ 1.5×ULN, International Normalized Ratio (INR) ≤ 1.5×ULN.  10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test  within 7 days prior to the first dose of the investigational drug. The patient and  his/her spouse must agree to take adequate contraception from signing of ICF through 6  months after last dose, during which time women should be nonlactating and men should  refrain from donating sperm. Exclusion Criteria:  1. Histologically or cytologically confirmed recurrent or metastatic nasopharyngeal  carcinoma, SCCHN with unknown primary lesion, salivary gland carcinoma, or  non-squamous tissue carcinoma (e.g., mucosal melanoma).  2. Patients with active brain metastasis and leptomeningeal metastasis. Patients with  brain metastasis for whom there is no evidence of PD by MRI at least 8 weeks after  treatment and within 28 days before the first dose of the investigational drug can be  included; Those who do not require systemic cortisol therapy (prednisone > 10 mg/day  or equivalent) at least 2 weeks before the first dose of the investigational drug can  be included; Patients with skull base lesions without definite evidence of dural or  parenchymal brain involvement can be considered to be included only after discussion  with the sponsor's medical monitor.  3. History of other malignancies within 5 years prior to the first dose of the  investigational drug, except for the following: a. Any other invasive malignancy (for  which the patient has received adequate treatment) with disease free status lasting >  3 years, which will not affect the assessment of tumor efficacy as assessed by the  investigator; b. Cured basal cell or squamous cell skin carcinoma, superficial bladder  cancer, prostate cancer, cervical cancer, or breast cancer in situ, and other locally  curable cancers.  4. Patients with known or suspected autoimmune disease within 2 years before the first  dose of the investigational drug, except for the following: a. well-controlled type I  diabetes; b. well-controlled hypothyroidism requiring only hormone replacement  therapy; c. skin diseases (such as vitiligo, psoriasis, or alopecia) not requiring  systemic treatment; d. patients who are not expected to relapse in the absence of  external triggers.  5. Patients with an uncontrollable third space effusion (e.g. pleural effusion, ascites,  or pericardial effusion), who, in the judgment of the investigator, are not suitable  for the study.  6. Patients with a history of severe cardiovascular disease within 6 months before the  first dose of the investigational drug, including but not limited to:  1. . Severe heart rhythm or conduction abnormalities, such as ventricular arrhythmia  requiring clinical intervention and third-degree atrioventricular block;  2. . History of myocardial infarction, angina pectoris, angioplasty and coronary  artery bypass surgery;  3. . Heart failure with New York Heart Association (NYHA) Classification of Class  III and above;  4. . Poorly controlled hypertension.  7. Patients with prolonged QT/QTc interval (QTcF > 480 ms, Fridericia's formula: QTcF =  QT/RR^0.33, RR = 60/heart rate) by ECG during the screening period and/or with left  ventricular ejection fraction (LVEF) ≤ 50% by echocardiography (ECHO) or multi-gated  acquisition (MUGA) during the screening period;  8. Patients with positive HCV antibody (+) (patients with negative HCV RNA can be  included, and anti-HCV treatment other than interferon is allowed), active hepatitis B  (patients with HBV DNA ≤ 500 IU/mL can be included, and anti-HBV treatment other than  interferon is allowed), known HIV positive or known acquired immunodeficiency syndrome  (AIDS) during the screening period.  9. Patients who have undergone major organ surgery within 4 weeks before the first dose  of the investigational drug, or who need to undergo elective surgery during the study.  10. Patients who fail to recover from the toxic responses caused by previous anti-tumor  treatment to Grade 1 and below (CTCAE 5.0), except for the following: Grade 2  neuropathy, alopecia, hypothyroidism caused by previous anti-tumor treatment  (including hormone replacement therapy) and toxicity without safety risks as judged by  the investigator.  11. Patients who have previously received T cell costimulating drugs or drugs acting on  immune checkpoint pathways (including PD-1, PD-L1/2, CTLA-4 inhibitors, etc.).  12. Patients who have previously received other immunotherapies and experienced ≥ Grade 3  irAE (immune-related adverse event).  13. Patients who have previously received taxanes (patients who previously received  taxane-containing induction chemotherapy and progressed after 6 months can be  included).  14. Patients who have received anti-tumor treatments such as chemotherapy, radiotherapy,  targeted therapy, immunotherapy and other clinical study drugs within 4 weeks before  the first dose of the investigational drug, and other conditions are as follows:  Local palliative radiotherapy within 2 weeks before the first dose of the  investigational drug; oral fluoropyrimidines, small molecule targeted drugs, etc.  within 2 weeks before the first dose of the investigational drug or within known 5  half-lives of the drug (whichever is longer); Traditional Chinese medicines with  anti-tumor indications within 2 weeks before the first dose of the investigational  drug.  15. Patients who have received corticosteroid (prednisone > 10 mg/day or equivalent) or  other immunosuppressive therapies within 2 weeks before the first dose of the  investigational drug, except for the following: a. use of topical, ocular,  intra-articular, intranasal and inhaled glucocorticoids; b. short-term use of  glucocorticoids for prophylaxis (such as prevention of contrast agent allergy).  16. Patients who have received live attenuated vaccine within 2 weeks before the first  dose of the investigational drug or planned to receive live attenuated vaccine during  the study period.  17. Patients who have used potent inhibitors or inducers of CYP3A4 within 2 weeks before  the first dose of the investigational drug.  18. Patients with known ≥ Grade 3 hypersensitivity and/or contraindication to albumin or  monoclonal antibodies.  19. Other situations that the investigator considers not suitable for participating in the  clinical study, including but not limited to: the patient is complicated by severe or  uncontrolled medical conditions, which interfere with the interpretation of study  results and affect the study compliance.

Temporomandibular joint (TMJ) arthroscopy has been used successfully for intra-articular  disorders. Until now, limited studies are available regarding the clinical evidence of  bilateral TMJ arthroscopy for Dimitroulis 2-3. This prospective study investigated the  efficacy of TMJ arthroscopy in patients with bilateral disorders, and also the need for a  posterior surgery. Temporomandibular joint (TMJ) arthroscopy has been used successfully for intra-articular  disorders. It was first introduced by Onishi at 1975, as a pioneering technique to treat  painful joints and has been associated with a reduction in the number of open joints  surgeries. This minimally invasive technique allows observation of the TMJ upper compartment  tissues, and sometimes the lower compartment. Moreover, this intervention allows joint lysis  and lavage (level 1 arthroscopy) and intra-articular surgical procedures (level 2-3  arthroscopy).  Recent studies updated that TMJ arthroscopy promotes a reduction in pain and inflammatory  process and restoring the mandibular function with low morbidity. Moreover, TMJ arthroscopy  seems to be also long-term effective for relieving TMJ symptoms. Until now, limited studies  are available regarding the clinical evidence of bilateral TMJ arthroscopy for Dimitroulis  2-3. This prospective study investigated the efficacy of TMJ arthroscopy in patients with  bilateral disorders, and also the need for a posterior surgery. Inclusion Criteria:  -  age >16 years;  -  clinical diagnosis of bilateral intra-articular disorder;  -  clinical criteria for bilateral TMJ arthroscopy;  -  magnetic resonance imaging (MRI) assessing the intra-articular derangement Exclusion Criteria:  -  The exclusion criteria included any history of previous TMJ surgical intervention or  any facial trauma within the last 4 weeks prior the study.  -  Severe medical problems or mental illness, and pregnancy were also exclusion criteria

The purpose of this clinical study is to evaluate the surgical, refractive, and visual  outcomes with implantation of an investigational intraocular lens (IOL). Eligible subjects will be enrolled into one of two groups: BAL-FAIOL IOL or Monofocal IOL.  Both eyes will receive cataract surgery with IOL implantation. IOL implantation in the second  eye is intended to occur between 7 and 15 days after IOL implantation in the first eye.  Subjects will be followed for 1 year after implantation. Inclusion Criteria: None Exclusion Criteria: None

Managing patients with renal failure requires an understanding of the molecular mechanisms  that lead to its occurrence (i.e. upstream of the disease), its worsening and its persistence  (i.e. downstream), while also specifying the risk of worsening renal failure (risk  stratification, intolerance to the treatment or complications (infectious, metabolic,  cardiovascular, cancer…). Nephrogene 2.0 aims to study these different components of kidney,  immune and solid organ transplantation (SOT)-related diseases. Acute renal failure (ARF) and chronic kidney disease (CKD) are frequent pathologies (850  million people are affected worldwide). Renal failure is associated with an increased  morbidity and mortality, including an increased risk of infections, drug toxicity and  cardiovascular death. The causes of renal failure are numerous: metabolic (diabetes,  hypertension), immunological (autoimmune diseases, monoclonal gammopathies), toxic  (environment, drugs), genetic, infectious, ischemic, paraneoplastic... Any episode of ARF is  also accompanied by a risk of secondary CKD (relative risk multiplied by 9).  The mechanisms leading to renal failure are multiple and combine predisposing genetic  factors, inadequate intra-renal or systemic immune response, endothelial and epithelial  dysfunctions, and potentially inappropriate regenerative capacity. In addition, renal failure  or its treatment itself may be accompanied by additional renal lesions (e.g. nephrotoxicity  of calcineurin inhibitors used as anti-rejection treatment in transplantation, hemodynamic  intolerance with secondary ARF during hemodialysis sessions, iatrogenic ARF when using  diuretics or inhibitors of the renin angiotensin system) or extra-renal complications (e.g.  immunosuppression and infections induced by immunomodulatory therapies during autoimmune  diseases or for prevention of transplant rejection; vascular diseases secondary to  phosphocalcic disorders).  Patients included in the NEPHROGENE 2.0 cohort will be followed during 10 years and clinical  data and biological samples will be collected at the inclusion in the cohort, at each  monitoring programmed in their usual care and and at each event (infection, acute kidney  injury, cancer…). Samples will be collected according to the symptoms of the patients. Inclusion Criteria:  -  Patients (> 18 year of age) with kidney disease or at risk to develop a kidney  disease,  -  Patients followed by a practitioner of the Department of Nephrology and Organ  Transplantations of the University Hospital of Toulouse (France) Exclusion Criteria:  -  consent deny  -  inability of the patient or its family to give consent.

Background:  Bladder and bowel dysfunction (BBD) is characterized by lower urinary tract symptoms  accompanied by bowel complaints. BBD is a common condition in childhood. The present  treatment strategy for BBD is a step-wise approach starting with management of bowel symptoms  before initiation of standard urotherapy and further medical treatment of LUTS symptoms. This  is, however, based on clinical experience and few retrospective, non-randomized studies and  high-level evidence of the succession of the elements in treatment of BBD children is  missing.  Our microbiome, and its role in health and disease, has gained increased focus during the  past years. Studies suggest the urine and gut microbiome to be critical for maintenance of a  well-functioning bladder- and bowel system. The microbiome in children is only sparsely  investigated and its role in BBD is to the investigator's knowledge still unexplored.  Study 1:  Aim: To investigate if combination therapy is more effective in treating urinary incontinence  in BBD children.  Materials and methods: A prospective randomized multicentre study on children with BBD  (n=100) between 5-14 years and 9 months old. They are randomized to: 1) Medical treatment of  bowel symptoms (n=50) or 2) Medical treatment of bowel symptoms combined with standard  urotherapy.  The effect of treatment will be evaluated after 3 months. Primary endpoint: Resolution of  incontinence after treatment. Secondary endpoint: Improved quality of life after successful  treatment of urinary incontinence.  Study 2:  Aim: To investigate the urofecal microbiome in children with BBD  Materials and methods:  1. A cohort study to investigate, whether the urofecal microbiome can predict response to  treatment and whether it changes during treatment period  2. A case control study to investigate whether the urofecal microbiome is different in  children with BBD and recurrent UTI 's and children with BBD without recurrent UTI 's.  The study population consists of children with BBD included in study 1. A urine-, stool  sample and a perineum swab will be collected from all participants before and after  treatment. Bacterial DNA will be extracted and the microbiome will be determined.  Perspectives:  BBD is a common condition in childhood. It is associated with a considerable psychological  burden and a risk of more severe physical complications.  The studies will provide basic knowledge about characteristics of the BBD patients and  contribute new information about the optimal treatment of BBD children. Background Bladder and bowel dysfunction (BBD) is characterised by lower urinary tract  symptoms (LUTS) accompanied by bowel complaints, primarily functional constipation and/or  faecal incontinence. To standardise the terminology used for BBD, LUTS symptoms related to  the disease have been defined by International Children's Continence Society (ICCS).  The prevalence of BBD is probably underestimated but studies suggest BBD to be present in up  to 20 % of school children and to represent up to 40% of paediatric urology consults.  Embryological, anatomical and functional interactions between the rectum and urinary bladder  are well known. Bladder and bowel are anatomically closely related and share innervation from  the parasympathetic S2-S4 and sympathetic L1-L3 nerve roots.  Research on successful treatment of BBD is sparse, with only few retrospective,  non-randomized studies, documenting that treatment of defecation problems in children with  BBD enhances successful management of lower urinary tract disturbances such as daytime  urinary incontinence (DUI), enuresis and urinary tract infections (UTI's). Based on this  knowledge and clinical experience, the present treatment strategy for children with BBD is a  step-wise approach starting with management of bowel symptoms before initiation of standard  urotherapy and further medical treatment of LUTS symptoms. Standard urotherapy encompasses  information and demystification of the disorder along with behavioural modification such as  timed voiding, proper voiding posture, avoidance of holding manoeuvers and balanced fluid  intake. Standard urotherapy is well-established as first-line treatment for children with  LUTS. However, high-level evidence of the succession of the elements in treatment of BBD  children is missing.  BBD is commonly associated with vesicoureteral reflux (VUR) and recurrent UTI's, which may  lead to renal scarring , kidney failure and hypertension. It is a potential cause of  significant physical and psychosocial burden for children and families. Therefore,  optimization of treatment is critical to avoid secondary comorbidities.  Our microbiome, and its role in health and disease, has gained increased focus during the  past few years.  Studies suggest the urine and gut microbiome to be critical for maintenance of a  well-functioning bladder- and bowel system.  Dysbiosis is defined by the presence of unbalanced and disease-promoting composition of the  microbiome. It is well-established that dysbiosis is associated with constipation in children  and the condition is suspected to be involved in urological disorders such as overactive  bladder, urge, incontinence and recurrent UTI's in adults. However, the composition of the  urine microbiome in children is only sparsely investigated and its role in BBD and childhood  UTI's is to the investigator's knowledge still unexplored.  Study 1: Does successful treatment of bowel symptoms resolve urinary incontinence in children  with BBD? Aim and hypothesis Aim: To investigate if effective treatment of bowel problems  resolves urinary incontinence in BBD children.  The hypothesis of the investigators is:  1. Treatment of bowel symptoms resolves urinary incontinence in BBD children.  2. It is more effective to initiate urotherapy from the beginning in combination with  treatment of bowel symptoms instead of the present regime where bowel symptoms are  managed before urotherapy is started.  3. Succesful treatment of urinary incontinence in children with BBD improves their quality  of life.  1.2 Materials and methods A prospective multicentre randomised study on children with BBD  referred to the Pediatric Incontinence and Gastroenterology outpatient clinics at the  Department of Pediatrics, Aarhus University Hospital, Aalborg University Hospital and  Regional Hospital Goedstrup.  Children (n=100) between 5-14 years and 9 months diagnosed with BBD at their first visit to  the outpatient clinic will be included if they meet in- and exclusion criteria.  The included children will be randomised to one of the following treatments:  1. Medical treatment of bowel symptoms in accordance with the guidelines of The European  Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (n=50)  2. Medical treatment of bowel symptoms in accordance with the ESPGHAN guidelines combined  with standard urotherapy (n=50)  At first visit to the outpatient clinic, enrolled children will undergo physical examination  including neurological examination. Data on medical history will be collected including  number of and time for UTI's. Participants will be asked to fill in a 48-hour flow-volume  chart and in case of enuresis nocturna the chart will also include registration for 7 nights.  Participants will also fill in "Toerfisk" which is a validated tool to monitor severity of  urinary incontinence. Routine uroflowmetry will be performed for further evaluation of lower  urinary symptoms. A urine sample will be collected for diagnosing on-going UTI and for  microbiome analysis in study 3. The children will be screened for constipation in accordance  with the ROME IV criteria. Rectal examination will be performed or transrectal diameter will  be evaluated with point-of-care ultrasound. Stool sample and perineum swab will be collected  for microbiome analysis.  The psychological burden from the children´s BBD condition will be evaluated by PinQ, a  validated questionnaire used for assessment of quality of life according to the incontinence  issue of the patients.  All participants will be informed about bladder and bowel function in order to demystify the  disorder. Daily defecation will be induced by reconditioning to normal bowel habits through  timed toilet sitting and daily administration of laxatives (e.g. PEG3350) in relevant dosage  according to the ESPGHAN guidelines.  Participants randomized to combined medical treatment for bowel symptoms and urotherapy will  be instructed in urotherapy in accordance with earlier description.  After 1 month of treatment the participants will be contacted by telephone to ensure  compliance and for adjustment of laxative dose depending on the bowel symptoms.  The second visit in the outpatient clinic will be after 3 months of treatment. Before the  consultation, the participants will be asked to fill in a second flow-volume chart as well as  "Toerfisk" and PinQ questionnaires. Uroflowmetry will be repeated and a second urine sample  will be collected for stix, culturing and microbiome analysis. Bowel symptoms will be  evaluated using ROME IV, rectal examination and transrectal diameter and a second stool  sample and perineum swab will be collected for microbiome analysis for study 3.  Data storage Data will be entered into RedCap, which is a secure web platform for building  and managing online databases.  Power estimation The sample size (n=100) was calculated for each group to achieve a power of  80% for detecting a difference in proportions of 0.30 between the two groups (test -  reference group) at a two sided p-value of 0.05.  Study 2: Urine, perineal and gut microbiome in children with BBD before and after treatment  Aim and hypothesis To investigate the urine, perineal and gut microbiome in children with BBD  before and after treatment.  The hypothesis of the investigators is that  1. Response to treatment can be predicted by the composition of the urine, perineal and gut  microbiome in children with BBD.  2. The composition of the urine, perineal and gut microbiome is different in BBD children  with recurrent UTI's compared to BBD children without recurrent UTI's.  3. The urine, perineal and gut microbiome in children with BBD will change when bladder and  bowel symptoms successfully treated.  Materials and methods  The study is a multicentre study consisting of two elements:  1. a cohort study to investigate, whether the urine, perineal and gut microbiome can  predict response to treatment and whether it changes during treatment period  2. a case control study to investigate whether the urine, perineal and gut microbiome is  different in children with BBD and recurrent UTI 's and children with BBD without  recurrent UTI 's.  The study population consists of children with BBD included in study 1.  Collection and analysis of samples A urine-, stool sample and a perineum swab will be  collected from all participants before initiation of treatment and after 3 months of  treatment as described in study 1. Bacterial DNA will be extracted and the microbiome will be  determined.  Data storage Biological material will be pseudonymised and stored in a -80 degree fridge  until analysis is performed.  Statistical analysis for all 3 studies Distribution and variance will be analysed by QQ plot,  Shapiro-Wilks test and Bartletts test. Microbiota alpha-diversity will be addressed by ASV  richness, Faith's phylogenetic diversity, Shannon diversity index, and Pielou's evenness  index. Beta-diversity analysis will include principal coordinate analysis (PCoA) using  Bray-Curtis dissimilarity, weighted and unweighted UniFrac. Parametric data will be compared  using Student's t-test or one-way ANOVA and Tukey´s post hoc test, while non-parametric data  will be compared with Kruskal-Wallis test or Mann-Whitney U-test. Chi Squared test will be  used for proportions. Level of significance will be as following *: p <0.05, **: p<0.01 and  ***: p<0.001.  Ethics The studies will be conducted in accordance with the Declaration of Helsinki. All side  effects will be handled in accordance with the actual legislation. No risk or unknown side  effects are expected to urotherapy or medical treatment of bowel symptoms. No risk, side  effects or discomfort is expected from collection of urine, stool and perineum samples or  from uroflowmetry or transabdominal ultrasound.  Perspectives BBD is a common condition in childhood. It is associated with a considerable  psychological burden and a risk of more severe physical complications.  The term BBD is recently defined and therefore only sparsely investigated. The studies will  provide basic knowledge about characteristics of the BBD patients and contribute new  information about the optimal treatment of BBD children. Inclusion Criteria:  -  Age 5-14 years and 9 months at time of inclusion  -  Diagnosed with urinary incontinence and/or enuresis nocturna defined by the ICCS  criteria  -  Diagnosed with constipation and/or faecal incontinence defined by the ROME IV criteria  -  Normal clinical examination  -  Parents/guardian can understand the written and spoken information  -  Informed assent to participation from both parents/guardian Exclusion Criteria:  -  Neuropathic or anatomical abnormalities in the urinary tract or gastrointestinal canal  -  Earlier surgical intervention of the urinary tract (except circumcision)  -  Neurological illness or earlier cerebral surgical intervention  -  On-going urinary tract infection  -  On-going treatment with anticholinergics and/or β3-adenoceptoragonist  -  On-going treatment with laxatives in correct dosage (PEG3350 1-2 g/kg/day)  -  Inflammatory bowel disease  -  Other disorder affection bladder or bowel function  -  For Study 2 (microbiome): Systemic antibiotics within the past 3 months

This project adopts a prospective clinical trial study to compare and evaluate the efficacy  of local transplantation of human umbilical cord mesenchymal stem cells combined with silver  ion dressing and simple silver ion dressing in the treatment of venous lower extremity ulcer  wounds. To improve the healing rate and quality of life of patients. Chronic wounds refer to the pathological changes such as cell senescence, imbalance of  synthesis and degradation of extracellular matrix, and decreased activity of growth factors  caused by different reasons when the wound is prolonged and does not heal after conventional  treatment for more than 1 month without healing tendency. Chronic wound can be caused by a  variety of diseases, including arterial disease, diabetes, vasculitis, venous disease and  skin malignant tumor, chronic venous insufficiency (CVI) is a disease leading to chronic  wound, Venous ulcer (VLU) of lower limbs is the advanced manifestation of CVI, and the  incidence of this disease ranges from 0.4% to 1.3% in China. 60% of VLU patients' ulcer  wounds heal in 3-6 months, 33% in 12 months, and 7% May be permanently unhealed. The  probability of recurrence is as high as 70% in patients 3-5 months after wound healing, which  not only seriously affects the health and quality of life of patients, but also causes a very  heavy social medical burden. At present, the conventional treatment for VLU mainly includes  drug therapy, stress therapy, wound treatment and surgical treatment, but the therapeutic  effect is not ideal. Inclusion Criteria:  1. Age from 18 to 70, no gender limitation;  2. It met the diagnostic criteria of venous ulcer of lower limbs in Clinical Vascular  Surgery (5th edition), and the following conditions were met: the ulcer lasted for  more than 1 month; The wound area was between 10cm2 and 40cm2. Wound depth: All wounds  were deep tissue ulcers below the epidermis.  3. Participate in the clinical study voluntarily, observe the study procedure, and  observe the curative effect cooperatively. Exclusion Criteria:  1. Pregnant or lactation women; Women who have planned to have children recently (within  6 months);  2. Patients with peripheral artery disease with ankle-brachial index (ABI) < 0.8;  3. Patients with active clinical systemic infection;  4. Serious skin wound infection is not under control;  5. low immune function and systemic failure; Severe heart, liver, lung, kidney and other  important organ lesions (ALT, AST, Cr & GT; Normal 1.5 times, congestive heart failure  ejection fraction &lt; Normal 30%) and severely impaired hematopoietic function;  6. Abnormal coagulation function or current anticoagulant treatment;  7. Systemic autoimmune diseases in the active stage;  8. With systemic organ or hematological malignancy;  9. PERSONS infected with HIV or addicted to drugs, tobacco and alcohol;  10. Have a clear history of mental illness;  11. Participation in clinical studies of any drug within 1 month prior to treatment (or  the 5 half-life of the investigational drug, whichever is longer).

Transfusion practice for surgical patients has changed from replacing surgically lost blood  with allogeneic blood transfusions to implementing strategies that reduce transfusion  requirements. Patient Blood Management (PBM), which is "the timely application of  evidence-based medical and surgical concepts designed to maintain haemoglobin concentration,  optimize hemostasis and minimize blood loss in an effort to improve patient outcome. There is  mounting evidence that multimodal patient blood management (PBM) programmes can be effective  at improving postoperative outcomes and reducing perioperative blood transfusions and costs  The Turkish Society of Anaesthesiologists PBM Task Force has been working on this subject and  studied transfusion practice throughout all through the peri-operative periods. Unfortunately  we documented a high transfusion rate in major surgical patients in Turkey. One of the  surgeries, that has high transfusion rate, was orthopaedic surgery. According to our recent  data we planned to implement PBM in major orthopaedic surgical patients and evaluate the  effects PBM in transfusion rate and patient outcomes. While some elements of PBM have a  strong evidence base in hip or knee replacement, such as the use of tranexamic acid (TXA) the  evidence for preoperative anaemia optimisation with iron is less robust. Implementing PBM all  through the operative period gains more importance. Active PBM Implementation: Patients undergoing hip or knee arthroplasty will be treated as  follows: PBM will be performed as shown in the graph below "PBM Implementation Group".  Active PBM group will be treated for preoperative anemia at least 3 weeks prior to the  surgical intervention as per the "Anemia Algorithm" below Other pillars of PBM will be also  performed to the treatment group as per the visual graph below. The parameters included in  the PBM pillars will be recorded including preoperative anemia parameters. Postoperative  variables and parameters related to complications will be recorded.  For the control group (Non-PBM group), the data of the patients, will be prospectively  included.  The 1:1 ratio of the control and active groups will be done. Inclusion Criteria:  In order to be eligible to participate in this trial, an individual must meet all of the  following criteria:  -  Signed patient informed consent  -  Male or female patient at least 18 years old  -  Patients scheduled for an elective major orthopaedic surgery (hip arthroplasty, knee  arthroplasty, primary and revision operations)  -  Patients with confirmed iron deficiency anemia (IDA), defined as Hb 100-130 g/L, and  serum ferritin < 100 ng/ml or TSAT < 20%.  Patients with iron deficiency anemia will be taken into surgery at least 3 weeks after the  treatment. Exclusion Criteria:  -  Patients that undergo emergency surgical procedure and trauma cases are excluded from  the study.  -  Patients with non-iron deficiency anaemia (thalassemia, sickle cell anaemia and etc.)  -  Patients with renal anaemia (Hb < 130 g/L and CCL < 50 mL/min, irrespective of iron  parameters) or any diagnosis that require EPO will be excluded  -  Patients with known anaphylactic/hypersensitivity reactions to parenteral iron  products.  -  Patients with iron overload or disturbances in utilization of iron (e.g.  haemochromatosis, hemosiderosis)  -  Patients with ≥3 times increase in aspartate aminotransferase or alanine  aminotransferase as per reference range.  -  Patients with excessive blood loss requiring massive transfusion (≥ 10 more red blood  cell units)  -  Patients with known myelodysplastic syndromes.  -  Patients with chronic kidney disease with an estimated GFR < 30 ml/min or with  end-stage renal disease requiring scheduled dialysis.  -  Patients with known urinary tract infections with urea-splitting bacteria  -  Any patient judged to lack the ability to give informed consent or perform the trial  assessments (e.g. due to dementia)  -  Women who are pregnant or breast feeding  -  Intention to become pregnant during the course of the study,  -  Lack of safe contraception, defined as: Female participants of childbearing potential,  not using and not willing to continue using a medically reliable method of  contraception for the entire study duration, such as oral, injectable, or implantable  contraceptives, or intrauterine contraceptive devices, or who are not using any other  method considered sufficiently reliable by the investigator in individual cases  (Female participants who are surgically sterilized / hysterectomized or  post-menopausal for longer than 2 years are not considered as being of child bearing  potential),  -  Known or suspected non-compliance, drug or alcohol abuse,  -  Participation in another study with investigational drug within the 30 days preceding  and during the present study

This will be a randomized, double-blind, double-dummy, placebo- and active-controlled, 6  treatment, 6-period crossover single-dose, Williams square design study in healthy male  and/or female adult, non-drug-dependent recreational opioid users. The study includes Screening, a Qualification Phase consisting of a Naloxone Challenge and  Drug Discrimination crossover study, a Treatment Phase and Follow-up. Following successful  completion of the Qualification Phase the participants will be enrolled in the Treatment  phase. The Treatment Phase is a randomized, double-blind, double dummy, placebo- and active  controlled, 6 treatment, 10-sequence, 6 period crossover, single-dose, Williams square design  study in healthy male and/or female adult, non drug-dependent recreational users. On Day 1 of  each of the Treatment Phase 6 periods, which will be separated by a washout of at least 14  days, participants will receive an oral dose of either gabapentin 600 mg or 1200 mg alone, or  concomitantly with a 20 mg dose of oxycodone HCl or 20 mg monotherapy of oxycodone HCl or a  placebo. Study treatments will be administered under fasted conditions (overnight fast and no  food until 4 hours after dosing). Water will be allowed without restriction until 1 hour  prior to dosing and 1 hour after dosing. Inclusion Criteria:  1. Male and female participants must be 18 to 55 years of age, inclusive, at the time of  screening. Participants must meet reproductive criteria as outlined in the protocol.  2. Male and female participants who are overtly healthy. Healthy is defined as no  clinically relevant abnormalities identified by a detailed medical history, complete  physical examination, vital signs, 12-lead ECG, and/or clinical laboratory tests.  3. Participants must have drug abuse experience with opioids; ie, must have used opioids  for non-therapeutic purposes (ie, for psychoactive effects) on at least 10 occasions  within the last year and at least once in the 8 weeks before the Screening Visit  (Visit 1).  4. Participants must satisfactorily complete both the Naloxone Challenge and the Drug  Discrimination.  5. Participants who are willing and able to comply with all scheduled visits, treatment  plan, laboratory tests, lifestyle considerations, and other study procedures.  6. Body mass index (BMI) of 17.5 to 34 kg/m2, inclusive; and a total body weight ≥50 kg  (110 lb).  7. Capable of giving signed informed consent as described in the protocol, which includes  compliance with the requirements and restrictions listed in the informed consent  document (ICD) and in this protocol. Exclusion Criteria:  1. Current or past diagnosis of any type of drug dependence within the past year.  Diagnosis of substance and/or alcohol dependence (excluding caffeine and nicotine)  will be assessed by the Investigator using the Diagnostic and Statistical Manual of  Mental Disorders-IV (DSM-IV) criteria performed at Screening. Current drug use will be  allowed if the candidate can produce a negative urine sample and are free of any  signs/symptoms of withdrawal. The candidate will be informed if they have a positive  breathalyzer test.  2. Evidence or history of clinically significant hematological, renal, endocrine,  pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or  allergic disease (including drug allergies, but excluding untreated, asymptomatic,  seasonal allergies at the time of dosing).  3. Any condition possibly affecting drug absorption (eg, gastrectomy) excluding  cholecystectomy within 1 year prior to study.  4. Abnormal baseline EtCO2 <35mm Hg or >45 mm Hg.  5. Clinical or laboratory evidence of active hepatitis A infection or a history of human  immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C, and/or positive  testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibody  (HBcAb), or hepatitis C antibody (HCVAb).  6. Participants with active suicidal ideation or suicidal behavior within 5 years prior  to Screening as determined through the use of the Columbia Suicide Severity Rating  Scale (C-SSRS) or active ideation identified at Screening or on Day 0.  7. Participants with any history of sleep apnea, myasthenia gravis or glaucoma.  8. Other acute or chronic medical or psychiatric condition including recent (within the  past year) or active suicidal ideation or behavior or laboratory abnormality that may  increase the risk associated with study participation or investigational product  administration or may interfere with the interpretation of study results and, in the  judgment of the investigator, would make the participant inappropriate for entry into  this study.  9. Use of prescription or nonprescription drugs and dietary supplements within 7 days or  5 half lives (whichever is longer) prior to the first dose of investigational product.  (Refer to Section 6.5 for additional details).  10. Herbal supplements, herbal medications and hormone replacement therapy must be  discontinued at least 28 days prior to the first dose of study medication.  11. Previous administration with an investigational drug within 30 days (or as determined  by the local requirement) or 5 half lives (whichever is longer) preceding the first  dose of investigational product used in this study.  12. Positive urine drug screen (UDS) for substances of abuse at each admission in  Qualification and Treatment Phase, excluding tetrahydrocannabinol (THC). If a  participant presents with a positive UDS excluding THC at any admission or any visit,  the investigator, at his/her discretion, may reschedule a repeat of UDS until the UDS  is negative, excluding THC, before the participate is permitted to participate in any  phase of the study.  13. Unable to abstain from using THC during the Qualification and Treatment Phase of the  study.  14. Has participated in, is currently participating in, or is seeking treatment for  substance and/or alcohol related disorders (excluding nicotine and caffeine).  15. Has a positive alcohol breathalyzer or urine test at each admission to the study  center during Qualification and Treatment Phases. Positive results may be repeated  and/or participants re scheduled at the Investigator's discretions.  16. Participants are heavy smokers or users of other types of nicotine products (>20  cigarettes equivalents per day).  17. Participants are unable to abstain from smoking for at least 2 hours before and at  least 8 hours after study drug administration.  18. Screening sitting blood pressure (BP) >=140 mm Hg (systolic) or >=90 mm Hg  (diastolic), following at least 5 minutes rest. If BP is >=140 mm Hg (systolic) or  >=90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the  3 BP values should be used to determine the participant's eligibility. Repeated BP  tests should be spaced at least 5 minutes apart.  19. Baseline (screening) 12 lead electrocardiogram (ECG) that demonstrates clinically  relevant abnormalities that may affect participant safety or interpretation of study  results (eg, baseline corrected QT (QTc) interval as determined by the Fridericia  method (QTcF) >450 msec, complete left bundle branch block [LBBB], signs of an acute  or indeterminate age myocardial infarction, ST T interval changes suggestive of  myocardial ischemia, second or third degree atrioventricular [AV] block, or serious  bradyarrhythmias or tachyarrhythmias). If the baseline uncorrected QT interval is >450  msec, this interval should be rate corrected using the Fridericia method and the  resulting QTcF should be used for decision making and reporting. If QTcF exceeds 450  msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average  of the 3 QTcF or QRS values should be used to determine the participant's eligibility.  Computer interpreted ECGs should be overread by a physician experienced in reading  ECGs before excluding participants.  20. Participants with ANY of the following abnormalities in clinical laboratory tests at  screening, as assessed by the study specific laboratory and confirmed by a single  repeat test, if deemed necessary:  -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level >=1.5 ×  upper limit of normal (ULN);  -  Total bilirubin level >=1.5 × ULN; participants with a history of Gilbert's  syndrome may have direct bilirubin measured and would be eligible for this study  provided the direct bilirubin level is <= ULN.  21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more  within 60 days prior to dosing.  22. History of sensitivity to heparin or heparin induced thrombocytopenia.  23. Unwilling or unable to comply with the criteria in the Lifestyle Considerations  section of this protocol.  24. History of hypersensitivity to gabapentin or oxycodone or any of the components in the  formulation of the study products.  25. Investigator site staff members directly involved in the conduct of the study and  their family members, site staff members otherwise supervised by the investigator, or  Sponsor employees, including their family members, directly involved in the conduct of  the study.

This phase Ib/II trial studies the side effects and best dose of ribociclib, tucatinib, and  trastuzumab for the treatment of HER2 positive breast cancer that has spread to other parts  of the body (metastatic), and then compares the effect of ribociclib, tucatinib, trastuzumab  with or without fulvestrant to docetaxel, carboplatin, trastuzumab, and pertuzumab (standard  of care) for the treatment of early stage breast cancer before surgery (neoadjuvant therapy).  Ribociclib and tucatinib may stop the growth of tumor cells by blocking some of the enzymes  needed for cell growth. Trastuzumab is a form of targeted therapy because it attaches itself  to specific molecules (receptors) on the surface of tumor cells, known as HER2 receptors.  When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are  blocked and the tumor cell may be marked for destruction by the body's immune system.  Pertuzumab is a monoclonal antibody that may interfere with the ability of tumor cells to  grow and spread. Estrogen can cause the growth of breast tumor cells. Fulvestrant blocks the  use of estrogen by the tumor cells. Chemotherapy drugs, such as docetaxel and carboplatin,  work in different ways to stop the growth of tumor cells, either by killing the cells, by  stopping them from dividing, or by stopping them from spreading. Giving ribociclib,  tucatinib, and trastuzumab with or without fulvestrant before surgery may make the tumor  smaller and may reduce the amount of normal tissue that needs to be removed. PRIMARY OBJECTIVES:  I. To assess the safety of the combination of ribociclib, tucatinib, and trastuzumab in  patients with metastatic, HER2+ breast cancer. (Phase 1 Dose Escalation Trial) II. To  determine the recommended phase 2 dose of ribociclib when combined with tucatinib and  trastuzumab. (Phase 1 Dose Escalation Trial) III. To assess the pathologic complete response  (pCR). (Phase 2 Neoadjuvant Study)  SECONDARY OBJECTIVES:  I. To evaluate the pharmacokinetics of ribociclib and tucatinib when given in combination.  (Phase 1 Dose Escalation Trial) II. To assess the clinical objective response rate after 3  cycles via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (Phase 1 Dose  Escalation Trial) III. To assess the clinical objective response rate in the experimental  arms. (Phase 2 Neoadjuvant Study) IV. To assess quality of life by evaluating toxicity burden  using a quality of life (QOL)/patient-reported outcomes (PRO) questionnaire- the European  Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30  (EORTC QLQ-C30) instrument. (Phase 2 Neoadjuvant Study) V. To assess the molecular changes in  tumor biomarkers after 1 cycle of targeted therapy (anti-HER2, anti-estrogen, and CDK 4/6  directed therapy). (Phase 2 Neoadjuvant Study) VI. Pathological Assessment According to  Residual Cancer Burden (RCB) Index at surgery. (Phase 2 Neoadjuvant Study)  EXPLORATORY OBJECTIVE:  I. To investigate potential serum and tumor predictive biomarkers to predict response to  experimental therapy. (Phase 2 Neoadjuvant Study)  OUTLINE: This is a phase Ib, dose-escalation study of ribociclib followed by a phase II  study.  PHASE Ib: Patients receive ribociclib orally (PO) once daily (QD) on days 1-21, tucatinib PO  twice daily (BID) on days 1-28, and trastuzumab intravenously (IV) over 30-90 minutes every 7  days. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or  unacceptable toxicity.  PHASE II: Patients with hormone receptor (HR) positive status are randomized to Arm A or Arm  B. Patients with HR negative status are randomized to Arm B or Arm C.  ARM A: Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28,  trastuzumab IV over 30-90 minutes every 7 days and fulvestrant subcutaneously (SC) on days 1  and 15 of cycle 1 and day 1 of every subsequent cycle. Cycles repeat every 28 days for up to  6 cycles in the absence of disease progression or unacceptable toxicity.  ARM B: Patients receive docetaxel IV over 1 hour on day 1, carboplatin IV on day 1,  trastuzumab IV over 30-90 minutes on day 1, and pertuzumab IV over 1 hour on day 1. Cycles  repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable  toxicity.  ARM C: Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, and  trastuzumab IV over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 6  cycles in the absence of disease progression or unacceptable toxicity.  After completion of study treatment, patients are followed-up within 7 and 30 days. Inclusion Criteria:  -  PHASE IB AND II: Patients over age of 18  -  PHASE IB AND II: Available archival tissue for confirmatory central HER2 testing.  Results not required prior to enrollment.  -  PHASE IB AND II: Left ventricular ejection fraction (LVEF) >= 50% based on  echocardiogram or multigated acquisition (MUGA).  -  PHASE IB AND II: Platelet count >= 100,000/mm^3 (within 7 days before enrollment)  -  For Phase Ib only: Phase Ib allows for red blood cell transfusion, filgrastim  (G-CSF), and hydration to meet eligibility requirements at the discretion of the  investigator  -  PHASE IB AND II: Hemoglobin >= 9.0 g/dL (within 7 days before enrollment)  -  For Phase Ib only: Phase Ib allows for red blood cell transfusion, G-CSF, and  hydration to meet eligibility requirements at the discretion of the investigator  -  PHASE IB AND II: Absolute neutrophil count (ANC) >= 1500/mm^3 (within 7 days before  enrollment)  -  For Phase Ib only: Phase Ib allows for red blood cell transfusion, G-CSF, and  hydration to meet eligibility requirements at the discretion of the investigator  -  PHASE IB AND II: Creatinine clearance >= 30 mL/min as calculated using the  Cockcroft-Gault equation or Serum creatinine =< 1.5 × upper limit of normal (ULN)  (within 7 days before enrollment)  -  For Phase Ib only: Phase Ib allows for red blood cell transfusion, G-CSF, and  hydration to meet eligibility requirements at the discretion of the investigator  -  PHASE IB AND II: Alanine aminotransferase (ALT) < 2.5 × ULN, except for patients with  liver metastasis, who are only included if the ALT is < 5 × ULN (within 7 days before  enrollment)  -  PHASE IB AND II: Aspartate aminotransferase (AST) < 2.5 × ULN, except for patients  with liver metastasis, who are only included if the AST is < 5 × ULN (within 7 days  before enrollment)  -  PHASE IB AND II: Total bilirubin =< 1.5 x ULN. Participants with Gilbert's syndrome  with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal limits are  permitted (within 7 days before enrollment)  -  PHASE IB AND II: Serum Albumin >= 2.5 g/dL (within 7 days before enrollment)  -  PHASE IB AND II: International normalized ratio (INR)/prothrombin time (PT) and  activated partial thromboplastin time (aPTT) =< 1.5 × ULN (within 7 days before  enrollment)  -  PHASE IB AND II: Potassium within normal limits or corrected to within normal limits  prior to first dose  -  PHASE IB AND II: Magnesium within normal limits or corrected to within normal limits  prior to first dose  -  PHASE IB AND II: Total calcium (corrected for serum albumin) within normal limits or  corrected to within normal limits prior to first dose  -  PHASE IB AND II: Willingness and ability to comply with scheduled visits, treatment  plans, laboratory tests, and other study procedures  -  PHASE IB AND II: Patient can be premenopausal, perimenopausal, or post-menopausal at  the time of study entry.  -  Premenopausal status is defined as either:  -  Patient had last menstrual period within the last 12 months, OR  -  If on tamoxifen or toremifene, plasma estradiol and follicle stimulating  hormone (FSH) are in the premenopausal ranges according to central/local  laboratory definition, OR  -  In case of therapy-induced amenorrhea, plasma estradiol and/or FSH are in  the premenopausal ranges according to central/local laboratory definition  -  Perimenopausal status is defined as neither premenopausal nor  postmenopausal  -  Postmenopausal is defined as not meeting premenopausal status  -  For pre-menopausal patients: Confirmed negative serum pregnancy test  (beta-hCG) before starting study treatment or patient has had a  hysterectomy. Male and female participants of reproductive/childbearing  potential must agree to use a highly effective form of contraception or  avoid intercourse during and upon completion of the study and for at  least 7 months for females and 4 months for males after the last dose  of study drug  -  PHASE IB AND II: Male and female participants of reproductive/childbearing potential  must agree to use a highly effective form of contraception or avoid intercourse during  and upon completion of the study and for at least 7 months for females and 4 months  for males after the last dose of study drug. Highly effective contraception methods  include:  -  Total abstinence (when this is in line with the preferred and usual lifestyle of  the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal,  post-ovulation methods) and withdrawal are not acceptable methods of  contraception  -  Double barrier method of contraception. The following are considered adequate  barrier methods of contraception, must use 2: diaphragm, condom (by the partner),  sponge, or spermicide/spermicidal jelly.  -  Female sterilization (have had surgical bilateral oophorectomy with or without  hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before  taking trial treatment. In case of oophorectomy alone, only when the reproductive  status of the woman has been confirmed by follow up hormone level assessment.  -  Male partner sterilization (at least 6 months prior to randomization). For female  patients on the trial the vasectomized male partner should be the sole partner  for that patient. If vasectomy of the male partner is the highly effective method  of contraception chosen, the success of the vasectomy should be medically  confirmed according to local practice  -  Placement of an intrauterine device (IUD)  -  PHASE IB: Locally advanced/non-operable or metastatic HER2/neu amplified breast  cancer, defined as 3+ by immunohistochemistry (IHC), or IHC 2+ and fluorescence in  situ hybridization (FISH) + breast cancer  -  PHASE IB: Received 1 or more prior lines of HER2 directed therapy in the metastatic  setting  -  PHASE IB: Recommended by the patient's treating oncologist to receive a tucatinib  containing regimen as part of the next standard of care (SOC) line of therapy  -  PHASE IB: Eastern Cooperative Oncology Group (ECOG) performance status 0-2  -  PHASE IB: Measurable or non-measurable disease per RECIST 1.1  -  PHASE IB: Based on screening contrast brain magnetic resonance imaging (MRI), patients  must have one of the following:  -  No evidence of brain metastases  -  Untreated brain metastases not needing immediate local therapy. For patients with  untreated central nervous system (CNS) lesions > 2.0 cm on screening contrast  brain MRI, discussion with and approval from the medical monitor is required  prior to enrollment  -  Previously treated brain metastases  -  Brain metastases previously treated with local therapy may either be stable  since treatment or may have progressed since prior local CNS therapy,  provided that there is no clinical indication for immediate re-treatment  with local therapy in the opinion of the investigator  -  Patients treated with CNS local therapy for newly identified lesions found  on contrast brain MRI performed during screening for this study may be  eligible to enroll if all of the following criteria are met:  -  Time since whole-brain radiotherapy (WBRT) is >= 21 days prior to first  dose of treatment, time since stereotactic radiosurgery (SRS) is >= 7  days prior to first dose of treatment, or time since surgical resection  is >= 28 days  -  Other sites of disease assessable by RECIST 1.1 are present  -  Relevant records of any CNS treatment must be available to allow for  classification of target and non-target lesions  -  PHASE II: Operable HER2/neu amplified invasive breast cancer, defined as 3+ by IHC, or  IHC 2+ and FISH +  -  PHASE II: Known Ki67 status  -  PHASE II: Previously untreated operable invasive carcinoma of the breast greater than  2.0 cm (cT2) in size based on imaging or physical exam or imaging. Patients with  clinical node negative disease or clinical node (cN1/cN2) positive are allowed  provided they are deemed to have operable disease at study entry  -  PHASE II: Patients with clinically involved lymph nodes should not have evidence of  distant disease based on standard of care staging imaging prior to informed consent  form (ICF) signature  -  PHASE II: Breast cancer suitable for mandatory baseline core biopsy  -  PHASE II: No prior systemic therapy or radiotherapy for currently-diagnosed invasive  or non-invasive breast cancer  -  PHASE II: Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Exclusion Criteria:  -  PHASE IB AND II: Concurrent therapy with any other non-protocol anti-cancer therapy  -  PHASE IB AND II: History of any other malignancy within the past 5 years, with the  exception of non-melanoma skin cancer or carcinoma-in-situ of the cervix  -  PHASE IB AND II: Proteinuria estimated by urine protein: creatinine ratio > 3.5 on a  random urine sample  -  PHASE IB AND II: Uncontrolled arterial hypertension despite optimal medical management  -  PHASE IB AND II: Patient has known active hepatitis B virus (HBV) or hepatitis C virus  (HCV), or Human immunodeficiency virus (HIV) infection (testing is not mandatory,  unless required by local regulation)  -  PHASE IB AND II: Uncontrolled infection; active, clinically serious infections (>  Common Terminology Criteria for Adverse Events [CTCAE] grade 2)  -  PHASE IB AND II: Clinically significant, uncontrolled heart disease and/or cardiac  repolarization abnormality, including any of the following:  -  History of documented myocardial infarction (MI), angina pectoris, symptomatic  pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to  study entry  -  Documented cardiomyopathy  -  Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated  acquisition (MUGA) scan or echocardiogram (ECHO)  -  Long QT syndrome or family history of idiopathic sudden death or congenital long  QT syndrome, or any of the following:  -  Risk factors for Torsades de Pointe (TdP) including uncorrected  hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or  history of clinically significant/symptomatic bradycardia  -  Concomitant medication(s) with a known risk to prolong the QT interval  and/or known to cause Torsades de Pointe that cannot be discontinued or  replaced by safe alternative medication (e.g., within 5 half-lives or 7 days  prior to starting study drug)  -  Inability to determine the corrected QT using Fridericia's formula (QTcF)  interval  -  Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),  complete left bundle branch block, high-grade atrioventricular (AV) block  (e.g., bifascicular block, Mobitz type II and third degree AV block)  -  Systolic blood pressure (SBP) > 160 or < 90 mmHg  -  PHASE IB AND II: Congestive heart failure > New York Heart Association (NYHA) class 2  -  PHASE IB AND II: History of baseline QT prolongation > 450 msec  -  PHASE IB AND II: Unstable angina (angina symptoms at rest), new-onset angina (begun  within the last 3 months)  -  PHASE IB AND II: Myocardial infarction less than 6 months before start of test drug  -  PHASE IB AND II: Anti-arrhythmic therapy (beta blockers or digoxin are permitted)  -  PHASE IB AND II: Arterial or venous thrombotic or embolic events such as  cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis  or pulmonary embolism within 3 months before the start of study medication.  -  PHASE IB AND II: Participants receiving anticoagulation therapy are not allowed  -  PHASE IB AND II: Patients with evidence or history of bleeding diathesis. Any  hemorrhage or bleeding event >= CTCAE Grade 3 within 4 weeks of start of study  medication  -  PHASE IB AND II: Non-healing wound or ulcer  -  PHASE IB AND II: History of, or current autoimmune disease (other than Hashimoto's  thyroiditis with normal thyroid stimulating hormone [TSH])  -  PHASE IB AND II: Major surgical procedure or significant traumatic injury (as judged  by the investigator) within 28 days before start of study medication, open biopsy  within 7 days before start of study medication  -  PHASE IB AND II: Unable to swallow pills or has significant gastrointestinal disease  which would preclude the adequate oral absorption of medications  -  PHASE IB AND II: Patients with seizure disorder requiring medication  -  PHASE IB AND II: Known hypersensitivity to any of the study drugs, study drug classes,  or excipients in the formulation  -  PHASE IB AND II: Systemic continuous corticosteroid therapy at a daily dose higher  than 15 mg prednisone or equivalent is not allowed. Patients may be using topical or  inhaled corticosteroids. Previous corticosteroid therapy must be stopped or reduced to  the allowed dose at least 7 days prior to the first study drug administration. If a  patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated  to the maximum allowed dose after the patient has signed the consent document  -  PHASE IB AND II: History of having received an allogeneic bone marrow or organ  transplant  -  PHASE IB AND II: Chronic oxygen therapy  -  PHASE IB AND II: Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5  half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days  prior to the first dose of study treatment  -  PHASE IB: Early stage (curable) breast cancer  -  PHASE IB: Based on screening brain MRI, patients must not have any of the following:  -  Any untreated brain lesions > 2.0 cm in size, unless discussed with medical  monitor and approval for enrollment is given  -  Ongoing use of systemic corticosteroids for control of symptoms of brain  metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent).  However, patients on a chronic stable dose of =< 2 mg total daily of  dexamethasone (or equivalent) may be eligible with discussion and approval by the  medical monitor  -  Any brain lesion thought to require immediate local therapy, including (but not  limited to) a lesion in an anatomic site where increase in size or possible  treatment-related edema may pose risk to patient (e.g. brain stem lesions).  Patients who undergo local treatment for such lesions identified by screening  contrast brain MRI may still be eligible for the study based on criteria  described under CNS inclusion criteria  -  PHASE IB: Known or suspected leptomeningeal disease (LMD) as documented by the  investigator  -  PHASE IN: Have poorly controlled (> 1/week) generalized or complex partial seizures,  or manifest neurologic progression due to brain metastases notwithstanding  CNS-directed therapy  -  PHASE II: Metastatic breast cancer (local spread to axillary or internal mammary lymph  nodes is permitted)  -  PHASE II: Current therapy with raloxifene, tamoxifen, aromatase inhibitor, or other  selective estrogen receptor modulator (SERM), gonadotrophin-releasing hormone (GNRH)  agonist/antagonist, either for osteoporosis or prevention of breast cancer. Subjects  must have discontinued therapies for at least 28 days prior to first baseline biopsy

Rationale: Nutrition and lifestyle interventions are currently not implemented in usual  clinical care of PAH-patients. Mainly because there is little known on the relation between  pathology, nutrition and lifestyle. Patients who suffer from Pulmonary Arterial Hypertension  feel insecure about their nutrition and lifestyle. The investigators hypothesize that an  intervention on nutrition and lifestyle can improve the patients' quality of life.  Objective: To explore the effect of a nutrition and lifestyle intervention on quality of life  for patients suffering from PAH.  Study design: Investigator initiated intervention study with control group. Study population:  investigators aim to include 70 patients (18 - 80 years) with idiopathic, hereditable or drug  related PAH, who have been stable for at least three months and are self-sufficient and/or  have a family who's willing to participate in the lifestyle changes.  Intervention (if applicable): Nutritional status, - education, - intervention and -  compliance.  Main study parameters/endpoints: This is an intervention study in which the investigators  will asses the effect of a nutrition and lifestyle intervention on quality of life measured  by SF-36 overall outcome with a significant difference of 6.35.  Nature and extent of the burden and risks associated with participation, benefit and group  relatedness: The burden for the patient exists of 12 extra visits to the hospital and contact  moments, over a period of 11 months, as well compliance to the diet and lifestyle. There is  minimal risk in participation. Baseline nutritional assessment  Nutritional education:  8 online lessons containing information about nutrition, lifestyle and general health with  complementary tips regarding PH. All participants recieve workbook with assignments.  Nutritional intervention:  Group A: MedDASH diet (55% carbohydrates, 25% amino acids, 20% fatty acids) Group B:  MedDASHfat diet (10% carbohydrates, 25% amino acids, 65% fatty acids) Control group: no diet.  Follow-up:  Patients in intervention arm followed for a period of 6 months to assess compliance. Inclusion Criteria:  -  Diagnosis of idiopathic PAH, hereditable PAH or drug related PAH  -  Age between 18 and 80  -  NYHA II or III and stable for at least 3 months, determined by a stable 6minute walk  test with a difference of <10%.  -  Self-sufficient and/or compliance from partner and/or family  -  Creatinine > 30 ml/min  -  Able to understand and willing to sign the Informed Consent Form Exclusion Criteria:  -  - Pregnant subjects  -  Fat percentage < 10% > 50 %  -  One or more of the following comorbidities: diabetes mellitus type one or two,  clinically relevant thyroid disease  -  Known history of noncompliance considering therapies

Diabetic kidney disease (DKD) occurs in up to 40% of people with type 1 diabetes (T1D), often  leading to kidney failure and markedly magnifying risks of cardiovascular disease and  premature death. Landmark T1D kidney biopsy studies identified the classic pathological  lesions of DKD, which have been attributed largely to hyperglycemia. Recent advances in  continuous glucose monitoring (CGM) and automated insulin delivery have facilitated improved  glycemic control, but the residual risk of DKD continues to be high. In addition, obesity and  insulin resistance (IR) have accompanied intensive glycemic therapy and may promote  mitochondrial dysfunction and inflammation. Deciphering the molecular underpinnings of DKD in  modern-day T1D and identifying modifiable risk factors could lead to more effective and  targeted therapies to prevent DKD. The overall goal of this project is to characterize the molecular, morphometric, and  metabolic features of DKD over the modern clinical course of T1D. The investigators  hypothesize that perturbed kidney energetics and hypoxia are central metabolic pathways in  the development of DKD. Kidney hypoxia stems from a mismatch between increased renal energy  demand (e.g., increased glomerular filtration rate [GFR] and tubular reabsorption of sodium)  and impaired substrate metabolism (e.g., IR and mitochondrial dysfunction) and results in  activation of the hypoxia-inducible factor (HIF) system. Although upregulation of HIF1α  confers favorable short-term effects, sustained activation promotes cellular injury.  Supporting these hypotheses, data from our group and others have shown that obesity, IR, and  The investigators also found that youth with T1D exhibit kidney hypoxia by MRI that strongly  associates with IR and mitochondrial dysfunction. Moreover, our preliminary single-cell RNA  sequencing (scRNA-seq) data from kidney biopsies demonstrate upregulated tubular expression  of HIF1α in adults with T1D vs. healthy controls. The investigators propose to build a unique  new longitudinal kidney biopsy cohort (N=100) spanning the critical duration of T1D over  which DKD initiates and progresses (5-30 years). Participants will be enrolled from our  existing CROCODILE study (adding longitudinal follow-up to completed kidney biopsies and  baseline data and biosample acquisition) and from new enrollment at the University of  Colorado and University of Washington. Normative kidney biopsy data will be provided from our  existing cohort of healthy controls (N=20) and the Kidney Precision Medicine Project (KPMP).  The investigators will implement state-of-the-art molecular (scRNA-seq) and morphometric  interrogation of kidney tissue and rigorous metabolic phenotyping to include kidney magnetic  resonance imaging (MRI), direct measurements of glycemia (continuous glucose monitoring),  intraabdominal fat (dual-energy X-ray absorptiometry), estimation of insulin sensitivity by a  T1D-validated equation, and (in a subset) GFR (iohexol clearance) and renal plasma flow  (p-aminohippurate clearance). Participants will be followed longitudinally for DKD outcomes.  A subset of 20 participants will undergo repeat kidney biopsies and associated procedures 3  years after baseline kidney biopsy. Inclusion Criteria:  -  Age ≥ 18 years at enrollment (rationale: this study focuses on determinants of early  DKD over the course of T1D in adults)  -  T1D duration >5 and ≤ 30 years (rationale: DKD in T1D rarely manifests prior to 5  years of disease duration; longstanding T1D above > 30 years subject to survivorship  bias)  -  HbA1c <11% (rationale: HbA1c ≥ 11% exceeds the average HbA1c at most academic center  and would limiting the generalizability of our study findings) Exclusion Criteria:  -  T2D and monogenic diabetes (rationale: our study focuses on T1D)  -  Recent diabetic ketoacidosis, i.e., <1 month (rationale: safety and insulin resistance  and tubular dysfunction of DKA can confound study findings)  -  eGFR < 30 ml/min/1.73m2 or dialysis treatment (rationale: to reduce the likelihood of  identifying secondary pathways that are not specific to kidney injury from T1D)  -  Kidney transplant recipients (rationale: molecular confounding from immunosuppression)  -  Kidney biopsy contraindications (rationale: safety - kidney biopsy):  -  Evidence of bleeding disorder or complications from bleeding  -  Use of aspirin, Nonsteroidal anti-inflammatory drugs (NSAIDS) or other blood  thinner that cannot be safely stopped for a sufficient time before and after the  biopsy to avoid additional risk of bleeding.  -  INR > 1.4  -  Hemoglobin (Hgb) < 10 mg/dL (Colorado) [altitude]  -  Hemoglobin (Hgb) < 9 mg/dL (Washington)  -  Platelet count < 100,000 / µL  -  Uncontrolled or difficult to control hypertension (> 150/90 mmHg at the day of  biopsy)  -  Single kidney (either by history, documented by prior imaging or ultrasound  performed prior to the biopsy)  -  Kidney size: One or both kidneys < 8 cm  -  Hydronephrosis or other important renal ultrasound findings such as significant  stone disease  -  Any evidence of a current urinary tract infection as indicated on day of biopsy  -  Clinical evidence of non-diabetic renal disease  -  Positive urine pregnancy test or pregnancy

To determine whether there is higher incidence of skewed X chromosome inactivation(SXCI) in  the recurrent miscarriage(RM) population compared with normal population, and verify the  existing hypothesis of the possible genetic mechanisms underlying the association between  SXCI and RM. Recurrent spontaneous abortion (RSA), defined as 2 or more consecutive pregnancy losses  before 20-22 weeks of gestation, is a multifactorial disorder that affects about 5% of all  couples.In up to 50% of women who have experienced RSA, the cause still remains unexplained,  with genetic problem proposed as a main cause. X chromosome inactivation (XCI) is a  physiological phenomenon in female mammals for 'dosage compensation' of X-linked genes with  males. A normal female is mosaic, with about one-half of her somatic cells expressing the  paternal derived X and the remainder of her cells using maternal X. In some situations,  however, the inactivation is not random, resulting in a female having most or even all her  somatic cells inactivating the same X chromosome from either paternal or maternal resource,  which is known as skewed X-chromosome inactivation (SXCI).Evidence of an association between  skewed X chromosome inactivation (SXCI) and idiopathic recurrent spontaneous abortion (RSA)  is conflicting. This is a single-center observational case-control trial to determine whether  there is higher incidence of skewed X chromosome inactivation(SXCI) in the recurrent  miscarriage(RM) population compared with normal population, and verify the existing  hypothesis of the possible genetic mechanisms underlying the association between SXCI and RM. Inclusion Criteria:  -  1) regular menstrual cycles and normal level of E2, P, FSH, LH, T, RPL in the early  follicular phase; 2) no history of gynecologic or other pelvic operations; 3) no  history of hormone medicine application in the last 3 months; 4) no history of poison  contact; 5) normal uterine and adnexal ultrasonography; 6) TORCH(-), chlamydia(-),  mycoplasma(-), normal leucorrhoea routine, anti-phospholipid antibody (-), antinuclear  antibody(-); 7) for the couple, no blood type incompatibility or ABO antibody IgG≤1：64  and normal blood chromosome analysis; 8) condoms are used for contraception. Exclusion Criteria:  -  1) BMI<18.5 or >24.9; 2) hydrosalpinx without operation; endometriosis; polycystic  ovary syndrome; adenomyosis; uterine leiomyomata(submucous myoma or non-submucous  myoma which size was exceed 4cm and/or with the compressed endometrium);uterine cavity  lesions(such as uterine malformation, intrauterine adhesions, the septate uterus,  endometritis etc); 3) the former abortion is because of luteal phase defect without  treatment; 4) FSH≥12IU/L or AMH<1.2ng/ml 5) thyroid dysfunction or increased CA125  level; 6) acute inflammation of genitourinary system or STD carriers; 7) unable to  comply with the study procedures.

This phase IV clinical trial investigates the impact of prostate cancer treatment,  specifically androgen deprivation therapy (ADT), on the heart and coronary vessels among men  with localized, non-metastatic prostate cancer undergoing definitive radiation therapy and  concomitant ADT. Recently, cardiovascular toxicity from hormone therapy that is routinely  used for prostate cancer (e.g. leuprolide) has emerged as a concern, yet studies identifying  who is at risk and the mechanism of cardiac damage are lacking. Additionally, a new hormone  therapy drug, relugolix, has recently been Food and Drug Administration (FDA)-approved and  may reduce toxicity to the heart. This trial intends to investigate the mechanism of  cardiovascular toxicity from ADT, investigate the mechanism by which relugolix reduces  cardiovascular toxicity, and identify predictive biomarkers to improve individualized  risk-assessment for cardiovascular toxicity from ADT. PRIMARY OBJECTIVES:  I. Identify and compare the association of gonadotrophin releasing hormone (GNRH)-agonist  leuprolide versus GNRH-antagonist relugolix with coronary atherosclerosis and progression in  men with prostate cancer.  II. Determine the relationship between leuprolide versus relugolix with downstream immune  effector response that is implicated in atherosclerosis.  II. Determine how pre-existing genomic alterations associated with proinflammatory immunity  impact development of CV toxicity following GNRH-agonist (GNRHa) versus relugolix.  III. Identify imaging biomarkers associated with increased risk of CV toxicity from ADT  OUTLINE: Patients undergoing radiation therapy alone as part of their standard treatment are  assigned to Arm I. Patients undergoing radiation therapy and ADT as part of their standard  treatment are randomized to Arm II or Arm III.  ARM I: Patients undergo definitive radiation therapy in the absence of disease progression or  unacceptable toxicity.  ARM II: Patients undergo radiation therapy as in Arm I and receive leuprolide subcutaneously  (SC) or intramuscularly (IM) every 3 or 6 months. Treatment continues for 6 to 24 months  (depending on cancer risk) in the absence of disease progression or unacceptable toxicity.  ARM III: Patients undergo radiation therapy as in Arm I and receive relugolix orally (PO)  once daily (QD) for 6 to 24 months (depending on risk) in the absence of disease progression  or unacceptable toxicity. Inclusion Criteria:  -  Men >= 18 years old  -  Non-metastatic prostate cancer  -  Non-metastatic, biochemically recurrent prostate cancer  -  Plan to undergo curative-intent pelvic radiation therapy with or without ADT Exclusion Criteria:  -  Metastatic prostate cancer requiring > 24 months of ADT  -  Prior exposure to androgen deprivation therapy  -  Prior exposure to chemotherapy or immunotherapy

The aim of this study is designed to evaluate the safety, tolerability, pharmacokinetics and  preliminary antitumor activity of docetaxel for injection (albumin-bound) in different dose  regimens in patients with advanced solid tumors. This study will be conducted in two stages. The first stage (Stage I) is a dose-escalation  study. A classic 3+3 design will be used to determine the maximum tolerated dose (MTD) and  the recommended phase 2 dose (RP2D). Patients will receive the docetaxel for injection  (albumin-bound) until disease progression, or intolerable toxicity, or other reasons for  termination of the study. All dose-escalation decisions will be based on the safety data  generated from the current highest dose group.  In the cohort-expansion study (Stage Ⅱ), patients with a potential to have better response to  the study drug will be recruited. Patients will receive the docetaxel for injection  (albumin-bound) at the recommended phase 2 dose (RP2D) and follow the treatment regimen  established in Stage I. Inclusion Criteria:  1. Patients aged ≥18, ≤75 years (subject to the date when the informed consent form is  signed) and voluntarily signed the informed consent form.  2. Histologically or cytologically confirmed diagnosis of advanced or metastatic solid  tumors, for which standard therapy either does not exist or has proven to be  ineffective, intolerable or unacceptable for the patient.  3. At least one measurable lesion according to RECISTv1.1.  4. Patients with Eastern Cooperative Oncology Group (ECOG) performance status score of  0-1.  5. Patients with estimated survival time of ≥ 3 months.  6. Main organ function meets the following criteria within 7 days before treatment (no  medical supportive treatments such as blood component transfusion, human granulocyte  colony-stimulating factor (G-CSF), thrombopoietin (TPO), interleukin-11, and  erythropoietin (EPO) within 2 weeks before baseline examination):  Absolute neutrophil count ≥1.5×10^9/L; Platelets ≥100×10^9/L; Hemoglobin ≥90 g/L or  ≥5.6 mmol/L; Serum creatinine ≤ 1.5×ULN or creatinine clearance rate ≥ 50 mL/min;  Liver function: total bilirubin≤ 1.0 × ULN, ≤ 1.5 × ULN for patients with liver  metastasis or liver cancer; alanine aminotransferase (ALT) and aspartate  aminotransferase (AST) ≤ 1.5 × ULN, ≤ 2.5 × ULN for patients with liver metastasis or  liver cancer.  7. Fertile patients must use contraceptive measures (such as intrauterine device [IUD],  contraceptive pill or condom) during the study period and within 6 months after the  end of the study, and men should avoid sperm donation; Women of childbearing age must  have negative serum pregnancy test within 7 days before study enrollment, and must be  non-lactating women. Exclusion Criteria:  1. Patients with central nervous system metastasis or meningeal metastasis, accompanied by  the following conditions:  1. Patients with clinical symptoms related to central nervous system metastasis or  meningeal metastasis;  2. New lesions in the brain or progression of the original lesions on imaging from the  end of brain radiotherapy or surgery to the first administration;  3. Central nervous system metastasis with cortical alcohols, radiotherapy, dehydration  drugs and other drugs for symptoms control within the last two weeks;  4. Patients has brain stem (midbrain, pons, medulla oblongata) metastasis;  5. Other evidence shows that the patient's central nervous system metastasis or meningeal  metastasis has not been controlled, which is not suitable for inclusion according to  the judgment of the researcher.  2. Known human immunodeficiency virus (HIV) test positive or known history of acquired  immunodeficiency syndrome (AIDS), history of organ transplantation, history of serious  autoimmune diseases judged by the researchers to be unsuitable for inclusion.  3. HCV antibody (+) or active hepatitis B (HBsAg positive and HBV DNA > 500 IU/mL) and  uncontrolled active infection (those who must receive systematic anti infection treatment,  or those with unexplained body temperature > 38 ℃ (axillary temperature) before  administration).  4. Patients have a history of serious cardiovascular diseases, including but not limited  to:  1. Severe heart rhythm or conduction abnormalities, such as ventricular arrhythmia  requiring clinical intervention and third-degree atrioventricular block;  2. History of myocardial infarction, angina pectoris, angioplasty, coronary artery bypass  surgery;  3. Patients with prolonged QT/QTc interval (QTcF > 480 ms, Fridericia's formula: QTcF =  QT/RR^0.33, RR = 60/heart rate) by ECG during the screening period;  4. left ventricular ejection fraction (LVEF) ≤ 50% by echocardiography (ECHO) or  multi-gated acquisition (MUGA) during the screening period;  5. Heart failure with New York Heart Association (NYHA) Classification of Class Ш and  above;  6. Poorly controlled hypertension (systolic blood pressure ≥ 150 mmHg and/or diastolic  blood pressure ≥ 95 mmHg despite optimal treatment);  7. Previous or current cardiomyopathy;  8. Patients with severe pulmonary hypertension or a history of pulmonary embolism within  6 months.  5. Patients with a third space effusion (e.g., pleural effusion, ascites, or pericardial  effusion) that is difficult to control, who, in the judgment of the investigator, are not  suitable for the study.  6. Allergic history to taxane or any excipients of the study drug (CTCAE 5.0 grade ≥ 3  grade).  7. Adverse reactions from the previous anti-tumor treatment have not yet recovered to ≤  level 1 based on CTCAE 5.0 (except for the toxicity without safety risk judged by the  investigator, such as alopecia).  8. Patients who have previously received docetaxel containing regimen and progressed during  treatment or within 6 months after treatment.  9. Patients who have undergone major organ surgery (excluding puncture biopsy) or  significant trauma within 4 weeks before the first dose of the investigational drug, or who  need to undergo elective surgery during the study period.  10. The time between the last anti-tumor treatment and the first medication meet the  following time interval: anti-tumor treatment such as chemotherapy, radiotherapy (except  local radiotherapy for pain relief), targeted therapy, immunotherapy and other clinical  research drugs within 4 weeks before the first administration; oral fluorouracils, small  molecule targeted drugs and traditional Chinese medicine with anti-tumor indications within  2 weeks before the first administration.  11. Patients who have received corticosteroid (prednisone > 10 mg/day or equivalent) or  other immunosuppressive therapies within 2 weeks before the first dose of the  investigational drug, except for the following: a. use of topical, ocular, intra-articular,  nasal and inhaled glucocorticoids; b. short-term use of glucocorticoids for prophylaxis  (such as prevention of contrast agent allergy).  12. Patients who have used potent inhibitors or inducers of CYP3A4 within 2 weeks before  the first dose of the investigational drug.  13. Patients with alcohol or drug dependence. 14. Patients have clear history of  neurological or psychiatric disorders, including epilepsy and dementia.  15. The researcher believes that the patient has other reasons that affect the safety or  compliance, or is not in the best interests of the subject and is not suitable to  participate in this clinical study (for example, eye diseases, venous thrombosis, etc.,  which affect the safety according to the judgment of the researcher).

The Swiss Patient Registry for DMD/BMD and SMA was launched in 2008 in order to give Swiss  patients access to new therapies. It was founded with the financial support of several  patient organizations and research foundations. Since 2008, children, adolescents and adults  with DMD, BMD and SMA are registered with the help of all major muscle centers in  Switzerland. After nearly ten years of activity, the Swiss Patient Registry for DMD/BMD and  SMA implemented several adaptations in 2018 to meet current and future expectations of  patient's organizations, health authorities and research organizations. Background:  The 'Swiss registry for neuromuscular disorders' (Swiss-Reg-NMD) collects medical information  from people with neuromuscular disorders. It is led by specialized physicians from all over  Switzerland and located at the Institute of Social and Preventive Medicine (ISPM) in Bern.  The registry includes children and adults living or treated in Switzerland who are diagnosed  with Duchenne-Becker Muscular Dystrophy (DMD/BMD), Spinal Muscular Atrophy (SMA) and recently  also merosin-deficient muscular dystrophy also called LAMA2-related muscular dystrophy (MDC1A  respectively LAMA2).  The Swiss Registry for neuromuscular disorders was initially founded in 2008 to give Swiss  patients with a neuromuscular disease access to new therapies. In 2018, the registry was  reorganized to meet new legal requirements and expectations of patients and research  organizations. The Swiss Ethics Commission approved the project (project ID: 2018-00289,  observational study, risk category A).  NMDs are rare diseases with few patients scattered across the country. A national patient  registry with a centralized registration facilitates the participation of Swiss patients in  therapeutic trials and the creation of Swiss trial sites.  Objectives:  Primary objectives of the Swiss-Reg-NMD project are:  1. Establish a representative population-based Swiss cohort of children, adolescents and  adults with NMDs  2. Provide epidemiological data to investigate the incidence, prevalence, spectrum of  diagnosis, survival rates and mortality of NMDs in Switzerland  3. Provide a platform for clinical research:  1. Offer a resource to recruit Swiss patients in current and future national and  international therapeutic trials or observational studies  2. Offer a resource to facilitate the establishment of therapeutic trial sites in  Switzerland  3. Answer questions in the following areas: health, health care, social-,  educational-, professional-, economic aspects, and quality of life  4. Offer a resource for post-marketing surveillance (effects and side effects of  therapies/treatments)  4. Provide a platform for communication:  1. Promote the exchange of knowledge between clinics, researchers, therapists and  national and cantonal health authorities in particular regarding standards of care  2. Facilitate national and international collaborations, in particular with the  international registry of TREAT-NMD and the upcoming Swiss Registry for Rare  Diseases  Inclusion/exclusion criteria:  All children, adolescents and adults living or treated in Switzerland who are diagnosed with  a NMD. The diagnosis needs to be confirmed, whenever possible, by genetic testing, or at  least by biopsy and/or electroneuromyography, according to international standards for the  diagnosis of the given NMD. Once the diagnosis is established, there is no specific exclusion  criteria.  Currently, patients with SMA, DMD/BMD, merosin-deficient muscular dystrophy also called  LAMA2-related muscular dystrophy (MDC1A respectively LAMA2) and Collagen 6 related muscular  dystrophy are included.  Procedure:  After a NMD diagnosis, the treating physician informs the patient and the parents (if the  patient is still a child) during a consultation in a clinic or practice in writing and orally  about the Swiss-Reg-NMD. The patient/parents who wish to participate sign the consent form  and the patient is registered in the Swiss-Reg-NMD. If the patient/parents do not wish to  participate, only a minimal anonymous data set is recorded.  The following data will be collected:  -  Medical data  -  Data from questionnaires for patients and families  -  Data from links to routine statistics and other medical registries  Clinical data (report of new cases and follow-up reports): NMD subtype, severity, and  associated conditions; Comorbidities; Medical care and medication; Therapies; (Serious)  adverse events; Hospitalisations; Motor Function Assessments; Socio-demographic  characteristics.  Questionnaire data: We will collect data through questionnaires with a focus on (but not  exclusively):  -  Health related questions like nutrition, sleep, pain  -  Health behaviours (e.g., physical activity, smoking)  -  Medical equipment use (type, usage, satisfaction)  -  Treatments and therapies: frequency, intensity, start, types  -  Quality of life and participation (involvement in a life situation)  -  Social-economic factors  -  Education (early childhood education, school, professional integration)  -  Patient/caregiver reported outcomes  -  Needs and concerns of persons with NMDs and their families  Routine data and linkages: e.g. Federal Statistical Office (e.g. birth registry, cause of  death statistics, hospital statistics); Swiss National Cohort (socioeconomic data, family  information); other medical registries (e.g. rare disease registry); Communities of residence  (vital status, date of death, address).  Funding:  Schweizerische Muskelgesellschaft; ASRIMM, Association Suisse Romande Intervenant contre les  Maladies neuromusculaire; MGR, Associazione malattie genetiche rare della svizzera italiana;  fsrmm, schweizerische stiftung für die erforschung der muskelkrankheiten; SMA Schweiz;  Duchenne Schweiz; Avexis; Biogen; Novartis; Pfizer, PTC Therapeutics; Roche; Sarepta.  Data protection:  Data generation, transmission, storage and analysis of health related personal data within  this project will follow strictly the current Swiss legal requirements for data protection.  Data analyses will always be done using pseudonymised datasets. Health related personal data  captured during this project are strictly confidential. Project data shall be handled with  uttermost discretion and only be accessible to authorized personnel. Direct access to source  documents will be permitted for purposes of monitoring, audits or inspections. The data  protection concept of ISPM ensures the secure handling of all sensitive data at ISPM and  within Swiss-Reg-NMD. The Swiss-Reg-NMD team is responsible for the implementation and  compliance with the confidentiality and data security measures. Inclusion Criteria:  -  Children, adolescents and adults diagnosed with a NMD  -  Who are living or treated for a NMD in Switzerland, and  -  Who gave informed consent Exclusion Criteria:  -  None if diagnosis is confirmed, whenever possible, by genetic testing, or at least by  biopsy and/or electroneuromyography, according to international standards for the  diagnosis of the given NMD.

The study aim is to look at the effect of the regular use of inhaled corticosteroids on the  response and received from mepolizumab treatment which you are receiving or had received  before. Examine the outcomes of 250 patients who have been treated with mepolizumab within BRSAS and  compare the adherence to ICS in the responders and non-responder groups. If confirmed that  non-adherence to ICS was related to poor response to mepolizumab, steps then will be  undertaken to better monitor and enhance adherence to ICS to improve patients outcomes and  response to mepolizumab treatment.  This study will rely on retrospective analysis of medically existing data within the service  ,the adherence to ICS treatment will be measured using the prescription possession ratio  "PPR" Data is available in the patients' GP records and forms part of the routine clinical  practice of the severe asthma clinic to monitor adherence to ICS treatment.  For a significant number of patients ,such data will be already available within patient  medical records held at University Hospitals Birmingham NHS Foundation Trust (UHB), however  missing data is expected and in such cases GP surgeries will be contacted to obtain the PPR.  Patients will be asked to agree to access to GP records as part of the informed consent  process. Inclusion Criteria:  -  Patients of 18 years of age or higher  -  Patients commenced on mepolizumab within the BRSAS network  -  Patients who have at least 1 mepolizumab injection and with at least 3 months  follow-up data from the time of treatment initiation  -  Patients must be able and willing to give informed consent to participate in the study  . An Interpreter will be provided for those patients where English is not their first  language. Exclusion Criteria:  -  Refusal or inability to provide informed consent

Phase 2 Study Investigating the Efficacy of AMT-101 in Subjects with Chronic  Antibiotic-resistant Pouchitis A Phase 2 12-week, Randomized, Double-blind, Placebo-controlled Study Investigating the  Efficacy of AMT-101 in Subjects with Chronic Antibiotic-resistant Pouchitis Inclusion Criteria:  • Chronic or recurrent pouchitis Exclusion Criteria:  -  Known gastrologic, or systemic condition that may compromise severity or diagnosis of  disease.  -  History or current evidence of colonic or abdominal abnormalities.  -  Previous exposure to AMT-101 or similar and known hypersensitivity to AMT-101 or its  excipients.

Multicentre, national, observational, retrospective and prospective study.  The BLITZ-COVID19 study aims at describing the epidemiology of admissions to Italian  Cardiology Intensive Care Units in the COVID-19 infection pandemia, the main aspects of the  clinical management of inpatients, their short-term outcome, the absorption of resources  related to their admission. The BLITZ-COVID19 study, aims at describing the epidemiology of admissions to Italian  Cardiology Intensive Care Units .  The study is observational, multicentre, national and involves the collection of clinical  data, both retrospectively and prospectively, using a web-based system. In conducting the  study, no drugs are tested, nor are diagnostic tests or non-pharmacological therapies  performed other than those that each participating cardiologist decides to perform following  the rules of normal clinical practice. Diagnostic procedures and pharmacological and  non-pharmacological therapies habitually prescribed for cardiovascular pathologies, which are  the object of hospitalization, and those used in the event of a COVID-19 infection, will be  recorded in the database. Inclusion Criteria:  - All patients aged ≥18 years admitted with any diagnosis to one of the participating ICU Exclusion Criteria:  - Refuse to signe consent

The prolonged β-lactam Antibiotics intravenous infusion strategy has emerged as the standard  treatment for sepsis despite its unknown efficacy. The investigators will conduct a  prospective, multi-center, cluster randomized controlled clinical trial. The investigators  aimed to compare the clinical efficacy and prognosis of prolonged β-lactam antibiotics  intravenous infusion versus short-term intravenous infusion in ICU patients with early  sepsis. The investigators expect to recruit 40 branch centers and enroll at least 2600  patients with sepsis. Sepsis and septic shock can lead to high morbidity and mortality. The mortality of sepsis is  related to inappropriate antibiotic treatment strategy. Due to the pathophysiological  characteristics of patients with sepsis, the pharmacokinetics of antibiotics have changed,  and antibiotic treatment strategies applied to general mild and severe infections may not be  suitable for those patients. The relevant international guidelines recommend that antibiotic  treatment for patients with sepsis should base on pharmacokinetic/pharmacodynamic principles,  but this recommendation is based on low-level clinical evidence.  β-lactam antibiotics, including penicillins, cephalosporins, carbapenems and so on, are the  most widely used antibacterial drugs in clinical practice. The best predictive parameter of  those antibiotic bactericidal activity is the time during which the free drug concentration  exceeds the target microbial MIC value (fT >MIC). According to Monte Carlo approach and  clinical studies, as a PK/PD target value, an effective bactericidal effect can be achieved  if fT>MIC reaches more than 40%; fT>MIC reaches more than 60%-70% can achieve the maximum  bactericidal effect, which can be used in the treatment of severe cases. For severe infection  and prevention of bacterial resistance, fT>MIC needs to reach 90%-100%.  The results of clinical studies have proved that improper or inadequate initial empiric  antibiotic treatment is an independent risk factor that affects the therapeutic effectiveness  and prognosis of severe infections. Important reasons for the lower-than-expected antibiotic  treatment effect in severely ill patients include at least the following two factors: (1)  Changes in the pathophysiological state of severely ill patients on drug metabolism, such as  capillary leakage leading to increased drug distribution volume. As well as the high  excretion and low obstruction hemodynamic characteristics of sepsis, increased renal blood  flow leads to high excretion of water-soluble drugs, which often reduces the effective plasma  concentration of the drug; (2) ICU infection of pathogenic bacteria has increased drug  resistance and increased MIC. The above factors lead to the decrease of drug fT>MIC, which  affects the efficacy of antibiotics. In recent years, the optimization of PK/PD-guided  time-dependent antimicrobial treatment programs have confirmed that the administration method  of prolonging the infusion time or continuous infusion can maintain a good steady-state blood  drug concentration, prolong fT> MIC, and improve clinical curative effect, and can reduce the  amount of antibiotics.  The main problems with PK/PD-guided antimicrobial therapy are: (1) Lack of convincing large  sample clinical research results; (2) It has not been confirmed which subgroup (such as the  sepsis severity, drug-resistant patterns of pathogens, immunocompetence) can be benefited  from this strategy; (3) It is not clear whether the method of prolonged infusion can be  applied in all kinds of β-lactam antibiotics .  This study adopts multi-center, openness, cluster randomization method to group, and  eliminates the bias caused by factors such as the treatment environment in a single ward  through the multi-center study; through Uniform training realizes the standardization of drug  delivery methods to eliminate researchers' human bias in treatment operations and  observations. At the same time, the regional randomization method sets the drug delivery  method for a certain research center in a certain research phase to be determined, which  eliminates the operational error and observation bias when the researcher needs to face  multiple drug delivery programs at the same time. It can greatly reduce research costs and  human bias, and more reliably obtain the impact of PK/PD-guided antibiotic treatment on the  prognosis of patients and the impact of bacterial resistance in the entire ward. Inclusion Criteria:  1. Patients in ICU who need to be treated with β-lactam antibiotics for clinical  diagnosis of infection;  2. Meet the diagnostic criteria of sepsis 3.0 in the previous 24h;  3. At assessment of eligibility, treating doctor expects patient to need treatment in ICU  beyond the next calendar day. Exclusion Criteria:  1. The infection is diagnosed clinically, but the acquired pathogens are not sensitive to  the study drug;  2. Has a history of allergies to study drugs;  3. Those who have a serious condition and the expected survival time is less than 72  hours.  4. Receipt of potential study medication for > 24 hours before randomization.  5. Pregnancy  6. Death is deemed imminent and inevitable.  7. Receiving palliative or supportive treatment only at the time of assessment for  eligibility.  8. Treating doctor not committed to provision of advanced life-support, including any of  mechanical ventilation, dialysis and vasopressor administration for at least the next  48 hours.  9. Consent not gained for study participation and entry under a waiver-of-consent not  approved by the jurisdictional human research ethics committee.

Several studies seem to indicate that emotional attention and change-related attention are  impaired in ASD. The goal of this study is to identify the relationships between those two  types of automatic attention in visual and auditory modalities in subjects with ASD compared  to healthy controls and also, over the course of development (children, adults). In order to  achieve this goal, the investigators will use complementary techniques (EEG and MRI-based  techniques (fMRI, DTI)). Autism Spectrum Disorders (ASD) are characterized by major handicap in social interaction and  in daily life adaptation. The orienting response towards potentially relevant events involves  automatic attentional mechanisms that would be elicited mainly by two classes of biologically  important stimulations: novel stimuli and emotional stimuli. The neural basis of emotional  and change-related attention in ASD will be explored by investigating brain reactivity in  both visual and auditory modalities, during tasks mixing emotional and non emotional stimuli. Inclusion Criteria:  -  No past history of central nervous system disorders  -  Written consent  -  Affiliated to the National Health Insurance  -  Do not participate to another biomedical research  -  For ASD group: Children with autism spectrum disorder (DSM-V criteria) and adults with  high-functioning autism  -  For healthy subjects: No past history of difficulties in early childhood for  acquisition of walk, language or reading and no psychiatric disorders Exclusion Criteria:  -  Abnormal corrected vision  -  Abnormal audition  -  Not stabilized psychoactive treatment or treatment that can modify electrogenesis  -  Infectious or metabolic diseases  -  Epilepsies  -  Impossibility to participate to the whole study  -  For subjects participating to the MRI recordings: MRI counter-indications (pace-makers  ...), claustrophobia or a positive pregnancy test

The practice of a physical activity, even moderate, plays an important role in the prevention  and the management of the main chronic non-communicable diseases (cardiovascular diseases,  certain cancers, diabetes, obesity, osteoporosis ...) as well as by improving psychological  health. Several studies have shown that physical activity has a positive impact on the  economy of companies via the reduction of absenteeism and the improvement of productivity.  However, it seems important to individualize these recommendations in order to prescribe the  best possible dose of physical activity for each individual. In this project, the  investigators want to test the physical qualities of employees in order to prescribe the best  possible dose of physical activity with the ultimate goal of improving quality of life. Physical activity (PA) is one of the major determinants of health. Indeed, the practice of a  physical activity, even moderate, plays an important role in the prevention and the  management of the main chronic non-communicable diseases (cardiovascular diseases, certain  cancers, diabetes, obesity, osteoporosis ...) as well as by improving psychological health.  The effects are beneficial regardless of age, gender and state of health. Moreover, in  addition to the well-being of employees, several studies have shown that physical activity  has a positive impact on the economy of companies via the reduction of absenteeism and the  improvement of productivity. Today, the World Health Organization (WHO) prescribes 150 min of  physical activity per week regardless of the person's profile (active employee, employee  working in his office, construction worker, etc.).. In this project,the investigators  therefore want to test the physical qualities of employees in order to prescribe the best  possible dose of physical activity with the ultimate goal of improving quality of life. Inclusion Criteria:  -  Sedentary people  -  Affiliate to health care organism  -  Subject who gave their consent Exclusion Criteria:  -  People with degenerative disease  -  Pregnant women  -  Cardiovascular trouble  -  Subject who are not able to understand the proceeding of the study or to give their  consent

Evaluate efficacy and safety of ADI-PEG 20 in patients with genotype WWOX-GG and HCC Safety will be evaluated by laboratory tests, vital sign measurements, physical examinations  and subject medical history which will be performed to detect new abnormalities and any  deterioration in pre-existing conditions.  Efficacy will be determined by overall survival, progression free survival, pharmacodynamics  (peripheral blood arginine and citrulline levels) and immunogenicity (antibodies to ADI-PEG  20). Inclusion Criteria:  1. Prior diagnosis of HCC confirmed by radiology, histology, or cytology.  2. Prior treatment with at least 1 systemic agent for Child-Pugh A subjects. However,  Child-Pugh B7 subjects without prior systemic treatment may be enrolled, if they are  not eligible for any approved systemic therapies.  3. WWOX genotype GG.  4. Measurable disease using RECIST 1.1. At least 1 measurable lesion must be present.  5. Child-Pugh (cirrhosis status) score class A-B7.  6. Barcelona Cancer of the Liver (BCLC) stage C.  7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment.  8. Expected survival of at least 3 months.  9. Age >20 years.  10. Fully recovered from prior surgery, radiation, or chemotherapy, and none within 2  weeks prior to week 1 visit. Liver biopsy for HCC confirmation is allowed.  11. Female subjects and male subjects must be asked to use appropriate contraception for  both the male and female for the duration of the study and for 35 days after last dose  of ADI-PEG 20. Male partners of female subjects and female partners of male subjects  must agree to use two forms of contraception or agree to refrain from intercourse for  the duration of the study if they are of childbearing potential. Females of  childbearing potential must not be pregnant at the start of the study, and a serum  human chorionic gonadotropin (HCG) pregnancy test must be negative before entry into  the study. If positive HCG pregnancy test, further evaluation to rule out pregnancy  must be performed according to GCP before this subject is deemed eligible. Females not  of childbearing potential must be post-menopausal (defined as cessation of regular  menstrual period for at least 12 months).  12. Informed consent must be obtained prior to study initiation.  13. No concurrent investigational studies are allowed.  14. Total bilirubin < 3.0 mg/dL and no evidence of bile obstruction.  15. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 x upper  limit of normal range.  16. Serum albumin level ≥ 3.0 g/dl.  17. Prothrombin time (PT)-international normalized ratio (INR): PT <3 seconds above  control or INR <1.7.  18. Absolute neutrophil count (ANC) >1,500/μL.  19. Platelets >50,000/μL.  20. Serum uric acid ≤ 8 mg/dL (with or without medication control).  21. Serum creatinine ≤ 1.5 x the upper limit of normal range, or, if serum creatinine >1.5  x the upper limit of normal range, then the creatinine clearance must be ≥ 40 mL/min.  22. Subjects with active hepatitis B or C on anti-viremic compounds may remain on such  treatment, except for interferon.  23. Encephalopathy - none or mild (grade 1 or 2, by Child-Pugh classification); lactulose  of other supportive care allowed.  24. Ascites - absent or slight (by Child-Pugh classification); diuretic therapy allowed Exclusion Criteria:  1. Candidate for potential curative therapies (i.e., resection or transplantation) or  eligible for approved systemic therapies according to the labeling of such drugs.  2. Prior allograft transplantation including liver transplantation.  3. Subjects who have not fully recovered from toxicities associated with previous HCC  loco-regional or systemic therapies, except for Grade 1 alopecia.  4. Serious infection requiring treatment with systemically administered antibiotics at  the time of study entrance, or an infection requiring systemic antibiotic therapy  within 7 days prior to the first dose of study treatment.  5. Pregnancy or lactation.  6. Expected non-compliance.  7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active  infection, symptomatic congestive heart failure (New York Heart Association Class III  or IV), cardiac arrhythmia, or psychiatric illness, social situations that would limit  compliance with study requirements.  8. Subjects with history of another primary cancer, including co-existent second  malignancy, with the exception of: a) curatively resected non-melanoma skin cancer; b)  curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no  known active disease present or in the opinion of the investigator will not affect  patient outcome.  9. Subjects who had been treated with ADI-PEG 20 previously.  10. History of uncontrolled seizure disorder not related to underlying cancer.  11. Allergy to pegylated compounds.  12. Allergy to E. coli drug products (such as GMCSF).  13. Bleeding esophageal or gastric varices within the prior three months, except if banded  or treated.  14. Uncontrolled ascites (defined as not easily controlled with diuretic treatment).  15. Having received any blood transfusion, blood component preparation, erythropoietin,  albumin preparation, or granulocyte colony stimulating factors (G-CSF) within 7 days  prior to screening laboratories or after screening laboratories have been obtained  until week 1 visit.  16. Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2.

COVID-19 or coronavirus disease 2019 is an emerging infectious disease. The disease was first  identified in China and then spread worldwide; hence, declared as a global pandemic on March  11, 2020 by World Health Organization (WHO). The pandemic is posing formidable challenges to  healthcare systems and humanities worldwide resulting in morbidities and mortalities  unthought of. Rapidly accumulating clinical evidence on COVID-19 paved the way for an  extensive and prompt characterization of the acute phase of the disease. The clinical  presentation is generally that of a respiratory infection with a symptom severity ranging  from a mild common cold-like illness, to a severe viral pneumonia leading to acute  respiratory distress syndrome that is potentially fatal. Characteristic symptoms include  fever, cough, and dyspnoea, although some patients may be asymptomatic. Complications of  severe disease include, but are not limited to, multi-organ failure, septic shock, and acute  respiratory distress syndrome. The COVID-19 infection fatality rate is between 0.5 and 1  percent and the remaining affected patients will mostly recover but need convalescent care.  However, discharge should not be considered as the final point of overcoming coronavirus and  till date evidence on sequelae of the COVID-19 recovered patients is very limited. COVID-19  is a complex multisystem disease that affects pulmonary function, as well as renal,  cardiovascular, and neuropsychiatric health, metabolic derangement; and nutritional status.  The extent to which these alterations may persist remains obscure, till date evidence on long  term sequelae of the COVID-19 recovered patients is very limited. Some of the aftereffects of  it may have a profound impact on 'recovered' patients in the future.  Long-term morbidities were observed in survivors of severe acute respiratory syndrome but it  is unidentified whether experience from SARS is applicable to COVID-19. The SARS-CoV-2  infection is severe in older, immune deficient people and who have any pre-existing medical  conditions. Hence, it is imperative to comprehend the possible long-term sequelae of the  COVID-19 recovered patients, and if they will develop any other harmful illnesses. This study  would help us to understand the in-depth prognosis and sequelae of the disease, as well as  help to uncover to what extent would COVID-19 recovered patients require post-acute care to  recuperate from any further infections or multi-organ damage. Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus, known as severe acute  respiratory syndrome coronavirus 2 (SARS-CoV-2). From December 2019, it has rapidly spread  across China and many other countries. COVID-19 pandemic is posing formidable challenges to  healthcare systems and humanities worldwide resulting in morbidities and mortalities  unthought of.  The first case of COVID-19 was officially detected in Bangladesh on March 8, 2020. As of  December 10, 2020, according to the Institute of Epidemiology, Disease Control and Research  (IEDCR), there are 485,965confirmed COVID-19 cases in Bangladesh with 6,967 related deaths  and the Case Fatality Rate (CFR) is 1.38%. The overall attack rate is 1,639 per 1 million.  Regarding age distribution, 27% of cases were between 31 and 40 years old, 21% in the age  group of 21 and 30 years, 19% were between 41 and 50 years, and 15% were in the age group of  51 and 60 years Regarding geographical distribution, 64% of reported confirmed cases were  from the Dhaka district, followed by 5.7%in Chattagram district. Case doubling time is 5 days  for both the Dhaka and Chattagram district.  COVID-19 is a complex multisystem disease that affects pulmonary function, as well as renal,  cardiovascular, and neuropsychiatric health, coagulation derangement as well as nutritional  status A significant proportion of patients who survive from COVID-19 may have the  possibility to get impairment in their overall health status after their recovery. The extent  to which these alterations may persist remains obscure. Some of the aftereffects of it may  have a profound impact on 'recovered' patients in the future This study would help us to  understand the in-depth prognosis and sequelae of the disease, as well as help to uncover to  what extent would COVID-19 recovered patients require post-acute care to recuperate from any  further infections or multi-organ damage.  This is a prospective cohort study which will be done in Dhaka hospital of icddr,b and BSMMU.  We will include all patients aged ≥ 18 years who have COVID-19, confirmed by  reverse-transcriptase polymerase-chain-reaction assay (RT-PCR), following their discharge  from Dhaka hospital or outpatient clinic or inpatient wards of BSMMU. Baseline data of  prognostic importance, including demographic, social information, lifestyle factors, medical  history, underlying comorbidities, anthropometric measurements, clinical, laboratory, imaging  and treatment records will be collected using a standard case report form. A detailed  clinical examination including measurement of vital signs, blood pressure, pulse oximetry,  anthropometric measurements, neurological, pulmonary, cardiovascular system examination will  be performed by trained research physicians at enrollment and at each follow-up visit. We  will perform routine laboratory assays including complete blood count (CBC), serum alanine  transaminase (ALT), serum creatinine, fasting capillary blood glucose using glucometer and  urine routine examination. We will also perform ECG, echocardiography, chest X-ray and  pulmonary function test. Additional tests will be done as and when required such as RT-PCR  test in nasopharyngeal specimen, as well as fasting blood sugar, glycated haemoglobin, MRI/CT  scan of brain etc. Thyroid function tests such as FT4, FT3 and TSH and C peptide will be  performed at 5 month follow-up time point along with other routine investigations.  Participants will be followed up at at 3,5,9,12 ,18 ,24-month time points following discharge  from hospital or OPD, and at any time they have a complain. Inclusion Criteria:  -  Age ≥ 18 years  -  Participants categorized as mild, moderate and severe/critical disease according to  the classification of WHO and the national guideline on COVID-19 case management  published by the DGHS [28], Bangladesh and discharged from the hospital or outpatient  clinic  -  Participants residing within Dhaka city corporation area  -  Willing to participate in this study  Same as exposed group except that they are not exposed to SARS-CoV-2 infection as evident  by negative RT-PCR test. Other criteria for comparison group are given below.  -  Participants will be included if the RT-PCR test is negative during enrollment  -  Age ≥ 18 years  -  Participants residing within Dhaka city corporation area  -  Willing to participate in this study Exclusion Criteria:  -  Participants will be excluded if they have a history mental illness before COVID-19  -  Participants with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant  clinical symptoms in the preceding fourteen days will be excluded.  -  Participants residing outside the Dhaka city corporation area and not willing to  participate in the study  • Participants with any known co morbidities including obesity will be excluded

Virtual reality (VR) has reported benefits of engagement, immersion, and motivation in  rehabilitation and has been proposed to be a solution for long-term engaging rehabilitation  methods. However, the use of VR within the multiple sclerosis (MS) population is not widely  investigated, and even less with regards to upper limb function. The main aim of this study  is to assess the feasibility of using the Oculus Quest VR headset and games for improving  upper limb function within the MS population. Recruited people with MS will be randomly  assigned to either an eight week intervention using VR games that have been designed by  co-production with people with MS and MS-specialists; or to a control group of usual care.  All participants will undertake testing at baseline, four weeks and eight weeks for multiple  outcomes measures related to upper limb and motor function. After completion of the  intervention, participants who undertook VR intervention will complete a survey regarding the  usability of the games, and some individuals will be invited to interviews to express their  experience of using VR and any suggestions for improvement for potential future trials. The aim of this study is to investigate the feasibility of an eight-week intervention of  co-produced virtual reality (VR) games delivered using the Oculus Quest for improving the  upper limb function of people with MS. This study is also a randomised controlled trial with  two arms, one group will undergo the intervention using VR and the other will be a control  group.  This study aims to recruit up to 30 people with MS who have some degree of self-reported  upper limb mobility difficulties from MS clinics in NHS Lanarkshire and MS Revive, a third  sector in Glasgow. Participants will be randomly allocated to a group: an eight week  intervention study using VR and exercise games or a control group of usual care. All groups  will have assessments at baseline, week 4 and week 8. However, only the VR intervention group  will undertake the USE questionnaire and only a select number of participants in the VR group  will participate in the semi-structured interviews.  The VR intervention group will involve participants travelling to a research site twice a  week for eight weeks and each session will be approximately 30 minutes. This 30-minute  intervention will include participating in game play and the participant using the game's  interface (e.g. navigating through menus, selecting which games to play). The games for the  intervention will involve facilitating and replicating upper limb movements: pushing buttons  for the interface; individual finger movement; grasp and release and one game includes  holding a controller for elbow flexion and extension (see table). The intervention group will  undergo exercises in a fully immersive VR environment using the Oculus Quest VR headsets. For  health and safety reasons participants will complete their programme whilst seated.  The control group will not receive a specific exercise programme but will be asked to  continue with their usual care, which could generally include any ongoing physiotherapy or  occupational therapy support or none whatsoever. Any ongoing physiotherapy or occupational  therapy (NHS or non-NHS) will be recorded, detailing the exercises and frequency. After  completion of the week 8 assessment, participants within the control group will be offered  the opportunity to take part in a 30-minute session trialling the VR games. Inclusion Criteria:  -  Confirmed diagnosis of multiple sclerosis.  -  Degree of self-reported hand or upper limb impairment which interferes with some  activities of daily living (ADL) (e.g. dressing, eating, grooming).  -  Objective upper limb impairment, in at least one hand, as determined by a Nine Hole  Peg Test (see Section Outcome Measures) of 2 standard deviations of more above the  published normative values depending on age and sex.  -  Must be able to travel to a research site. Exclusion Criteria:  -  If they have had a relapse in the last three months  -  Subjective cognitive problems resulting in them being unable to use the equipment or  participate in virtual reality.  -  Visual problems such that they cannot see the visual display within the headset (this  does not include participants who have glasses that are enough to correct eyesight  issues)  -  Have a current eye infection.  -  Have any significant co-existing neurological or orthopaedic conditions affecting the  upper limb.  -  Are unable to understand verbal or written explanations of the study or are unable to  speak or understand English.  -  Individuals who are currently enrolled in any clinical trials will be excluded, but  those who have previously taken part in research and other trials will be eligible.

Rehabilitation is crucial in the treatment of people with Parkinson's disease (PD) as it can  ameliorate motor and non-motor impairments, improving their clinical profile and quality of  life. Considering the complex biological processes occurring in PD brain, the identification  of accessible and measurable biomarkers to monitor the events induced by intensive  rehabilitation would help in i)testing rehabilitation effectiveness, ii)improving the design  of clinical trials and iii)personalizing the rehabilitation strategies by the prediction of  patients' responsiveness. The objective of this project is the validation of Raman analysis  of saliva and salivary extracellular vesicles (EV) for the differential diagnosis of  Parkinson's disease (PD) and atypical Parkinsonism. The proposed diagnostic method can be  integrated in the preliminary assessment and monitoring of the patient by providing a quickly  and repeatable measurable biomarker. In the end, this will bring tothe personalization of the  rehabilitation path and provide an indication on the outcome of the rehabilitation treatment. Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms such  as bradykinesia, tremor, rigidity and postural instability. An accurate rehabilitation  program designed considering the specific characteristics of the patient allows you to  maximize the effect of drug therapy, improve the patient's quality of life, while also  limiting secondary complications related to the progression of the disease. At the time of  diagnosis, however, it is particularly important to be able to quickly identify individuals  with idiopathic Parkinson's and distinguish them from those who have an atypical form of  Parkinsonism, such as Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA),  Corticobasal Degeneration (CBD) and Dementia with Lewy bodies (DLB). Atypical Parkinsonisms  are in fact progressive diseases that share some signs and symptoms with PD, however these  patients do not respond as effectively to drug therapy since the cellular and degenerative  mechanisms that characterize them are very different. For these reasons, their early  identification is particularly important to identify the best pharmacological and  rehabilitative path for each patient.  To ensure a more accurate patient profiling that takes into account the individual complex  clinical picture, the discovery of a biomarker that can be periodically measured in an easily  accessible biofluid would allow for better patient stratification, monitoring of the course  of the disease and careful study of the effects of the pharmacological and rehabilitation  program as well as its personalization, with a view to precision medicine designed, defined  and built on the patient.  The Laboratory of Nanomedicine and Clinical Biophotonics (LABION) of Fondazione Don Gnocchi  has been working for years on using innovative methods such as Raman spectroscopy to identify  biomarkers of neurodegenerative diseases in easily accessible biological fluids, such as  blood and saliva. Raman Spectroscopy (RS) allows to obtain a specific and complete  characterization of a specific fluid in a rapid, sensitive and non-destructive way, without  particular procedures for the preparation of the sample to be analyzed. In RS the entire  spectrum obtained from the sample is used as a highly specific "fingerprint" for the selected  sample (eg saliva, blood, serum, cerebrospinal fluid) which represents the diagnostic  biomarker. The Raman analysis of saliva has already demonstrated the possibility of profiling  patients with progressive pathologies with good accuracy and, specifically, of distinguishing  subjects suffering from amyotrophic lateral sclerosis compared to subjects with other types  of neurodegenerative diseases.  At the same time, LABION has verified the possibility of characterizing by Raman  spectroscopy, the extracellular vesicles (EV) circulating in the blood of patients with PD.  Since 2017, LABION has been working on the biochemical study of circulating EVs in the serum  of PD patients by analyzing the EVs in spectroscopy and the ability of RS to identify a  specific biochemical profile of blood vesicles that correlates with clinical scales has been  demonstrated. UPDRS III and Hoehn and Yahr. The analysis of the EVs present in the saliva of  patients with PD could help to understand the origin of biochemical alterations in the saliva  as well as identify even more specific markers.  Raman spectroscopy is therefore proposed as a useful method for the rapid and comprehensive  biochemical characterization of saliva and the vesicular component present within it, without  the use of staining and labeling procedures.  The objective of this project is the validation of a specific Raman molecular signature for  the different experimental groups, which can lead to the determination of a biomarker useful  for the differential diagnosis of people with PD compared to subjects with atypical  Parkinsonism, through the analysis of a biological fluid that is not invasive, thus filling  the current lack of a measurable biomarker for rapid differential diagnosis and for  monitoring the evolution of the diseases.  The rapid identification and differential diagnosis of subjects with Parkinson's disease and  atypical parkinsonisms will allow to promptly identify the optimal pharmacological and  rehabilitative therapy for each subject, leading to a significant improvement in the quality  of life for the patient and, in the future, an increased probability slowing the progression  of the disease.  SAMPLE COLLECTION: Saliva collection from all the selected subjects will be performed  following the Salivette (SARSTEDT) manufacturer's instructions. Saliva will be obtained from  all subjects after an appropriate lag time from feeding and teeth brushing. Pre-analytical  parameters (i.e. storage temperature and time between collection and processing), dietary and  smoking habit will be properly recorded. Briefly, the swab will be placed in the mouth and  chewed for 60 seconds to stimulate salivation. Then the swab will be centrifuged for 2  minutes at 1,000 g to remove cells fragments and food debris. Collected samples will be  stored at -80° C.  SAMPLE PROCESSING: For the Raman analysis, a drop of each sample will be casted on an  aluminium foil in order to achieve the Surface Enhanced Raman Scattering (SERS).  EV ISOLATION: different isolation methods will be tested for effective EV isolation. Purified  EVs will be then concentrated and analysed by means of standard techniques and by Raman  spectroscopy following a previously optimized protocol for blood EVs. The experimetal  settings will be adapted to the salivary EVs, considering variations in substrate,  acquisition time, etc.  DATA COLLECTION: Salivary and EV spectra will be acquired using an Aramis Raman microscope  (Horiba Jobin-Yvon, France) equipped with a laser light source operating at 785 nm and 532  nm. The instrument will be calibrated before each analysis using the reference band of  silicon at 520.7 cm-1. Raman spectra will be acquired in the region between 400 and 1600 cm-1  for saliva, 500-1800 nad 2600-3200 cm-1 for EVs using a 50x objective. The software package  LabSpec 6 (Horiba Jobin-Yvon, France) will be used for the acquisition of spectra.  DATA PROCESSING: All the acquired spectra will be baseline corrected and normalized by unit  vector using the dedicated software LabSpec 6. The contribution of the substrate will be  removed from each spectra, if necessary. The statistical analysis to validate the method,  will be performed using a multivariate analysis approach. Principal Component analysis (PCA)  will be performed in order to reduce data dimensions and to evidence major trends. The first  20 resultant Principal Components (PCs) will be used in a classification model, Linear  Discriminant Analysis (LDA), to discriminate the data maximizing the variance between the  selected groups. The smallest number of PCs will be selected to prevent data overfitting.  Leave-one-out cross-validation and confusion matrix test will be used to evaluate the method  sensitivity, precision and accuracy of the LDA model. Mann-Whitney will be performed on PCs  scores to verify the differences statistically relevant between the analysed groups.  Correlation and partial correlation analysis will be performed using the Spearman's test,  assuming as valid correlation only the coefficients with a p-value lower than 0.05. The  statistical analysis will be performed using Origin2018 (OriginLab, USA).  ROC Curve will be calculated to assess thediagnostic potential of the method. Inclusion Criteria:  For Pakinson's disease: diagnosis following "MDS clinical diagnostic criteria for  Parkinson's disease" (Postuma et al. Movement Disorders vol. 30 1591-1601, 2015), with  Hoehn&Yahr between 1 and 3.  The diagnosis of Progressive Supranuclear Palsy will be made according to the criteria of  the Movement Disorders Society (Höglinger et al. Mov. Disord. 32, 853-864, 2017). The  diagnosis of Corticobasal Syndrome will be made according to the 2013 Armstrong criteria  (Armstrong et al. Neurology 80, 496-503, 2013).  The diagnosis of multiple system atrophy will be made according to the Gilman criteria of  The diagnosis of Behavior Disorder in REM phase will be made according to the criteria of  the "International Classification of Sleep Disorders, Third Edition (ICSD-3)". Exclusion Criteria:  For all the experimental groups considered and for healthy controls, subjects with  concomitant chronic and / or inflammatory diseases of the oral cavity, other systemic  diseases (eg anemia, cardiovascular or respiratory diseases), oncological or infectious  diseases will be excluded.  Vascular parkinsonisms, monogenic parkinsonisms will also be excluded as well as iatrogenic  parkinsonisms, parkinsonisms secondary to exposure to known neurotoxins; parkinsonisms  secondary to tumor lesions; parkinsonisms due to normotensive hydrocephalus; subjects with  a form of dementia, severe speech disorders and other psychiatric and / or neurological  pathologies.

To assess the safety, immunogenicity and preliminary efficacy of 3D189 in patients with  hematological malignancies. This is a phase 1, open-label, non-comparative, multicenter study of 3D189 (also known as  galinpepimut-S), a multivalent peptide vaccine targeting Wilms Tumor-1 (WT1), for maintenance  immunotherapy in patients with WT1-positive hematological malignancies, including patients  with acute leukemia (AL) patients in complete remission (CR), or multiple myeloma (MM),  non-Hodgkin lymphoma (NHL) or higher-risk myelodysplastic syndrome (MDS) patients who have  received at least first-line standard therapy and recently achieved CR or partial remission  (PR), if the latter is the best achievable response for the patient. Inclusion Criteria:  -  Subjects must be willing and able to understand and provide signed informed consent  for the study.  -  Male or female patients ≥ 18 years of age on the day of signing informed consent.  -  Have a histologically or cytologically confirmed hematological malignancy and have  achieved complete remission (CR) or partial remission (PR) after at least one line of  standard therapy, and are not suitable for hematopoietic stem cell transplant (HSCT)  for the following reasons: a) not eligible for HSCT due to intercurrent medical  conditions; b) lack of an available HLA-matched donor for allogeneic HSCT; c) not able  to accept HSCT for financial reasons; d) without a potential indication for HSCT (e.g.  having a relatively favorable prognosis or low risk of relapse). However, patients who  have previously received autologous HSCT but remain MRD+ or in remission after salvage  therapy for post-transplant relapse are allowed to be recruited.  Including the following 4 types of hematological malignancies:  1. Acute Leukemia (AL): including acute myeloma leukemia (AML) and acute lymphoblastic  leukemia (ALL), in morphological complete remission with complete or incomplete blood  count recovery (CR or CRi), and having completed any planned post-remission therapy;  2. Myelodysplastic Syndrome (MDS): Revised International Prognostic Scoring System  (IPSS-R) risk score > 3.5, having achieved CR or PR following prior therapy;  3. Multiple Myeloma (MM): having achieved stringent complete response (sCR), CR or very  good partial response (VGPR), or PR if deeper response cannot be obtained from  adequate therapy.  4. Non-Hodgkin Lymphoma (NHL): preference for patients with diffuse large B-cell lymphoma  (DLBCL) and follicular lymphoma (FL) who have achieved CR or PR following prior  therapy.  -  Have a documented WT1 positive disease. This is defined as detectable presence of  WT1 transcript via real-time quantitative polymerase chain reaction (RT-PCR) in  patients'bone marrow or peripheral blood samples, or WT1 expression by  immunohistochemistry (IHC) in archived (paraffin embedded, unstained slides) or  freshly biopsied tumor tissues from bone marrow or lymph nodes or extranodal  lesions ( for NHL patients).  -  Eastern Cooperative Oncology Group (ECOG) performance status of 0~1.  -  Estimated life expectancy ≥ 6 months.  -  The interval between the last antitumor therapy (including surgery, radiotherapy  and systemic therapy) and the first study treatment must be at least 4 weeks, and  the toxicity of the previous therapies have recovered to ≤ grade 1 [according to  the Common Terminology Criteria for Adverse Events (CTCAE) 5.0], except for  toxicity such as alopecia, which in the judgment of the investigator is not a  safety risk.  -  Have adequate organ and bone marrow function, defined as follows:  1) Blood count (participants must not have received transfusion of blood products or  hematopoietic growth factors within 14 days prior to this test): hemoglobin (Hb) ≥ 9.0  g/dL; neutrophil (NEUT) ≥ 1.0×109/L; platelet (PLT) ≥ 50×109/L; 2) Liver function: alanine  aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ×ULN (upper limit of  normal); but for subjects with liver metastasis, ALT or AST ≤ 5×ULN; total bilirubin (TBIL)  ≤ 1.5 × ULN, or TBIL > 1.5 × ULN, but direct bilirubin (DBIL) ≤ 1.0 × ULN; 3) Renal  function: serum creatinine ≤ 1.5 × ULN or endogenous creatinine clearance rate ≥ 50 ml/min  (Cockcroft-Gault formula); 4) Coagulation: international normalized ratio (INR) ≤ 1.5,  activated partial thromboplastin time (APTT) ≤ 1.5 ×ULN, unless subjects are receiving  anticoagulant therapy as long as INR or APTT is within the therapeutic range of intended  use of anticoagulants; 5) Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50%  by echocardiography.  • Subjects (including partners) must agree to use an adequate method of contraception,  starting with the screening visit through 4 months after the last dose of study treatment. Exclusion Criteria:  -  Previously treated with any therapy targeting WT1.  -  Have known hypersensitivity to peptide biologics, or to immune adjuvants Montanide  and/or GM-CSF.  -  Subjects with acute promyelocytic leukemia (APL or M3).  -  Presence of central nervous system (CNS) invasion and/or carcinomatous meningitis;  participants with previously cured brain or meningeal metastasis can be allowed.  -  Have undergone prior allogeneic HSCT, or plan to perform HSCT during the study period.  -  Received live vaccine within 4 weeks prior to the first dose of study treatment.  -  Currently participate in or have participated in a study of an interventional agent or  device within 4 weeks prior to the first dose of study treatment.  -  Have a known additional malignancies within the past 5 years, with the exception of  cured skin basal cell carcinoma or cervical cancer in situ or other carcinoma in situ.  -  Have an active autoimmune disease or any disease that requires long-term use  (including use within 4 weeks prior to the first dose of study drug) of systemic  corticosteroids (at doses greater than 10 mg daily of prednisone equivalent) or any  other form of immunosuppressive agents, hormone replacement therapy for adrenocortical  insufficiency, hypopituitarism, hypothyroidism, or type I diabetes mellitus is not  considered a form of systemic treatment and is allowed.  -  Have a diagnosis of primary immunodeficiency disease, or acquired immunodeficiency  syndrome, or a positive test for human immunodeficiency virus (HIV).  -  Presence of active tuberculosis.  -  Have a history of a severe cardiovascular disease such as class III or IV heart  failure [New York Heart Association (NYHA) criteria], myocardial infarction or stroke,  unstable arrhythmia or unstable angina within 6 months prior to start of study  treatment.  -  QTcF interval tested during the screening period ≥ 450 msec (for male subjects) or ≥  470 msec (for female).  -  Have an acute severe infection requiring systemic therapy during the screening period.  -  Positive for HBsAg and HBV DNA ≥ 103 IU/ml; or positive for HCV antibodies and HCV RNA  level is above the detection limit.  -  Are pregnant or breastfeeding, or have a positive serum pregnancy test during the  screening period (for female subjects of childbearing potential).  -  Have a known psychiatric or substance abuse disorder that would interfere with the  participant's ability to cooperate with the requirements of the study.  -  Any condition, therapy or laboratory abnormality that, in the opinion of the  investigator, might affect the participant's compliance, pose an unwarranted high risk  to the participant, or interfere with the interpretation of the study results.

The aim of this study is to examine the performance of determining the sarcopenia by  anthropometric measurements (mid-upper arm circumference and calf circumference) added to the  SARC-F questionnaire developed as a screening tool for the risk of sarcopenia in the  community-dwelling older adults. The risk of sarcopenia of the individuals over 65 years of  age who applied to the Geriatrics Department of Ege University Medical Faculty Hospital  Internal Diseases Department. was determined by the SARC-F questionnaire, muscle mass was  established by bioelectrical impedance analysis, muscle strength was assessed by handgrip  strength, physical performance was assessed by a 4-meter walking test and presence of  malnutrition was assessed with an MNA-long form. For the diagnosis of sarcopenia; old (EWGSOP  1) and revised (EWGSOP 2) diagnostic criteria of Sarcopenia Study Group in Elderly  Individuals of the European Union Geriatric Medicine Association were used. New parameters  were obtained by adding calf circumference (SARC-CC) and mid-upper arm circumference  (SARC-MUAC) measurements were added separately and together (SARC-CC-MUAC) to the SARC-F. For  the calf circumference cut-off points of <31 cm and <33 cm and for the mid-upper arm  circumference cut-off points of <25 cm and <31 cm were used for the sensitivity and  specificity analyses. The population of the research is individuals aged 65 and over who applied to Ege University  Medical Faculty Hospital Internal Diseases Department, Geriatrics BD Outpatient Clinic. For  statistical power analysis; When α=0.05 and the power of the study are 0.80, the minimum  number of samples required for the study was determined as 190. The relevant sample size was  calculated with the G-Power 3.0.8 package program.  Data collection tools:  1. General information collection form: Investigator collect data about age, gender,  chronic diseases, economic status, etc of participants  2. Measurement of Muscle Mass, Muscle Strength, and Gait Speed Body composition analysis  was determined by electrical bioimpedance using the Tanita MC-780 multi-frequency  segmental Body Composition Analyzer (Tanita Corporation, Tokyo). The appendicular  skeletal muscle mass (ASM) was calculated with the Janssen equation for EWGSOP criteria  and Sergi equation for EWGSOP 2 criteria. The appendicular muscle mass index (ASMI) was  calculated based on the equation: ASM(kg) /height (m2).  Muscle strength (kg) was assessed with the Takei Grip Strength Dynamometer®. Handgrip  strength (HS) measurements were made with the subjects in a sitting position, with the  elbow and wrist in full extension, three times with an interval of five seconds on both  hands, and the highest value among the measurement results was used for analysis.  Gender-specific cut-offs were used to define low muscle strength (30 and 20 kg in males  and females) for EWGSOP criteria, and (27 and 16 kg in males and females) for EWGSOP 2  criteria. Usual gait speed (m/s) was performed by the subjects walking 4 m with usual  speed and ≤0.8 m/s was defined as low walking speed.  3. Anthropometric measurement:  In all participants, height was measured using a stadiometer to the nearest 0.1 cm,  weight was measured unclothed to the nearest 0.1 kg using a calibrated balance scale.  Body mass index (BMI) was calculated by the weight (kg)/height (m2) equation.  The calf circumference (CC) of participants was measured with an inflexible tape  measure, in the sitting position, with the knee flexed to 90º, and the circumference of  the widest part of the calf. Both the standard CC cut-off (<31 cm) and  population-specific cut-off (<33 cm) were used and compared in SARC-CalF analysis. Mid  upper arm circumference (MUAC) was measured in a stand position, the mid-point of the  participant's left upper arm- located between the acromion and olecranon- was marked  when the elbow bent to a 90o angle and measured with the inflexible tape around the  marked midpoint with the participant's arm hung down naturally.  4. Screening of sarcopenia risk and assessment of sarcopenia SARC-F, SARC-CalF, and  SARC-MUAC were used for screening sarcopenia risk. For the SARC-F total score of ≥4,  SARC-CalF ≥11, and SARC-MUAC≥11 were defined as positive sarcopenia risk. Investigator  used EWGSOP and EWGSOP 2 criteria for sarcopenia diagnosis.  5. Statistic analysis: SPSS 25.0 (SPSS Statistics; IBM, Armonk, NY) and MedCalc Statistical  Software 19.1.6-free trial (MedCalc Software, Ostend, Belgium) statistical package  programs were used for statistical analysis. The level of significance was defined as  p<0.05.  For categorical variables, the data were presented as numbers (percentage). Continuous  variables with normal or skewed distribution were presented as mean (standard deviation) or  median (interquartile range), respectively. Group differences were investigated using the  t-test for normally distributed data and the Mann-Whitney test for skewed data and the X2 or  Fisher's exact test for categorical data was used. Using EWGSOP and EWGSOP 2 criteria as the  reference standard, the investigator calculated the diagnostic value of the SARC-F,  SARC-CalF- 31, and SARC-CalF-33 [sensitivity, specificity, positive predictive value (PPV),  negative predictive value (NPV), and accuracy] for identifying sarcopenia. A receiver  operating characteristics (ROC) curve was used to compare the overall accuracy of SARC-F,  SARC-CalF-31, and SARC-CalF-33. The area under the ROC curve (AUC) and 95% confidence  interval (CI) were calculated.  The exclusion criteria are as follows: an implanted pacemaker, severe mental illness, unable  to walk, severe heart failure, severe renal failure, clinically visible edema, and unable to  communicate.  Participants in which all the evaluations in the research protocol were carried out and  answered all the questions. Inclusion Criteria:  participants who applied to the geriatrics outpatient clinic for any reason Exclusion Criteria:  Participants with an implanted pacemaker, severe mental illness, unable to walk, severe  heart failure, severe renal failure, clinically visible edema, and unable to communicate.

This is an interventional, multicenter, 2-arm, parallel-group, randomized, double-blind,  placebo controlled, dose-escalation, safety and efficacy study of F-652 treatment versus  placebo in patients aged 18 years or older with a COVID-19 diagnosis confirmed by PCR.  Eligible patients will have moderate to severe COVID-19 symptoms within 5 days post  hospitalization and a positive COVID-19 testing. The study is planned to include 4 cohorts, with enrolled patients being randomized 1:1 in a  blinded manner on Day 1, following screening, to F-652 or placebo as follows:  -  Cohort 1 (sentinel cohort): Four patients will receive either dose level 1 F-652 or  placebo. Upon completion of sentinel, the Data Monitoring Committee will evaluate the  safety and tolerability data of the sentinel patients and determine if it is acceptable  to dose the remaining patients in this dosing group in Cohort 2.  -  Cohort 2: Fourteen patients will receive either dose level 1 F-652 or placebo. Upon  completion of Cohort 2, the DMC will convene and review all available safety data to  determine if the study can proceed to the next dose level.  -  Cohort 3 (sentinel cohort): Four patients will receive either dose level 2 F-652 or  placebo. Upon completion of sentinel dosing, the DMC will evaluate the safety and  tolerability data of the sentinel patients and determine if it is acceptable to dose the  remaining patients in this dosing group in Cohort 4.  -  Cohort 4: Sixteen patients will receive either dose level 2 F-652 or placebo. Treatment  will begin on Day 1 following randomization. Patients assigned to active drug will  receive a total of 2 doses of F-652 (1 IV infusion on Day 1 and 1 IV infusion on Day 8).  Patients assigned to placebo will receive identical IV infusions of placebo vehicle on  Days 1 and 8. All patients will receive available supportive and antiviral therapies as  standard of care. Efficacy will be assessed on Days 15 and 29. Patients will be followed  for safety until Day 60.  The primary efficacy endpoint is the proportion of patients with a ≥2-point increase in the  National Institute of Allergy and Infectious Diseases (NIAID) 8-point ordinal scale from  baseline to Day 29.  The secondary efficacy endpoints include the proportion of patients with a ≥2-point increase  in the NIAID 8-point ordinal scale from baseline to Day 15, mortality rate by Days 15 and 29,  percentage of patients who have recovered and discharged from the hospital by Days 15 and 29,  and percentage of patients progressed to severe/critical disease by Day 15.  The safety endpoints include all cause treatment-emergent adverse events (TEAEs) and serious  adverse events (SAEs); change from screening (baseline) in clinical symptoms and abnormal  vital signs, abnormal laboratory tests; and relationship of any AEs with F-652 treatment.  The exploratory endpoints include time to negative SARS-CoV-2 PCR test from randomization;  and changes in pharmacodynamic parameters. Inclusion Criteria:  -  Willing to provide informed consent and able to comply with protocol requirements  -  18 years or older  -  Has a COVID-19 diagnosis confirmed by PCR  -  Hospitalized within 5 days and meets the following criteria at screening:  Peripheral capillary oxygen saturation (SpO2) ≤ 93% on room air or SpO2 ≥93% on ≤10 liters  per minute of supplemental oxygen via nasal cannula  -  Radiographic (chest X-ray, computed tomography scan, or ultrasound) evidence of  bilateral pulmonary infiltrates consistent with SARS-CoV-2/COVID-19  -  Clinical symptoms consistent with COVID-19 per Investigator judgement  -  Body mass index between 18 to 40 kg/m2  -  If of reproductive potential, willing to abstain or agree to the use of highly  effective contraception Exclusion Criteria:  -  Respiratory failure at screening  -  History of heart failure  -  History of COPD or bronchial asthma  -  Active TB or history of TB of the following types  -  Uncontrolled arrhythmia within 3 months prior to randomization  -  Heart disease of the following types  -  Moderate to severe renal insufficiency  -  Abnormal white cell and platelet counts  -  History of transplantation of vital organs (e.g., heart, lung, liver, and/or kidney);  -  Malignant tumor  -  Uncontrolled systemic or local autoimmune or inflammatory disease besides SARS-CoV-2  -  Unhealed wounds, active gastric ulcer, had surgery  -  Received other investigational therapeutic products  -  Used interferon therapies  -  History of HIV infection, hepatitis B, and/or hepatitis C  -  Known serious allergic reaction or hypersensitivity to components of F-652  -  Pregnant or breastfeeding  -  History of drug abuse or use of narcotics  -  Treated with immunomodulators or immunosuppressants  -  Other conditions resulting in increased risk

The primary objective of this study is to evaluate whether the management of colorectal  cancer (CRC) patients with 5-fluorouracil (5-FU) exposure optimization testing reduces 5-FU  related toxicities and improves outcomes compared to the current standard of care. A  secondary objective is to characterize the variability of 5-FU levels among CRC patients  managed with 5-FU exposure optimization testing and the impact of such management on 5-FU  plasma levels and drug doses during the course of chemotherapy. This is a multi-center retrospective matched cohort study of early and late stage CRC  patients who received 5-FU doses determined using body surface area (BSA) and in patients who  underwent pharmacokinetically (PK)-guided 5-FU dose monitoring and adjustment. A  retrospective chart / electronic medical record review of colorectal cancer patients treated  with infusional 5-FU regimens between May 1, 2009 and December 31, 2013, satisfying the  inclusion/exclusion criteria, will be performed. In this multi-center study, patients who  underwent PK-testing during at least two different 5-FU administrations will be matched to  patients who received doses based on their BSA, treated at the same institution. Matching for  selection of the BSA cohort at each site will be done using the following criteria (based on  factors that may influence 5-FU metabolism): age, gender, disease stage, prior chemotherapy  treatment, and 5-FU containing treatment regimen being used. Each patient will be assigned a  random five-digit Study ID number to protect patient confidentiality. Minimal medical  history/demographics data will be collected from the patient's medical records / clinic chart  using paper case report forms (CRFs). The data to be collected from each patient's records  will include: patient demographics (i.e. gender, age, height, and race), colorectal cancer  diagnosis (i.e. date of primary diagnosis, tumor stage, grade, histology and phenotype, and  date of metastatic diagnosis and sites of metastases if applicable), use of prior therapies  for treatment of CRC, 5-FU containing regimen details throughout the 5-FU treatment (i.e.  weight, BSA, ECOG status, doses of each drug used in the regimen, and 5-FU infusion  start/stop dates and times), 5-FU PK testing results (if applicable), concomitant procedures  and medications, CBC and chemistry testing results, adverse events experienced during 5-FU  therapy regimen, and tumor response and follow-up information. Patients will not be contacted  for the purposes of this study and a waiver of HIPAA authorization will be requested from the  appropriate IRB. Once data has been collected and monitored, all records tying the random  Study ID number to a specific patient at the sites will be destroyed, rendering all  information de-identified. Inclusion Criteria:  -  Male or female patients 18 years of age or older.  -  Patients with histologically confirmed colorectal cancer who were treated with an  infusional 5-FU regimen between May 1, 2009 and December 31, 2013.  -  PK-Guided Cohort: Patients monitored with 5-FU PK-testing at a minimum of two  administrations of 5-FU throughout the course of a single infusional 5-FU containing  treatment regimen.  -  BSA Cohort: Patients who received infusional 5-FU doses calculated based on their BSA. Exclusion Criteria:  -  Patients less than 18 years of age.  -  Patients with concurrent treatment of other active malignancies.  -  Patients that underwent radiation therapy concurrently with chemotherapy.

The effect of therapeutic touch applied to hemodialysis patients on the level of loneliness  and hopelessness is being investigated. It encourages nurses to practice therapeutic touch. Chronic diseases are a challenging process that affects human life physiologically and  psychologically. Chronic Renal Failure, which shows a significant increase in the world and  in our country, also affects human life in every aspect. Hemodialysis treatment is used with  a high rate in the treatment of patients diagnosed with End Stage Renal Failure.  Hemodialysis patients experience loneliness and hopelessness during their difficult and  compulsory treatmet. Fear of being alone is an important problem affecting the patient's  compliance with treatment. In addition, the other problem these patients experience is  hopelessness. Hopelessness is an important factor that affects the patient's expectations for  the future and the process of solving problems.  Therapeutic touch is a complementary and alternative treatment method. It is stated that this  treatment method, which is successfully used by nurses, is good for loneliness and  hopelessness. This method, which will be used on hemodialysis patients, is aimed to get away  from the problems of loneliness and hopelessness.  In this study, two scales will be used to measure the loneliness and hopelessness levels of  hemodialysis patients. Patients will fill in UCLA Loneliness Scale and BECK Hopelessness  Scale.  Nurses should not ignore the problems of loneliness and hopelessness in hemodialysis  patients. Therapeutic touch treatment method wil lprovide nurses the holistic caregiver role  for the feelings of loneliness and hopelessness experienced by the patients. When the  literature is scanned, this study is unique because it has not been done before on  hemodialysis patients. Inclusion Criteria:  -  Having hemodialysis treatment for at least 3 months,  -  Cognitive patients,  -  Having a score of UCLA> 20 and BECK≥4 scoring,  -  Involved in the work with us. Exclusion Criteria:  • Patients using traditional treatment for the disease were not included in the study.

This intervention pilot feasibility study will assess the impact of auricular acupressure as  an additional non-pharmacologic therapy for infants at risk for developing Iatrogenic  Withdrawal Syndrome (IWS) in the Pediatric Cardiac Intensive Care Unit (PCICU) of Monroe  Carrell Jr Children's Hospital at Vanderbilt (MCJCHV). The investigators will recruit 40  healthy, 34 weeks gestational age or older infants exposed to prolonged medications (greater  than 5 days) for cardiac procedures that may cause withdrawal upon cessation such as opioids,  benzodiazepines, or other sedative medications. Participants will receive the auricular  acupressure in addition to the standard of care such as clustered nursing care, touch,  position change, environmental controls, holding, and swaddling. This intervention pilot feasibility study will assess the impact of auricular acupressure as  an additional non-pharmacologic therapy for infants at risk for developing Iatrogenic  Withdrawal Syndrome (IWS) in the Pediatric Cardiac Intensive Care Unit (PCICU) of Monroe  Carrell Jr Children's Hospital at Vanderbilt (MCJCHV). The investigators will recruit 40  healthy, 34 weeks gestational age or older infants exposed to prolonged medications (greater  than 5 days) for cardiac procedures that may cause withdrawal upon cessation such as opioids,  benzodiazepines, or other sedative medications. Participants will receive the auricular  acupressure in addition to the standard of care such as clustered nursing care, touch,  position change, environmental controls, holding, and swaddling. Within 24 hours of  implementing a weaning protocol, acupressure will be applied to three designated points of  one ear following the NADA protocol acupuncture technique while also incorporating the  Near-Term Infant (NTI) conceptual framework identified elements (see figure 3). Acupressure  will be administered via stickers that are adhesive to the skin like a Band-Aid (see figure  1). These stickers include a vaccaria plant seed in the center that applies continuous light  pressure on the designated points. This form of acupressure was selected as it is organic and  does not contain metal which may interfere with emergency medical care such as imaging. After  the initial 24 hours of application, stickers will be removed, the infant's skin will be  assessed for any disruption such as bruising or discoloration, and the stickers will be  rotated to the infant's other ear at the same NADA protocol auricular sites. Acupressure  stickers will be removed and applied to the opposite ear every 48 hours until withdrawal  symptoms improve (1). Withdrawal symptoms are measured every 6 hours with the enhanced  Withdrawal Assessment tool (WAT) as part of the standard of care. Upon completion of the  weaning regimen, infants with a score of less than or equal to 3 or less than 2 above  baseline with no more than 2 rescue medication doses in 24 hours will have the acupressure  removed. Inclusion Criteria:  -  Infants, 34 weeks or greater gestation  -  Exposure to opioids and/or benzodiazepine medications for 5 days or more  -  Beginning a stable wean  -  Maternal age of 18 or older Exclusion Criteria:  -  Hemodynamic instability  -  Transfer to another facility prior to completion of the weaning regimen  -  Death

Evaluation of a workplace intervention to implement supported wellbeing centres in a  healthcare workplace during and after the COVID-19 pandemic.  Mixed-Methods Evaluation study - including collection of service use monitoring data, online  survey and qualitative interviews. Project Aims:  1. To describe the cost, reach and usage of the Staff Wellbeing Centres  2. To gather insight into experiences of those who access the facility ('service users') as  well as those of support workers ('wellbeing buddies').  3. To identify any facilitators, obstacles or barriers to accessing the facility.  4. To identify perceptions of facility users and non-users towards the value of the  facilities during and after the coronavirus pandemic.  5. To establish recommendations for longer-term sustainability of the wellbeing centres.  Interviews will be conducted with up to 45 interview participants (10-15 Wellbeing Buddies,  25-30 Staff).  Online survey will be conducted - all Nottingham University Hospitals National Health Service  (NHS) staff invited to take part (>14,000).  The survey will include measures of mental wellbeing (Warwick-Edinburgh Wellbeing Scale,  14-item - license received), and single items measures of job stressfulness, job  satisfaction, presenteeism, turnover intentions and work engagement. Inclusion Criteria:  -  National Health Service staff which includes employees, volunteers or healthcare  students, as well as bank staff (all have access to the Staff Wellbeing Centres).  -  Ability to give informed consent. For survey element: Ability to access the internet  (to complete the online survey) For interview element: Ability to attend an individual  interview. Exclusion Criteria: • Inability to communicate in spoken English.