bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Treatment of Subjective BPPV in the Medically Complex Geriatric Patient
Authors: Stam Daniel , Pernu Jenna
Published: January 2020

Background and Purpose:

Peripheral vestibular disorders such as benign paroxysmal positional vertigo (BPPV) are a common, yet costly health care burden. In the older adult population, BPPV may go undiagnosed and contribute to a poorer quality of life and increased risk for falls and secondary injury. The presence of both acute and chronic medical complexities increases the challenge clinicians face in examination and evaluation. The purpose of this article is to present a case report of the treatment of subjective BPPV in an older adult with acute contraindications to traditional intervention techniques.

Case Description:

A geriatric patient presented to acute inpatient rehabilitation with multiple comorbidities and orthopedic restrictions after falling down a flight of stairs. The patient described vertiginous symptoms consistent with BPPV.

Intervention and Outcome:

In absence of objective nystagmus, the diagnosis of subjective BPPV was established and the patient was treated using a novel intervention method to accommodate orthopedic restrictions. Positional symptoms were absent during remaining hospital stay and at a 1-week phone follow-up.

Discussion:

In acute settings of practice, therapists are frequently presented with many restrictive factors preventing conventional performance of BPPV diagnosis and treatment. With increased knowledge regarding modification factors, new techniques can be developed to improve clinical outcomes.
Electrocochleography During Translabyrinthine Approach for Vestibular Schwannoma Removal
Authors: Riggs William J. , Fitzpatrick Douglas C. , Mattingly Jameson K. , Harris Michael S. , Hiss Meghan M. , Rajkumar Shashank , Zhan Kevin Y. , Brown Kevin D. , Moberly Aaron C. , Dodson Edward E. , Adunka Oliver F.
Published: January 2020

Hypothesis:

Intraoperative electrocochleography (ECochG) can differentiate hair cell and neural dysfunction caused by a vestibular schwannoma (VS) and help define the site of lesion as peripheral or central to the spiral ganglion.

Background:

Hearing loss in patients with a VS can be caused by both sensory (cochlear) and neural dysfunction.

Methods:

Round-window ECochG using low and high-frequency tone bursts was performed in 49 subjects with a VS. Responses were analyzed for magnitude, spectrum, and shape of the time waveform. Components examined included the cochlear microphonic, auditory nerve neurophonic, compound action potential (CAP), and summating potential (SP).

Results:

Variability in the summed response magnitudes across frequency, or “total response” (ECochG-TR), varied from 0.1 to 100 μV. Responses were larger for lower frequencies. Subjective estimates revealed a wide range of neural contributions from the auditory nerve neurophonic to low frequencies and the CAP to high frequencies. Cases with larger CAPs had smaller SPs. The correlation of ECochG-TR, with word recognition score (WRS), was moderate (r = 0.67), as well as the correlation between pure-tone averages and ECochG (r = 0.63). The cochlea remained functional in two cases of sudden sensorineural hearing loss with 0% WRS.

Conclusion:

Reduced ECochG-TR and neural activity in many cases indicates both sensory and neural deficits. Smaller SPs when CAPs are present indicate a neural contribution to the SP. Good cochlear function with 0% WRS, and cases of sudden sensorineural hearing loss with retained cochlear function, indicate retrocochlear effects, typically proximal to the spiral ganglion cells.
Rare benign and malignant testicular lesions: histopathology and management
Authors: Kern Sean Q. , Speir Ryan W. , Akgul Mahmut , Cary Clint
Published: January 2020

Purpose of review

The presence of vascular solid tumors within the testicle is considered to be malignant until proven otherwise. However, it is prudent for clinicians to be aware of rare benign and malignant intratesticular lesions as management can differ from the established treatment algorithms for germ-cell tumors.

Recent findings

Utilizing certain histopathologic findings can assist with the diagnosis of rare testis tumors. Often times the tumor subtypes are an important consideration in the grading and classification of the disease, which drives management. The multidisciplinary management of rare malignant testis tumors at an experienced center seems to provide optimal patient outcomes. Regardless of the primary treatment, prolonged follow-up for sex cord stromal tumors and other rare testis malignancies is advocated due to the delayed metastatic potential.

The clinical presentation of rare benign and malignant testis tumors is often similar to that of germ-cell tumors. Likewise, imaging characteristics are also often indistinguishable. However, the management of these rare tumors is often different from the well established treatment algorithms of germ-cell tumors. To that end, it is important for the practicing urologist to be familiar with the current principles of these tumor characteristics and the management.
A Multiregion Analysis of Shale Drilling Activity and Rates of Sexually Transmitted Infections in the United States
Authors: Johnson Nicholaus P. , Warren Joshua L. , Elliott Elise G. , Niccolai Linda M. , Deziel Nicole C.
Published: January 2020

Background

Fossil fuel extraction from deep shale rock formations using new drilling technologies such as hydraulic fracturing has rapidly increased in the Unites States over the past decade. Increases in nonlocal, specialized workers to meet the demands of this complex industry have been suggested to influence the rates of sexually transmitted infections (STIs) in counties with shale drilling activity; these associations may vary geographically. In this multiregion analysis, we examine the associations between shale drilling activity and rates of 3 reportable STIs in Colorado, North Dakota, and Texas, states with active shale drilling.

Methods

We obtained annual reported rates of chlamydia, gonorrhea, and syphilis from the Centers for Disease Control and Prevention, number of active shale wells from Enverus (formerly known as DrillingInfo), and sociodemographic covariates from the US Census Bureau. We used multivariable mixed-effects Poisson regression modeling to estimate rate ratios (RR) with 95% confidence intervals (CIs) adjusted for potential confounders and secular trends.

Results

In Texas, county-years with high drilling activity had 10% increased rates of chlamydia (RR, 1.10; 95% CI, 1.04–1.17) and 15% increased rates of gonorrhea (RR, 1.15; 95% CI, 1.04–1.28), compared with county-years with no drilling. No statistically significant associations were reported for syphilis or for any STIs in Colorado or North Dakota.

Conclusions

Associations between shale drilling and chlamydia and gonorrhea in Texas may reflect increased risk in areas with higher drilling activity and a greater number of major metropolitan areas. Interstate differences highlight the need for local epidemiology to prioritize community health policies.
Drug cost savings resulting from the outpatient pharmacy services collaborating with oncologists at outpatient clinics
Authors: Kamata Hayato , Suzuki Shinya , Demachi Ken , Suzuki Hidetaka , Sugama Yuka , Ikegawa Kiwako , Igarashi Takashi , Yamaguchi Masakazu , Okudera Hiroshi , Tahara Makoto , Kawasaki Toshikatsu
Published: January 2020

Objectives:

Impact of outpatient collaborative pharmacy services performed by pharmacists on drug costs has not yet been reported. Therefore, this study evaluated direct interventions made by pharmacists in the form of prescription proposals that resulted in drug cost savings from outpatient collaborative pharmacy services performed by pharmacists to support outpatient cancer chemotherapy.

Methods:

This was a retrospective cohort study wherein the drug cost savings resulting from the outpatient collaborative pharmacy services performed by 6 pharmacists and physicians from 6 medical departments were calculated and investigated from June 2016 to November 2016. Drug costs as of August 31, 2016 were used to calculate the drug cost savings.

Results:

During the 6-month study period, 6 pharmacists performed outpatient collaborative pharmacy services on weekdays within a span of 120 days for a total of 2177 hours each. The total drug cost savings were ¥6984,637, including ¥5842,061 for anticancer drugs, ¥1086,484 for oral drugs other than anticancer, ¥39,388 for premedications, and ¥16,704 for drugs for abuse. The total cost of the added drugs was ¥3224,227, allocated as follows: nonanticancer medicines, ¥1441,317; supportive medicines for adverse drug reactions in chemotherapy, ¥359,127; premedications for chemotherapy, ¥307,961; and anticancer medicines, ¥1115,822.

Conclusion:

The results of the present study are limited to “pharmacists assisting in reducing drugs by adjusting expensive anticancer drugs through a collaborative effort with physicians via outpatient consultations”; however, it indicated a significant overall health economic effect.
Increased Retention in Care After a Palliative Care Referral Among People Living With HIV
Authors: Gilliams Elizabeth A. , Ammirati Rachel J. , Nguyen Minh L.T. , Shahane Amit A. , Farber Eugene W. , Marconi Vincent C.
Published: January 2020

Background:

Early palliative care addresses biopsychosocial needs for people living with HIV in an outpatient setting. We sought to describe patients referred to a palliative care program and compare the medical outcomes of emergency department (ED) visits, hospitalizations, primary care visits, and viral load suppression among patients enrolled in the program, to patients who did not enroll (no-show group).

Setting:

We completed a retrospective cohort study at an urban, academically affiliated HIV primary care clinic.

Methods:

Data were collected from electronic medical records. Descriptive statistics characterized patient demographics at baseline, comorbidities, and reasons for referral to palliative care. Viral load suppression, rates of ED visits, hospitalizations, primary care visits, and retention in care were compared between the palliative and no-show groups.

Results:

The most common reasons for referral were chronic pain management and medication/appointment adherence. Median percent of viral load measurements suppressed increased over time, but did not differ statistically between groups (pre: 28.6% and 15.5%, post: 70.8% and 50.0%, palliative and no-show groups, respectively). Median rates of ED visits and hospitalizations were low and were not impacted by palliative care. Rates of primary care visit attendance remained stable in the palliative group (4.6/year) but declined in the no-show group (3.5/year), P < 0.05. Retention in care improved significantly after the palliative intervention (palliative: 85.4%–96.1%, no-show: 94.4%–82.5%), and at high and low palliative engagement, suggesting a threshold effect of the intervention.

Conclusion:

Outpatient early palliative care is a promising intervention that might impact retention in HIV care.
The Association Between Magnetic Resonance Imaging Disc Pathology and Provocative Discography at the Lumbar Level
Authors: Waldrop Greer , Trent Graham , Dagher Azar P. , Reinig James , Thompson Kerry J.
Published: January 2020

Objective

The objective of this study was to show that degenerative lumbar magnetic resonance imaging findings variably increase discography pain by level.

Methods

Lumbar discography and magnetic resonance imaging of 736 patients were retrospectively reviewed. Univariate/multivariate logistic regressions calculated the odds ratio (OR) (95% confidence interval, P < 0.05).

Results

L3-4 multivariate regression OR for a degenerative disc is 9.9; for bulge, 10.9; for annular tear, 38.9; for herniation, 51.5; and for degenerative facet, 2.158. Endplate changes were not significant. L4-5 OR for a degenerative disc is 4.52; for bulge, 13.74, for tear, 19.13; for herniation, 28.65; for endplate edema, 3.47; and fatty change, 3.84. Degenerative facet ORs were not significant. L5-S1 OR for a degenerative disc is 6.86; for bulge, 5.65; for tear, 40.56; and for herniation, 77.98. Endplate changes and degenerative facet OR's were not significant.

Conclusions

Advancing degeneration increases pain at L5-S1 followed by L3-4. Endplate signal is significant only at L4-5.
Neurovascular Perfusion Study With DynaPBV During Preoperative Balloon Test Occlusion: A Feasibility Study on Aneurysm and Tumor Lesions
Authors: Ciceri Elisa F. , Caldiera Valentina , Talenti Giacomo , Caputi Luigi , Cordella Roberto , D'Onofrio Giovanni , Faragò Giuseppe
Published: January 2020

To report feasibility, safety, and technical advantages of flat-detector computed tomography perfusion (FD-CTP) during balloon test occlusion (BTO) angiography studies, 10 patients patients scheduled for BTO were evaluated. Cerebral blood volume maps were extracted from FD-CTP images acquired during the test. The FD-CTP perfusion combined with BTO is feasible and safe in intracranial tumor, and aneurysm cases in which vessel sacrifice should be considered.
Microsurgery Training in the Digital Era
Authors: Margulies Ilana G. , Xu Hope , Henderson Peter W.
Published: January 2020

Introduction

Significant variation exists in microsurgery training resources provided across plastic surgery residency programs, and dedicated microsurgery courses can be logistically difficult to access (cost, location, protected time, etc). Widespread use of personal digital technology has facilitated the emergence of resources that enable easily accessible microsurgical training through digital modalities that augment traditional training. The authors sought to conduct the first systematic review of all such resources.

Methods

A systematic review of MEDLINE, PubMed Central, and EMBASE was performed according to Preferred Reporting Items for Systematic Review and Meta-analysis guidelines to identify articles describing easily accessible microsurgery training resources. Additional searches on Google, the iOS application store, the Google Play store, and YouTube were conducted using comparable search terms.

Results

Nineteen articles describing easily accessible digital microsurgery training resources were identified, which included 9 interactive and 10 passive training resources. Interactive resources included methods for using smartphones, tablets, and computers to provide magnification for microsurgical skill training. Passive resources included training videos, educational forums, and 3-dimensional anatomical models. Google search revealed an additional interactive, commercially available device for positioning a smartphone above a microsurgical training platform. iOS Store and Google Play search revealed 5 passive training applications with tutorials and technique videos. YouTube search revealed 146 videos on microsurgical technique and training models from 19 users with verifiable affiliations.

Conclusions

In contrast to costly and variable microsurgical courses and laboratories, digital technology gives trainees the opportunity to learn about and practice microsurgical techniques in any setting at any time and can serve as a valuable adjunct to traditional training modalities.
Surgical Management and Outcomes of Cutaneous Mold Infections in Immunocompromised Children
Authors: Mauch Jaclyn T. , Xu Wen , Nathan Shelby L. , Lin Ines C.
Published: January 2020

Background

Cutaneous mold infections occur infrequently but can be life-threatening in immunocompromised children. The literature regarding its surgical management is limited. This study aims to describe the surgical management and outcomes of cutaneous mold infections in immunocompromised children.

Methods

Hospitalized patients receiving a skin biopsy at a single pediatric hospital in 2003 to 2017 were identified. Inclusion criteria were immunocompromised status, younger than 21 years, and surgical excision of a confirmed cutaneous mold infection. Patient information, details of immunosuppression, operative details, and 6-month postoperative and disease outcomes were collected.

Results

Seventeen patients (21 lesions) were identified with an average age of 6.8 years (range = 0.2–19.5 years). Affected anatomic regions included limb (15, 71%), chest (2, 10%), axilla, back, abdomen, and head (1 or 5% each). Excisions occurred, on average, within 1.7 days of initial biopsy (range = 0–7 days). When specified, margins were 0.5 to 2.0 cm, and surgeons used intraoperative fungal detection techniques in 8 cases (47%). Definitive closure was achieved by secondary intention/dressings changes (9, 43%), skin graft (7, 33%), a skin substitute (2, 10%), immediate primary closure (2, 10%), and delayed primary closure (1, 5%). Overall, 14 patients were alive 6 months after resection (82%).

Conclusions

This study is the first to critically evaluate the methodology for surgical resection of cutaneous fungal infections in immunocompromised children. We suggest timely excision once diagnosed with, at minimum, 0.5-cm margins and intraoperative pathologic study when considering surgical treatment for this rare but serious infection.
Lavage With Lidocaine and Adrenaline Mixture Reduces the Early Side Effects of Septorhinoplasty
Authors: Gümüş Nazım
Published: January 2020

Background

Pain, ecchymosis, and edema are well-known temporary consequences of septorhinoplasty procedure. They give rise to patient's complaints, discomfort, and dissatisfaction, increasing the patient's anxiety and recovery time in the early postoperative course. Several approaches have been described to reduce the level of these complaints.

The aim of this clinical study was to determine the effect of nasal lavage with lidocaine and adrenaline mixture on early postoperative levels of pain, edema, and ecchymosis in 24 hours after a septorhinoplasty procedure.

Methods

This study included 40 consecutive patients who underwent septorhinoplasty procedure in which nasal septum was entirely dissected and corrected. Patients were randomly divided into 2 groups of 20 patients. At the end of the operation, incisions were closed with sutures, and both blood and seroma collections beneath the flaps were sufficiently drained by means of finger pressure, and then in patients of group A (control group), 5 mL of saline solution was given under the dorsal nasal flap to make lavage and in patients of group B (study group), 5 mL of 2% lidocaine with 1:100,000 adrenaline was given to the area under the dorsal nasal flaps. Five minutes later, nasal package and splint were applied and the operation was finished.

Patients were evaluated for the level of pain sensation, degree of periorbital edema, and ecchymosis at the 1st, 3rd, 6th, 12th, and 24th hours postoperatively. Overall satisfaction scores were also determined at the 24th hour.

Results

A total of 40 patients (19 males and 21 females) between 18 and 42 years of age with a mean ± standard deviation of 24.5 ± 4.52 years were included in the study. Statistically significant differences were found between the A and B groups with regard to early postoperative pain, edema, ecchymosis, analgesic use, and satisfaction scores, suggesting the effectivity of the lavage with lidocaine-adrenaline mixture on the early postoperative pain, edema, and ecchymosis relief.

Conclusions

Lavage of nasal flaps with lidocaine-adrenaline mixture seems an effective and simple way in the control of early postoperative pain, edema, and ecchymosis in septorhinoplasty patients. In addition, it considerably reduces total analgesic consumption and patients' discomfort, leading to high level of satisfaction.
Hospital-level intensive care unit admission for patients with isolated blunt abdominal solid organ injury
Authors: Bowman Jessica A. , Jurkovich Gregory J. , Nuño Miriam , Utter Garth H.
Published: January 2020

BACKGROUND

The optimal level of care for hemodynamically stable patients with isolated blunt hepatic, renal, or splenic injuries (solid organ injuries [SOIs]) is unknown. We sought to characterize interhospital variability in intensive care unit (ICU) admission of such patients and to determine whether greater hospital-level ICU use would be associated with improved outcomes.

METHODS

We conducted a retrospective cohort study using the 2015 and 2016 National Trauma Data Bank. We included adult patients with blunt trauma with SOIs with an Abbreviated Injury Scale score of 2 to 4. We excluded patients with other significant injuries, hypotension, or another indication for ICU admission, and hospitals with less than 10 eligible patients. We categorized hospitals into quartiles based on the proportion of eligible patients admitted to an ICU. The primary outcome was a composite of organ failure (cardiac arrest, acute lung injury/acute respiratory failure, or acute kidney injury), infection (sepsis, pneumonia, or catheter-related blood stream infection), or death during hospitalization.

RESULTS

Among 14,312 patients at 444 facilities, 7,225 (50%), 5,050 (35%), and 3,499 (24%) had splenic, hepatic, and renal injuries, respectively. The median proportion of ICU use was 44% (interquartile range, 27–59%, range 0–95%). The composite outcome occurred in 180 patients (1.3%), with death in 76 (0.5%), organ failure in 97 (0.7%), and infection in 53 (0.4%). Relative to hospitals with the lowest ICU use (quartile 1), greater hospital-level ICU use was not associated with decreased likelihood of the composite outcome (adjusted odds ratios, 1.31; 95% confidence interval [95% CI], 0.88–1.95; 0.81; 95% CI, 0.52–1.26; and 0.94; 95% CI, 0.62–1.43 for quartiles 2–4, respectively) or its components. Unplanned ICU transfer was no more likely with lower hospital-level ICU use.

CONCLUSION

Admission location of stable patients with isolated mild to moderate abdominal SOIs is variable across hospitals, but hospitalization at a facility with greater ICU use is not associated with substantially improved outcomes.

LEVEL OF EVIDENCE

Therapeutic/care management, Level IV.
Effect of preharvest aminoethoxyvinylglycine (AVG) on fruit quality attributes 'Formosa' plum stored at ambient temperature
Authors: Kwon Jung-Geun , Yoo Jingi , Kwon Hye-Won , Kim Dae Hyun , Cho Young-Je , Jung Hee-Young , Kang In-Kyu
Published: January 2020

This study was carried out to investigate the effect of a preharvest treatment with aminoethoxyvinylglycine (AVG) on fruit quality during ambient temperature storage of ‘Fomosa’ plum (Prunus salicina). Flesh firmness of the control fruit during storage decreased to less than 2.00 N after 12 days of storage, but AVG treated fruits remained above 4.00 N after 20 days of storage. The amount of ethylene produced in the control fruit began to increase from 12 days after storage and rapidly increased to 90.0 μL/kg/h after 20 days of storage. However, AVG treated fruits showed low ethylene production of 20.0 μL/kg/h after 24 days of storage. The titratable acid (TA) of control fruit decreased from 1.15% at harvest to 0.87% at 20 days after storage, but AVG treated fruits remained high at 1.04-1.08% after 24 days of storage. The redness (a*) of the fruit peel at harvest was not statistically significant but increased in the AVG treated fruits during storage. Therefore, pre-harvest AVG treatment in 'Formosa' plums was effective to maintain the quality of fruits by decreasing the ethylene production and maintaining flesh firmness and TA of fruit during ambient temperature storage.
Genetic hearing impairment affects cochlear processing and, consequently, speech recognition in noise
Authors: Lanting Cris , Snik Ad , Leijendeckers Joop , Bosman Arjan , Pennings Ronald
Published: January 2020

The relation between speech recognition and hereditary hearing loss is not straightforward. Impaired cochlear processing of sound might be determined by underlying genetic defects. Data obtained in nine groups of patients with a specific type of genetic hearing loss were evaluated. For each group, the affected cochlear structure, or site-of-lesion, was determined based on previously published animal studies. Retrospectively obtained speech recognition scores in noise were related to several aspects of supra-threshold cochlear processing, as assessed by psychophysical measurements. The differences in speech perception in noise between these patient groups could be explained by these factors, and partially by the hypothesized affected structure of the cochlea, suggesting that speech recognition in noise was associated with genetics-related malfunctioning of the cochlea.
Cardiac Microstructural Abnormalities Identify Women at Risk of Incident Heart Failure
Authors: Kwan Alan C. , Demosthenes Emmanuella , Nguyen Trevor , Luong Eric , Salto Gerran , Osypiuk Ewa , Stantchev Plamen , Kim Elizabeth H. , Hiremath Pranoti , Xanthakis Vanessa , Vasan Ramachandran S. , Cheng Susan
Published: January 2020

Background

Incidence of congestive heart failure is difficult to predict by standard methods. We have developed a method called the signal intensity coefficient that uses echocardiographic texture analysis to quantify microstructural changes which may occur in at-risk patients prior to development of a clinical heart failure syndrome.

Methods

Participants from the Framingham Offspring Cohort study who attended the 8th visit and received screening echocardiography were included. Participants were followed for a mean of 7.4 years for incident congestive heart failure. Cox proportional hazards modeling was used to assess the hazard ratio of signal intensity coefficient in the top quartile of values versus other quartiles in the total and sex-stratified population.

Results

2511 participants with interpretable echocardiography and no history of congestive heart failure, stroke, or myocardial infarction were included in this study. The top quartile signal intensity coefficient had a hazard ratio of 1.83 (p=0.0048) for incident heart failure. When additional clinical risk factors were added to the model, this became non-significant. Within women, an elevated hazard ratio was significant in multiple models including age and hypertensive medication use. Models were not significant in men.

Conclusions

Elevated signal intensity coefficient is associated with an increased risk of incident congestive heart failure. This trend remains significant in women after inclusion of age and hypertensive medication use. The signal intensity coefficient may be able to identify patients at risk of developing congestive heart failure using echocardiographic texture analysis.
Computational Exploration of Phytochemicals as Potent Inhibitors of Acetylcholinesterase Enzyme in Alzheimer’s Disease
Authors: Sarkar Bishajit , Ullah Md. Asad , Prottoy Md. Nazmul Islam
Published: January 2020

Alzheimer’s Disease (AD) is the most common type of age related dementia in the world. Many hypotheses shed light on several reasons that lead to AD development. The cholinergic hypothesis describes that the destruction of an essential neurotransmitter, acetylcholine (AChE) by acetylcholinesterase (AChE) enzyme, leads to the AD onset. The hydrolysis of acetylcholine by excess amount of AChE decreases the amount of acetylcholine in the brain, thus interfering with the normal brain functions. Many anti-AChE agents can be used to treat AD by targeting AChE. In our study, 14 anti-AChE agents from plants: 1,8-cineol, berberine, carvacrol, cheilanthifoline, coptisine, estragole, harmaline, harmine, liriodenine, myrtenal, naringenin, protopine, scoulerine, stylopine were tested against AChE and compared with two controls: donepezil and galantamine, using different techniques of molecular docking. Molecular docking study was conducted for all the 14 selected ligands against AChE to identify the best three ligands among them. To determine the safety and efficacy of the three best ligands, a set of tests like the druglikeness property test, ADME/T test, PASS & P450 site of metabolism prediction, pharmacophore mapping and modelling and DFT calculations were performed. In our experiment, berberine, coptisine and naringenin were determined as the three ligands from the docking study. Further analysis of these 3 ligands showed coptisine as the most potent anti-AChE agent. The molecular dynamics simulation study showed quite good stability of the coptisine-AChE docked complex. Administration of berberine, coptisine and naringenin might be potential treatments for AD.
FDA orphan drug designations for lysosomal storage disorders – a cross sectional analysis
Authors: Garbade Sven F. , Zielonka Matthias , Mechler Konstantin , Kölker Stefan , Hoffmann Georg F. , Staufner Christian , Mengel Eugen , Ries Markus
Published: January 2020

Purpose

To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSD’s).

Methods

Assessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics.

Results

Between 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N=16), Pompe disease (N=16), Fabry disease (N=10), MPS II (N=10), MPS I (N=9), and MPS IIIA (N=9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N=6), cystinosis (N=5), Pompe disease (N=3), and Fabry disease (N=2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSD’s (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8-203, N=23) months.

Conclusions

The development pipeline is growing and evolving into diversified small molecules and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included “me-too” – enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.
Psychiatric symptoms and syndromes transcending diagnostic boundaries in Indian multiplex families: The cohort of ADBS study
Authors: Sreeraj Vanteemar S , Holla Bharath , Ithal Dhruva , Nadella Ravi Kumar , Mahadevan Jayant , Balachander Srinivas , Ali Furkhan , Sheth Sweta , Narayanaswamy Janardhanan C. , Venkatasubramanian Ganesan , John John P. , Varghese Mathew , Benegal Vivek , Jain Sanjeev , Reddy YC Janardhan ,   ADBS Consortium, Viswanath Biju
Published: January 2020

Accelerator program for discovery in brain disorders using stem cells (ADBS) is an ongoing longitudinal study investigating the neurobiological aspects of five psychiatric disorders (Alzheimer’s dementia, bipolar disorder, obsessive-compulsive disorder, substance use disorder or schizophrenia) in India. The study uses several techniques (brain-imaging, psychophysics, neuropsychology, next-generation sequencing, cellular models), and in-depth clinical assessments in a longitudinal cohort from multiple-affected families. This article explores the frequency of manifestations of different psychiatric symptoms and syndromes in the participants and their relatives from the first wave of this study (August 2016 to October 2019). We screened 3,583 families and enrolled 481 families (1406 participants; 773 affected with any of the 5 disorders, and 633 relatives). The participants had a high familial prevalence with nearly a third of FDRs affected. Though similar disorders aggregated, the majority (61%) of the families had dissimilar diagnoses among members. Moreover, 15% of affected participants had two or more co-occurring syndromes. Diverse cross-cutting symptoms, unrestricted to the index syndrome, were observed in participants across diagnostic categories. The pattern and extent of co-occurrence validate the need for a transdiagnostic approach. The repository of biomaterials as well as digital datasets will serve as a valuable resource for the larger scientific community.
Autoantibodies to the N-Methyl-D-Aspartate Receptor in Adolescents with Early Onset Psychosis and Healthy Controls
Authors: Engen Kristine , Wortinger Laura Anne , Jørgensen Kjetil Nordbø , Lundberg Mathias , Bohman Hannes , Smelror Runar Elle , Myhre Anne Margrethe , Jacobson Leslie , Vincent Angela , Agartz Ingrid
Published: January 2020

Background

Autoantibodies to the N-methyl-D-aspartate receptor (NMDAR-Abs) in autoimmune encephalitis have been associated with prominent psychiatric symptoms. The aims of the present study are to identify the prevalence of NMDAR-Abs in adolescents with early onset psychosis disorders (EOP) and healthy controls (HC) and examine its clinical significance.

Method

Plasma samples were acquired from 46 adolescent EOP patients and 69 age- and sex matched HC, and assessed for the presence of immunoglobulin G NMDAR-Abs. All participants underwent psychiatric evaluation, neurological examination and head magnetic resonance imaging.

Results

NMDAR-Abs were detected in three of 46 (6.5%) EOP patients and in two of 69 (2.9%) HC. One NMDAR-Abs EOP patient presented with unusual psychopathology and minor T1 weighted lesions of vasculopathological origin located bi-frontally and in the basal ganglia, and had a recent diagnosis of a separate autoimmune disease. One NMDAR-Abs HC displayed a T2 weighted FLAIR hyperintensity lesion in the left frontal lobe. The remaining three NMDAR-Abs participants were two EOP patients without neurological or radiological findings, and one HC without any clinical findings.

Conclusions

We report the presence of NMDAR-Abs in both adolescent EOP patients and HC, similar to the incidence in other studies. This may support the hypothesis of an immunological disease component in a small proportion of adolescent psychosis, but the positive antibody tests must be carefully interpreted and reviewed within the individual clinical context.
Circulating tumor cell characterization of lung cancer brain metastasis in the cerebrospinal fluid through single-cell transcriptome analysis
Authors: Ruan Haoyu , Zhou Yihang , Shen Jie , Zhai Yue , Xu Ying , Pi Linyu , Huang RuoFan , Chen Kun , Li Xiangyu , Ma Weizhe , Wu Zhiyuan , Deng Xuan , Wang Xu , Zhang Chao , Guan Ming
Published: January 2020

Metastatic lung cancer accounts for about half of the brain metastases (BM). Development of leptomeningeal metastases (LM) are becoming increasingly common, and its prognosis is still poor despite the advances in systemic and local approaches. Cytology analysis in the cerebrospinal fluid (CSF) remains the diagnostic gold standard. Although several previous studies performed in CSF have offered great promise for the diagnostics and therapeutics of LM, a comprehensive characterization of circulating tumor cells (CTCs) in CSF is still lacking. To fill this critical gap of lung adenocarcinoma LM (LUAD-LM), we analyzed the transcriptomes of 1,375 cells from 5 LUAD-LM patient and 3 control samples using single-cell RNA sequencing technology. We defined CSF-CTCs based on abundant expression of epithelial markers and genes with lung origin, as well as the enrichment of metabolic pathway and cell adhesion molecules, which are crucial for the survival and metastases of tumor cells. Elevated expression ofCEACAM6andSCGB3A2was discovered in CSF-CTCs, which could serve as candidate biomarkers of LUAD-LM. We identified substantial heterogeneity in CSF-CTCs among LUAD-LM patients and within patient among individual cells. Cell-cycle gene expression profiles and the proportion of CTCs displaying mesenchymal and cancer stem cell properties also vary among patients. In addition, CSF-CTC transcriptome profiling identified one LM case as cancer of unknown primary site (CUP). Our results will shed light on the mechanism of LUAD-LM and provide a new direction of diagnostic test of LUAD-LM and CUP cases from CSF samples.
Exploring perspectives from stroke survivors, carers and clinicians on virtual reality as a precursor to using telerehabilitation for spatial neglect post-stroke
Authors: Morse Helen , Biggart Laura , Pomeroy Valerie , Rossit Stéphanie
Published: January 2020

Spatial neglect is a common and severe cognitive consequence of stroke, yet there is currently no effective rehabilitation tool. Virtual Reality (VR) telerehabilitation tools have the potential to provide multisensory and enjoyable neuropsychological therapies and remotely monitor adherence without the presence of a therapist at all times. Researchers and industry need to better understand end-user perspectives about these technologies to ensure these are acceptable and user-friendly and, ultimately, optimize adherence and efficacy. Therefore, this study aims to explore end-user perspectives on the use of self-administered VR for spatial neglect in a university environment to identify barriers and facilitators prior to extending its use remotely or within the home as a VR telerehabilitation tool. We used a mixed-method design including focus groups, self-administered questionnaires and individual interviews with stroke survivors (N = 7), their carers (N = 3) and stroke clinicians (N = 6). End-user perspectives identified clarity of instructions, equipment (cost, available resources) and for some, level of experience with technology as barriers of use. Perceived facilitators of use were performance feedback, engagement and enjoyment, and psychological benefits associated by self-administered VR telerehabilitation. Overall, end-users were positive and interested in using VR telerehabilitation for spatial neglect. These perspectives enabled us to produce practical recommendations to inform development, enhance engagement and uptake of self-administered VR telerehabilitation and inform feasibility and usability studies.
Neutrophil-lymphocyte ratio across psychiatric diagnoses: An electronic health record investigation
Authors: Brinn Aimee , Stone James M
Published: January 2020

Objectives

The main objective of this study was to compare neutrophil-lymphocyte ratio, a marker of systemic inflammation, between patients diagnosed with ICD-10 psychiatric disorders and control participants.

Design

A cross-sectional methodology was employed to retrospectively analyse electronic health records and records derived from a national health survey.

Setting

A secondary mental health care service consisting of four boroughs in South London.

Participants

A diverse sample of 13,888 psychiatric patients extracted from South London and Maudsley electronic health records database and 3,920 control participants extracted from National Health and Nutrition Survey (2015-2016) were included in the study.

Primary and secondary outcome measures

Primary: NLR levels in patients with mental health diagnoses, NLR between patients with different mental health diagnoses. Secondary: Relationship of NLR to length of hospitalisation and to mortality.

Results

NLR was elevated compared to controls in patients with diagnoses including dementia, alcohol dependence, schizophrenia, bipolar affective disorder, depression, non-phobic anxiety disorders, and mild mental retardation (p < 0.05). NLR also correlated with age, antipsychotic use and hypnotic use. NLR was found to be higher in individuals of “White” ethnicity and lower in individuals of “Black” ethnicity. Elevated NLR was associated with increased mortality (β = 0.103, p = 2.9e-08) but not with hospital admissions or face-to-face contacts.

Conclusions

Elevated NLR may reflect a transdiagnostic pathological process occurring in a subpopulation of psychiatric patients. NLR may be useful to identify and stratify patients who could benefit from adjunctive anti-inflammatory treatment.

Article Summary

Strengths and limitations of this study

Largest study to date of cross-diagnostic neutrophil-lymphocyte measurements in a psychiatric population.

Sample is representative of diverse adult psychiatric patients in South London.

Systematic differences between patients and controls reduce the validity of these comparisons.

This study was retrospective and thus, confounding measures such as body mass index, smoking status and diet were unavailable.
A blood miRNA signature associates with sporadic Creutzfeldt-Jakob disease diagnosis
Authors: Norsworthy Penny J. , Thompson Andrew G.B. , Mok Tze H. , Guntoro Fernando , Dabin Luke C. , Nihat Akin , Paterson Ross W. , Schott Jonathan M. , Collinge John , Mead Simon , Viré Emmanuelle A.
Published: January 2020

Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are currently available for diagnosis or disease monitoring. Here, we profiled blood microRNA (miRNA) expression in sCJD. Small RNA-sequencing of 57 sCJD patients and 48 healthy controls revealed differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicated in an independent cohort using quantitative PCR, with concomitant upregulation of four of their mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes paralleled the lack of association between rate of decline in miRNA expression and rate of disease progression in a longitudinal cohort of 50 samples from 21 sCJD patients. Finally, the miRNA signature showed a high level of accuracy in discriminating sCJD from Alzheimer’s disease (AD). These findings highlight novel molecular alterations in the periphery in sCJD which can provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.
Propranolol promotes bone formation and limits resorption through novel mechanisms during anabolic parathyroid hormone treatment in female C57BL/6J mice
Authors: Treyball Annika , Bergeron Audrey C. , Brooks Daniel J. , Langlais Audrie L. , Hashmi Hina , Nagano Kenichi , Barlow Deborah , Nevola Kathleen T. , Houseknecht Karen L. , Baron Roland , Bouxsein Mary L. , Guntur Anyonya R. , Motyl Katherine J.
Published: January 2020

Although the non-selective β-blocker, propranolol, improves bone density with PTH treatment in mice, the mechanism of this effect is unclear. To address this, we used a combination ofin vitroandin vivoapproaches to address how propranolol influences bone remodeling in the context of PTH treatment. In female C57BL/6J mice, intermittent PTH and propranolol had complementary effects in the trabecular bone of the distal femur and L5 vertebra, with combination treatment achieving micro-architectural parameters beyond that of PTH alone. Combined treatment improved the serum bone formation marker, P1NP, but did not impact other histomorphometric parameters relating to osteoblast function at the L5.In vitro, propranolol amplified the acute, PTH-induced, intracellular calcium signal in osteoblast-like cells. The most striking finding, however, was suppression of PTH-induced bone resorption. Despite this, PTH-induced receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA and protein levels were unaltered by propranolol, which led us to hypothesize that propranolol could act directly on osteoclasts. Usingin situmethods, we foundAdrb2expression in osteoclastsin vivo, suggesting β-blockers may directly impact osteoclasts. Taken together, this work suggests a strong anti-osteoclastic effect of non-selective β-blockersin vivo, indicating that combining propranolol with PTH could be beneficial to patients with extremely low bone density.
Investigating the impact of combination phage and antibiotic therapy: a modeling study
Authors: Banuelos Selenne , Gulbudak Hayriye , Horn Mary Ann , Huang Qimin , Nandi Aadrita , Ryu Hwayeon , Segal Rebecca
Published: January 2020

Antimicrobial resistance (AMR) is a serious threat to global health today. The spread of AMR, along with the lack of new drug classes in the antibiotic pipeline, has resulted in a renewed interest in phage therapy, which is the use of bacteriophages to treat pathogenic bacterial infections. This therapy, which was successfully used to treat a variety of infections in the early twentieth century, had been largely dismissed due to the discovery of easy to use antibiotics. However, the continuing emergence of antibiotic resistance has motivated new interest in the use of phage therapy to treat bacterial infections. Though various models have been developed to address the AMR-related issues, there are very few studies that consider the effect of phage-antibiotic combination therapy. Moreover, some of biological details such as the effect of the immune system on phage have been neglected. To address these limitations, we utilized a mathematical model to examine the role of the immune response in concert with phage-antibiotic combination therapy compounded with the effects of the immune system on the phages being used for treatment. We explore the effect of phage-antibiotic combination therapy by adjusting the phage and antibiotics dose or altering the timing. The model results show that it is important to consider the host immune system in the model and that frequency and dose of treatment are important considerations for the effectiveness of treatment. Our study can lead to development of optimal antibiotic use and further reduce the health risks of the human-animal-plant-ecosystem interface caused by AMR.
Auto-regulatory J-domain interactions control Hsp70 recruitment to the DnaJB8 chaperone
Authors: Ryder Bryan D. , Matlahov Irina , Bali Sofia , Vaquer-Alicea Jaime , van der Wel Patrick C.A. , Joachimiak Lukasz A.
Published: January 2020

The Hsp40/Hsp70 chaperone families combine versatile folding capacity with high substrate specificity, which is mainly facilitated by Hsp40s. The structure and function of many Hsp40s remain poorly understood, particularly oligomeric Hsp40s that suppress protein aggregation. Here, we used a combination of biochemical and structural approaches to shed new light on the domain interactions of the Hsp40 DnaJB8, and how they regulate recruitment of partner Hsp70s. We identify an interaction between the J-Domain (JD) and C-terminal domain (CTD) of DnaJB8 that sequesters the JD surface, preventing Hsp70 interaction. We propose a new model for DnaJB8-Hsp70 regulation, whereby the JD-CTD interaction of DnaJB8 acts as a reversible autoinhibitory switch that can control the binding of Hsp70. These findings suggest that the evolutionarily conserved CTD of DnaJB8 is a regulatory element of chaperone activity in the proteostasis network.