bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the long-term treatment effects of intravenous idursulfase in patients with mucopolysaccharidosis II (MPS II) using statistical modeling: data from the Hunter Outcome Survey (HOS)
Authors: Muenzer Joseph , Botha Jaco , Harmatz Paul , Giugliani Roberto , Kampmann Christoph , Burton Barbara K. 
Published: October 2021

Abstract
Background
Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase can stabilize or improve many somatic manifestations, but there remains a need for further analysis of long-term treatment outcomes. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the effects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The modeling population comprised male patients followed prospectively in HOS who had received IV idursulfase for at least 5 years and who had data available for two or more time points (at least one post-ERT). Age at ERT start and time since ERT start were included as covariates.

Results
In total, 481 patients were eligible for inclusion in at least one model. At 8 years post-ERT start, improvement from baseline was predicted for each age group (< 18 months, 18 months to < 5 years and ≥ 5 years at treatment start) in the following parameters: mean urinary glycosaminoglycan levels (percentage changes of > –75% in each group), mean left ventricular mass index (decreases of ~ 1 g/m2) and mean palpable liver size (decreases of > 2 cm). Improvements in mean 6-min walk test distance (increase of > 50 m) and stabilization in percent predicted forced vital capacity and forced expiratory volume in 1 s (decreases of ~ 4 and ~ 9 percentage points, respectively) at 8 years post-ERT start were predicted for patients aged ≥ 5 years at ERT start (these assessments are unsuitable for patients aged < 5 years). Predicted changes over time were similar across the three age groups; however, overall outcomes were most favorable in children aged < 18 months at ERT start.

Conclusions
These findings suggest that the previously reported positive effects of IV idursulfase on the somatic manifestations of MPS II are predicted to be maintained for at least 8 years following ERT initiation and highlight the value of statistical modeling to predict long-term treatment outcomes in patients with rare diseases.
Development of the Myasthenia Gravis (MG) Symptoms PRO: a case study of a patient-centred outcome measure in rare disease
Authors: Cleanthous Sophie , Mork Ann-Christin , Regnault Antoine , Cano Stefan , Kaminski Henry J. , Morel Thomas 
Published: October 2021

AbstractBackgroundMyasthenia gravis (MG) is a chronic autoimmune neuromuscular disease, characterised by fluctuating muscle weakness which makes it challenging to assess symptom severity. Mixed methods psychometrics (MMP), which combines evidence from qualitative research and modern psychometrics, is a versatile approach to the development of patient-centred outcome measures (PCOM) in the context of rare disease. Our objective was to develop the MG Symptom patient-reported outcome (PRO) to assess key aspects of MG severity from the patient perspective.MethodsWe used MMP to develop a novel PRO instrument in a multi-step process. An initial conceptual model for MG patient experience was developed and expanded based on preliminary literature review and two waves of concept elicitation interviews with people with MG (Step 1). Based on this, the novel PRO instrument, the MG Symptoms PRO, was drafted. The draft instrument was refined by combining qualitative and quantitative data collected in a Phase 2 clinical study (Step 2).ResultsFindings from the literature review and concept elicitation interviews (n = 96) indicated that patient experience in MG includes proximal muscle weakness symptoms related to several body parts, along with muscle weakness fatigability and general fatigue. Then, a set of 42 items across five scales (ocular-, bulbar-, and respiratory muscle weakness, physical fatigue, and muscle weakness fatigability) was developed. Qualitative evidence endorsed its relevance, clarity, and ease of completion; quantitative analysis with Rasch measurement theory methods demonstrated strong measurement properties, including good targeting and high reliability. Classical test theory analyses showed adequate reliability of the instrument and mild to moderate correlations with other widely used MG-specific outcome measures.ConclusionsThe MG Symptoms PRO has potential to be used both to measure treatment benefit in clinical trials and monitor symptom severity in clinical practice. Its component scales were purposefully designed to stand alone, enhancing interpretability of scores given the heterogeneity of MG, and enabling modular use. Compared with existing MG PROs, it contains more detailed assessments of muscle weakness and muscle weakness fatigability symptoms, which are of key importance to people with MG. The MMP approach used may serve as a case study for developing PCOMs across rare disease indications.
Efficacy of rikkosan for primary burning mouth syndrome: a retrospective study
Authors: Hato Hiroyuki , Sakata Ken-ichiro , Sato Jun , Asaka Takuya , Ohga Noritaka , Yamazaki Yutaka , Kitagawa Yoshimasa 
Published: October 2021

Abstract
Background
Burning mouth syndrome (BMS) is a chronic condition characterized by pain in the oral cavity. Kampo medicine is a traditional Japanese medical system that has its roots partly in ancient Chinese medicine. The purpose of this study is to evaluate the efficacy of rikkosan—a traditional Japanese herbal medicine (Kampo)—in the treatment of primary BMS.

Main body
A single-center retrospective study was conducted in 32 patients who were diagnosed with primary BMS and treated with rikkosan alone through gargling (2.5 g rikkosan dissolved in 50 mL hot water) three times daily. Patients were asked to evaluate their pain using a numerical rating scale (NRS) at first visit and after 1 month. One patient had stomatitis as a side effect after gargling with rikkosan, however, no side effects were observed in other patients. Overall NRS scores decreased significantly between the first visit (7.6 ± 2.7) and the 1-month visit (5.6 ± 2.8).

Conclusions
Rikkosan may be an effective treatment for primary BMS.
Targeting CD47 for cancer immunotherapy
Authors: Jiang Zhongxing , Sun Hao , Yu Jifeng , Tian Wenzhi , Song Yongping 
Published: October 2021

AbstractMuch progress has been made in targeting CD47 for cancer immunotherapy in solid tumors (ST) and hematological malignancies. We summarized the CD47-related clinical research and analyzed the research trend both in the USA and in China. As of August 28, 2021, there are a total 23 related therapeutic agents with 46 clinical trials in the NCT registry platform. Among these trials, 29 are in ST, 14 in hematological malignancies and 3 in both solid tumor and hematological malignancy. The ST include gastric cancer, head and neck squamous cell carcinoma and leiomyosarcoma, while the hematological malignancies include non-Hodgkin's lymphoma, acute myeloid leukemia, myelodysplastic syndrome, multiple myeloma and chronic myeloid leukemia. Majority of the CD47-related clinical trials are at the early phases, such as 31 at phase I, 14 at phase II and 1 at phase III in the USA and 9, 6, 1, in China, respectively. The targets and spectrums of mechanism of action include 26 with mono-specific and 20 with bi-specific targets in the USA and 13 with mono-specific and 3 with bi-specific targets in China. The new generation CD47 antibodies have demonstrated promising results, and it is highly hopeful that some candidate agents will emerge and make into clinical application to meet the urgent needs of patients.
High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer
Authors: Böttger Franziska , Vallés-Martí Andrea , Cahn Loraine , Jimenez Connie R. 
Published: October 2021

AbstractMounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC). Early phase clinical trials have confirmed safety and indicated efficacy of IVC in eradicating tumour cells of various cancer types. In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and boosting immune response. Moreover, high-dose IVC is powerful as an adjuvant treatment for cancer, acting synergistically with many standard (chemo-) therapies, as well as a method for mitigating the toxic side-effects of chemotherapy. Despite the rationale and ample evidence, strong clinical data and phase III studies are lacking. Therefore, there is a need for more extensive awareness of the use of this highly promising, non-toxic cancer treatment in the clinical setting. In this review, we provide an elaborate overview of pre-clinical and clinical studies using high-dose IVC as anti-cancer agent, as well as a detailed evaluation of the main known molecular mechanisms involved. A special focus is put on global molecular profiling studies in this respect. In addition, an outlook on future implications of high-dose vitamin C in cancer treatment is presented and recommendations for further research are discussed.
An overview of FSH-FSHR biology and explaining the existing conundrums
Authors: Bhartiya Deepa , Patel Hiren 
Published: October 2021

AbstractFSH was first identified in 1930 and is central to mammalian reproduction. It is indeed intriguing that despite being researched upon for about 90 years, there is still so much more to learn about FSH-FSHR biology. The purpose of this review is to provide an overview of current understanding of FSH-FSHR biology, to review published data on biological and clinical relevance of reported mutations, polymorphisms and alternately spliced isoforms of FSHR. Tissue-resident stem/progenitor cells in multiple adult tissues including ovaries, testes and uterus express FSHR and this observation results in a paradigm shift in the field. The results suggest a direct action of FSH on the stem cells in addition to their well-studied action on Granulosa and Sertoli cells in the ovaries and testes respectively. Present review further addresses various concerns raised in recent times by the scientific community regarding extragonadal expression of FSHR, especially in cancers affecting multiple organs. Similar population of primitive and pluripotent tissue-resident stem cells expressing FSHR exist in multiple adult tissues including bone marrow and reproductive tissues and help maintain homeostasis throughout life. Any dysfunction of these stem cells results in various pathologies and they also most likely get transformed into cancer stem cells and initiate cancer. This explains why multiple solid as well as liquid tumors express OCT-4 and FSHR. More research efforts need to be focused on alternately spliced FSHR isoforms.
Endogenous, tissue-resident stem/progenitor cells in gonads and bone marrow express FSHR and respond to FSH via FSHR-3
Authors: Bhartiya Deepa , Patel Hiren , Kaushik Ankita , Singh Pushpa , Sharma Diksha 
Published: October 2021

AbstractFollicle stimulating hormone (FSH) is secreted by the anterior pituitary and acts on the germ cells indirectly through Granulosa cells in ovaries and Sertoli cells in the testes. Extragonadal action of FSH has been reported but is still debated. Adult tissues harbor two populations of stem cells including a reserve population of primitive, small-sized, pluripotent very small embryonic-like stem cells (VSELs) and slightly bigger, tissue-specific progenitors which include ovarian stem cells (OSCs) in ovaries, spermatogonial stem cells (SSCs) in testes, endometrial stem cells (EnSCs) in uterus and hematopoietic stem cells (HSCs) in the bone marrow. Data has accumulated in animal models showing FSHR expression on both VSELs and progenitors in ovaries, testes, uterus and bone marrow and eventually gets lost as the cells differentiate further. FSH exerts a direct action on the stem/progenitor cells via alternatively spliced FSHR-3 rather than the canonical FSHR-1. FSH stimulates VSELs to undergo asymmetrical cell divisions to self-renew and give rise to the progenitors that in turn undergo symmetrical cell divisions and clonal expansions followed by differentiation into specific cell types. Excessive self-renewal of VSELs results in cancer and this explains ubiquitous expression of embryonic markers including nuclear OCT-4 along with FSHR in cancerous tissues. Focus of this review is to compile published data to support this concept. FSHR expression in stem/progenitor cells was confirmed by immuno-fluorescence, Western blotting, in situ hybridization and by quantitative RT-PCR. Two different commercially available antibodies (Abcam, Santacruz) were used to confirm specificity of FSHR expression along with omission of primary antibody and pre-incubation of antibody with immunizing peptide as negative controls. Western blotting allowed detection of alternatively spliced FSHR isoforms. Oligoprobes and primers specific for Fshr-1 and Fshr-3 were used to study these alternately-sliced isoforms by in situ hybridization and their differential expression upon FSH treatment by qRT-PCR. To conclude, stem/progenitor cells in adult tissues express FSHR and directly respond to FSH via FSHR-3.These findings change the field of FSH-FSHR biology, call for paradigm shift, explain FSHR expression on cancer cells in multiple organsand provide straightforward explanations for various existing conundrums including extragonadal expression of FSHR.
Minimum acceptable diet and associated factors among children aged 6–23 months in Ethiopia
Authors: Abebe Haimanot , Gashu Molla , Kebede Aynalem , Abata Habtemariam , Yeshaneh Alex , Workye Haile , Adane Daniel 
Published: October 2021

Abstract
Introduction
The health and growth of children less than two years of age can be affected by the poor quality of complementary foods and poor feeding practices even with optimal breastfeeding. In Ethiopia, empirical evidence on the minimum acceptable diet and its associated factors is limited. Therefore, this study was aimed to assess the level of minimum acceptable diet and its associated factors among children aged 6–23 months in Addis Ababa Ethiopia.

Methods
An institution-based Cross-sectional study was conducted among a total of 575 mother-child pairs. A simple random sampling technique was used to recruit participants. For infant and young child feeding practices, the data collection tools were adapted from world health organizations’ standardized questionnaire which is developed in 2007. Data entry and analysis were performed using EPI data version 3.1 and SPSS version 20 respectively. Bivariable and multivariable logistic regression analyses were performed to determine predictor variables. Statistical significance was declared at p-value < 0.05.

Result
In this study, the level of minimum acceptable diet was found to be 74.6%.. About 90.6 and 80.2% of the children received minimum meal frequency and dietary diversity respectively. Having a husband secondary and above educational level [AOR = 4.789(95%CI:1.917–11.967)], being a housewife [AOR = 0.351(95% CI: 0.150–0.819)], having a history of more than three postnatal follow-ups [AOR = 2.616(95%CI:1.120–6.111], Having mothers age between 25 and 34 years [AOR = 2.051(95%CI:1.267–3.320)], being male child [AOR = 1.585(95%CI:1.052–2.388)] and having children age between 18 and 23 months [AOR = 3.026(95%CI:1.786–5.128)] were some of the factors significantly associated with a minimum acceptable diet.

Conclusion
In this study, the minimum acceptable diet among children aged 6–23 months was significantly associated with the educational status of the husband, mother’s occupation, history of postnatal follow-up, age of the mother, sex of the child, and age of the child. Thus, attention should be given to educating the father, empowering mothers to have a job, promoting gender equality of feeding, and counseling on the benefit of postnatal care visits. In addition, the ministry of health should work on educating and advocating the benefit of feeding the recommended minimum acceptable diet to break the intergenerational cycle of malnutrition.
Video Intervention Therapy for primary caregivers in a child psychiatry unit: a randomized feasibility trial
Authors: Leyton Fanny , Olhaberry Marcia , Morán Javier , De la Cerda Cecilia , León María José , Sieverson Catalina , Alfaro Ángela , Hernández Camila , Alvardo Rubén , Steele Howard 
Published: October 2021

AbstractBackgroundDuring child psychiatry hospitalization, working with the families or attachment figures is a challenge, most of the children who are admitted to these units come from multi-problem families, with limited research in this area. Video feedback (VF) interventions have proved to be a powerful resource to promote parental and child well-being in small children and has been used with parents with a psychiatric condition. Parental Reflective Functioning (PRF) is one of the parental abilities that can be improved with VF and could be especially important in coping with conflict and negative emotions in older children. The aim of this study is to implement Video Intervention Therapy (VIT) to enhance PRF in primary caregivers of inpatient psychiatric children. As there is no published research using VF with parents of children with severe psychopathology in a hospitalized context. This report, then, becomes a much needed pilot study providing evidence for a larger randomized control trial (RCT).MethodsThe study is a single-center, two-arm feasibility randomized control trial with a qualitative component. Block randomization was done to generate a 2:1 allocation, leaving more participants in the intervention group. The intervention comprises four modules; every module has both one video-recorded play session and one VIT session (in a group setting) per week. Evaluation of the caregivers included assessments of PRF and well-being, and child assessment included parent-ratings and clinician-ratings of symptomatology and general functioning.ResultsThirty participants were randomized; eligibility and recruitment rate were 70.6% and 83.3%, respectively. The compliance-to-intervention rate was 85% in the VIT group and 90% in the control group. All participants completed entry evaluation and 90% at the 3-month follow-up. The intervention was acceptable to participants and feasible for therapists to deliver. Outcome data must be treated with caution due to the small numbers involved, yet indicate that the VIT may have a positive effect in improving parental and child mental health outcomes.ConclusionsVIT for primary caregivers of child inpatient children was feasible to deliver and acceptable for participants, therapist, and the staff unit involved; there is sufficient evidence to undertake a full-scale effectiveness RCT.Trial registrationClinicalTrials.govNCT03374904. Registered on 14 December 2017
Bridging Recovery Initiative Despite Gaps in Entry (BRIDGE): study protocol for a randomized controlled trial of a bridge clinic compared with usual care for patients with opioid use disorder
Authors: Marcovitz David E. , White Katie D. , Sullivan William , Limper Heather M. , Dear Mary Lynn , Buie Reagan , Edwards David A. , Chastain Cody , Kast Kristopher A. , Lindsell Christopher J. ,   Vanderbilt Learning Health System Investigators
Published: October 2021

Abstract
Background
Patients with substance use disorders are overrepresented among general hospital inpatients, and their admissions are associated with longer lengths of stay and increased readmission rates. Amid the national opioid crisis, increased attention has been given to the integration of addiction with routine medical care in order to better engage such patients and minimize fragmentation of care. General hospital addiction consultation services and transitional, hospital-based “bridge” clinics have emerged as potential solutions. We designed the Bridging Recovery Initiative Despite Gaps in Entry (BRIDGE) trial to determine if these clinics are superior to usual care for these patients.

Methods
This single-center, pragmatic, randomized controlled clinical trial is enrolling hospitalized patients with opioid use disorder (OUD) who are initiating medication for OUD (MOUD) in consultation with the addiction consult service. Patients are randomized for referral to a co-located, transitional, multidisciplinary bridge clinic or to usual care, with the assignment probability being determined by clinic capacity. The primary endpoint is hospital length of stay. Secondary endpoints include quality of life, linkage to care, self-reported buprenorphine or naltrexone fills, rate of known recurrent opioid use, readmission rates, and costs. Implementation endpoints include willingness to be referred to the bridge clinic, attendance rates among those referred, and reasons why patients were not eligible for referral. The main analysis will use an intent-to-treat approach with full covariate adjustment.

Discussion
This ongoing pragmatic trial will provide evidence on the effectiveness of proactive linkage to a bridge clinic intervention for hospitalized patients with OUD initiating evidence-based pharmacotherapy in consultation with the addiction consult service.

Trial registration
ClinicalTrials.govNCT04084392. Registered on 10 September 2019. The study has been approved by the Vanderbilt Institutional Review Board. The current approved protocol is dated version May 12, 2021.
A randomised controlled multicentre investigator-blinded clinical trial comparing efficacy and safety of surgery versus complex physical decongestive therapy for lipedema (LIPLEG)
Authors: Podda Maurizio , Kovacs Maximilian , Hellmich Martin , Roth Rebecca , Zarrouk Marouan , Kraus Daria , Prinz-Langenohl Reinhild , Cornely Oliver A. 
Published: October 2021

Abstract
Background
Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT.

Methods/design
LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0–10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction.
The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher’s exact test in a hierarchical test strategy.

Discussion
LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema.

Trial registration
ClinicalTrials.gov NCT04272827. Registered on February 14, 2020.

Trial status
Protocol version is 02_0, December 17, 2019