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Usher syndrome (USH) represents a group of genetically heterogenous autosomal recessive disorders, characterized by combined vision and sensorineural hearing loss, and in some cases vestibular dysfunction.1–3 It primarily affects the light-sensitive photoreceptor cells in the retina and the auditory hair cells in the cochlea. Vision loss in all cases is progressive, and manifests as retinitis pigmentosa (RP), characterized by the gradual degeneration of the photoreceptor cells.4 Peripheral rod function is lost first, leading to night blindness and constricted visual fields, followed by the death of cones and severe visual impairment. There are currently no drugs or biological therapies proven to be effective in treating USH syndrome. Cochlear implantation, which bypasses the damaged hair cells and stimulates the primary auditory neurons directly, is an effective approach to alleviate the hearing impairment in patients. However, there is no remedy for the progressive loss of the photoreceptor neurons in the retina, and thus a critical unmet need exists to develop therapeutic strategies to prevent blindness in USH syndrome. The generation of animal models that faithfully mimic the human USH disorder, the timing of gene therapy interventions, the identification of correct target cells and patient selection are key factors in successfully reaching this goal. USH syndrome was named after Dr Charles Howard Usher, a Scottish ophthalmologist who described 69 patients with the disease in 1914.5 As is commonly the case in medicine, the disease was first described much earlier (1858) in brothers suffering from blindness and deafness by von Grafe6 and was further characterized by his student, Liebreich,7 3 years later in a larger population of patients. From its discovery until recently, USH syndrome and its subgroups were delineated by clinical characteristics.8 Now the disease is recognized by symptomology and classified by genotyping. To date, there are at least 10 causative genes that are associated with USH syndrome, summarized in previous reviews.1,2,9 In general, based on its diverse clinical symptoms, particularly the onset and severity of the sensorineural hearing impairment and the presence of vestibular dysfunction, USH syndrome is grouped into 3 clinical subtypes. Type I disease is associated with severe-to-profound prelingual hearing loss, vestibular abnormalities and prepubescent onset of RP symptoms.10,11 USH1 results from mutations in MYO7A (USH1B), HARMONIN (USH1C), CDH23 (USH1D), PCDH15 (USH1F), SANS (USH1G), and CIB2 (USH1J). Patients with type II disease display moderate-to-severe congenital hearing loss without vestibular dysfunction, and account for >50% of all USH cases. Their RP symptoms generally begin in the second decade.12 USH2 is caused by mutations in USH2A (USH2A), ADGRV1 (USH2C), and WHRN (USH2D). Patients with type III disease caused by mutations in CLRN1 (USH3A) gene have postlingual progressive hearing loss, variable vestibular dysfunction, and variable onset of RP that rapidly progresses to legal blindness by the fourth decade of life.13–17 Mutations in the HARS gene (Histidyl-tRNA synthetase) are associated with the ultra-rare form USH3B.18,19 Other genes have been described in cases of atypical USH, including: CEP250 and CEP78, encoding members of the CEP family of centrosome-associated proteins; ESPN, encoding the F-actin cross-linker espin; ARSG, encoding the arylsulfatase G enzyme.20

Purpose: Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). 18F-DCFPyL is a highly selective, small-molecule prostate-specific membrane antigen–targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of 18F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging. Experimental Design: Men with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization between 18F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority (i) histopathology, (ii) subsequent correlative imaging findings, or (iii) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval (CI) for CLR exceeded 20% for two of three 18F-DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety. Results: A total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2–98.4 ng/mL) underwent 18F-DCFPyL-PET/CT. The CLR was 84.8%–87.0% (lower bound of 95% CI: 77.8–80.4). A total of 63.9% of evaluable patients had a change in intended management after 18F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by 18F-DCFPyL-PET/CT by central readers). Conclusions: Performance of 18F-DCFPyL-PET/CT achieved the study’s primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of 18F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer. See related commentary by True and Chen, p. 3512

In recent years, the idea of global citizenship has grown in scholarly circles and developed into a nascent discipline known as global citizenship education. As a general matter, global citizenship education strives to deepen cross-cultural understanding through the study of current transnational issues. This qualitative, interpretivist case study examined the roles and responsibilities of global studies teachers at an urban New Jersey public high school. The study included interviews with an administrator, two global studies teachers, and six students enrolled in the second sequence of a two-year course in the global studies curriculum; as well as observations and analysis of the course curriculum, syllabus, and student assignments. This study highlights the continuing need for increased pre-service and in-service training opportunities for teachers of global studies related courses, including teacher education and professional development programs. This study also underscores the need for more research on global citizenship education, and global studies training and certification programs in the United States.

Small fiber neuropathy has a broad array of presentations. Length-dependent symptoms and findings present little diagnostic difficulty, but non-length-dependent or multifocal symptoms can be challenging. Intraepidermal nerve fiber density (IENFD) testing in apparent fibromyalgia warrants further study, but skin biopsy testing of this patient population is reasonable. Avoidance of IENFD testing in situations where diagnosis of neuropathy is already clear or where neuropathy is not the cause of symptoms helps to prevent incorrect conclusions. Careful history and physical examination plus pretest probability are important factors to consider when assessing the results of an IENFD test report.

This hypothetical teaching case illustrates the complex issues that human resources (HR) professionals in higher education may face when making day-to-day employment decisions. This is particularly evident with recruiting and hiring—from applications to interviews, from offers to background checks. Here, an HR professional, with many years of experience but new to higher education, weighs the results of criminal background checks for two Associate Dean positions at a small private university in New York City. As part of the review and decision-making process, the HR professional has a series of meetings with the HR Director, the Dean, and in-house legal counsel. This case considers how HR professionals must navigate through sometimes competing institutional interests.

Novel coronavirus disease (COVID-19) is a pandemic affecting over 10 million people in 160 countries. Its spread, and the medical communities' response, cast light on an important deficiency in the speed and effectiveness for evidence-based recommendations to reach the bedside in academic medical practice. We built a clinical decision support tool on the avoMD platform that systematizes and personalizes the treatment of COVID-19 by bringing point-of-care access to the guidelines specific to individual cases to the clinician's hands. This app has the potential to improve the mortality for COVID-19.

INTRODUCTION AND OBJECTIVE:Several PSMA-targeted imaging agents are currently in development for initial staging of men at risk of harboring metastatic prostate cancer (PCa) not detected by convent...

Introduction Causes of small-fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) in cryptogenic SFN. Methods One hundred fifty-five patients with biopsy-proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS-HDS and IgG vs FGFR-3. Results Forty-eight percent of SFN patients had serum antibodies, 37% with IgM vs TS-HDS and 15% with IgG vs FGFR-3. TS-HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non-length-dependent nerve pathology. Nintey-two percent of patients with acute-onset SFN had serum IgM vs TS-HDS. Discussion Autoantibodies directed against TS-HDS and FGFR-3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS-HDS may be a marker for SFN with an acute onset.

Response to transarterial chemoembolization (TACE) in patients with liver cancer is commonly assessed on MRI or CT to quantify tumor necrosis and morphologic changes that occur gradually. However, the efficacy of embolotherapies remains limited because of local recurrence, as treated tumors demonstrate individual molecular characteristics that alter susceptibility and response to embolotherapies. Upregulation of cancer cell glycolysis can be detected by fluorine-18-fluorodeoxyglucose PET. Therefore, the combination of functional (PET) with commonly used cross-sectional imaging techniques (MRI, CT) can help characterize and monitor liver tumors with the potential to improve TACE toward becoming a more personalized and tumor microenvironment-directed therapy.

To date, no measures are available that permit differentiation of discrete, clinically distinct subtypes of schizophrenia (SZ) with potential differential underlying pathophysiologies. Over recent years, there has been increasing recognition that SZ is heterogeneously associated with deficits in early auditory processing (EAP), as demonstrated using clinically applicable tasks such as tone-matching task (TMT). Here, we pooled TMT performances across 310 SZ individuals and 219 healthy controls (HC), along with clinical, cognitive, and resting-state functional-connectivity MRI (rsFC-MRI) measures. In addition, TMT was measured in a group of 24 patients at symptomatic clinical high risk (CHR) for SZ and 24 age-matched HC (age range 7–27 years). We provide the first demonstration that the EAP deficits are bimodally distributed across SZ subjects (P d = 2.1) and SZ-EAP+ patients (d = 3.4). The SZ-EAP− group predominated among samples drawn from inpatient sites, showed higher levels of cognitive symptoms (PANSS), worse social cognition and a differential deficit in neurocognition (MATRICS battery), and reduced functional capacity. rsFC-MRI analyses showed significant reduction in SZ-EAP− relative to controls between subcortical and cortical auditory regions. As opposed to SZ, CHR patients showed intact EAP function. In HC age-matched to CHR, EAP ability was shown to increase across the age range of vulnerability preceding SZ onset. These results indicate that EAP measure segregates between discrete SZ subgroups. As TMT can be readily implemented within routine clinical settings, its use may be critical to account for the heterogeneity of clinical outcomes currently observed across SZ patients, as well as for pre-clinical detection and efficacious treatment selection.

An adult male rhesus macaque (Macaca mulatta) that was enrolled in a study evaluating cognition and memory presented with suppurative exudate along the margins of a long-standing cranial implant that included a stainless-steel head post, plastic left-sided recording cylinder, and acrylic over a previously placed right-sided recording cylinder. Both cylinders were located at the level of the prefrontal cortex. After treatment comprising systemic antibiotics and daily cleaning with povidone-iodine for several months, the macaque underwent single-photon emission computed tomography-computed tomography (SPECT-CT) in which his neutrophils were labeled with 99mTc-hexamethylpropylene amine oxime ( 99m Tc-HMPAO) to evalu- ate for active infection below the implant. Soft tissue inflammation and osteomyelitis were found at the site of the previous right-sided recording cylinder. Cephalosporin and tetracycline antibiotics were administered for 12 wk. Follow-up SPECT-CT imaging was then performed to evaluate response to medical treatment. Results indicated no change in the degrees of soft tissue inflammation and osteomyelitis associated with the right-sided recording cylinder site. SPECT-CT imaging was used to guide the surgical removal of the implant and debridement of the infected tissue. On removal of the entire cranial implant, the osteomyelitis and soft tissue inflammation observed on the pre- and posttreatment SPECT-CT scans were confirmed. In addition, a large cavitary defect through the calvarium with suppurative exudate was discovered below the base of the head post. Infection in this defect was not apparent on SPECT; however, the bony defect was confirmed on reevaluation of the CT images. We concluded that the infection in this defect was silent on SPECT due to the limited vascularization of the sur-rounding bone and the chronicity of the infection. This case study is the first to describe the use of SPECT-CT for evaluating soft tissue inflammation and osteomyelitis beneath a cranial implant in a NHP.

Our purpose was to identify baseline imaging features in patients with liver cancer that correlate with 90Y distribution on postprocedural SPECT and predict tumor response to transarterial radioembolization (TARE). Methods: This retrospective study was approved by the institutional review board and included 38 patients with hepatocellular carcinoma (HCC) (n = 23; 18/23 men; mean age, 62.39 ± 8.62 y; 34 dominant tumors) and non-HCC hepatic malignancies (n = 15; 9/15 men; mean age, 61.13 ± 11.51 y; 24 dominant tumors) who underwent 40 resin-based TARE treatments (August 2012 to January 2018). Multiphasic contrast-enhanced MRI or CT was obtained before and Bremsstrahlung SPECT within 2 h after TARE. Total tumor volume (cm3) and enhancing tumor volume (ETV [cm3] and % of total tumor volume), and total and enhancing tumor burden (%), were volumetrically assessed on baseline imaging. Up to 2 dominant tumors per treated lobe were analyzed. After multimodal image registration of baseline imaging and SPECT/CT, 90Y distribution was quantified on SPECT as tumor-to-normal-liver ratio (TNR). Response was assessed according to RECIST1.1 and quantitative European Association for the Study of the Liver criteria. Clinical parameters were also assessed. Statistical tests included Mann-Whitney U, Pearson correlation, and linear regression. Results: In HCC patients, high baseline ETV% significantly correlated with high TNR on SPECT, demonstrating greater 90Y uptake in the tumor relative to the liver parenchyma (P < 0.001). In non-HCC patients, a correlation between ETV% and TNR was observed as well (P = 0.039). Follow-up imaging for response assessments within 1-4 mo after TARE was available for 23 patients with 25 treatments. The change of ETV% significantly correlated with TNR in HCC (P = 0.039) but not in non-HCC patients (P = 0.886). Additionally, Child-Pugh class B patients demonstrated significantly more 90Y deposition in nontumorous liver than Child-Pugh A patients (P = 0.021). Conclusion: This study identified ETV% as a quantifiable imaging biomarker on preprocedural MRI and CT to predict 90Y distribution on postprocedural SPECT in HCC and non-HCC. However, the relationship between the preferential uptake of 90Y to the tumor and tumor response after radioembolization could be validated only for HCC.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense RNA virus causing coronavirus disease 2019 (COVID-19), an ongoing pandemic claiming millions of lives [1–3]. Rapidly evolving SARS-Cov-2 outbreak continues with recent spikes in cases in some countries, while few have significantly curbed the numbers of new cases thanks to the recent deployment of vaccines [3]. Connecticut is a relatively small-sized northeastern state (approximate population 3.5 million) that is ranked #3 in healthcare access among the US states, according to US News data. The geographical proximity of the state of Connecticut to New York, an epicenter of the initial outbreak in the USA, resulted in the immediate spread of the virus in the Connecticut area as well. Governors of New York, New Jersey and Connecticut followed a similar course of action, and the timeline of the pandemic followed a similar path in this region. The first case in our hospital system was seen on 8 March 2020. Decreased numbers of screening studies and elective surgeries, as well as on in-person appointments took in place in parallel with state-wide administrative policy implementations. COVID-19 has less favorable clinical outcomes in patients with preexisting health conditions including cancer [4]. Unprecedented strain in healthcare systems and rapid development of the outbreak led to readjustment of cancer treatment, deferral of procedures and alteration of surveillance algorithms [5]. The dual danger of COVID-19 and cancer have forced practitioners to make decisions based on experience and risk/benefit analysis, particularly at the early stage of the pandemic, due mainly to the scarcity of clinical and epidemiologic data on COVID-19. Identification of factors that are potentially associated with the decline in molecular cancer imaging, will help better understand the dynamics of cancer imaging at the time of respiratory outbreaks. Providing real-world data during a pandemic may play a role in understanding potential vulnerabilities in similar future outbreaks or the future waves of COVID-19 outbreak that may ensue. This may also assist oncology practitioners to manage imaging studies of their patient population in an evidence-based approach. A decline in the volume of radiology studies as well as in nationwide new cancer diagnoses in 2020 as compared to prior years has been shown [6,7]. Two Italian studies recently demonstrated a potential increase in interstitial lung findings in cancer patients during the COVID-19 pandemic [8,9]. The impact of the COVID-19 pandemic on cancer imaging based on factors such as cancer types, patient demographics and imaging findings is not well-demonstrated in the literature, particularly with respect to epidemiologic dynamics. In this study, we aimed to analyze the impact of the ongoing pandemic on molecular imaging of cancer patients in a comprehensive cancer hospital by in-depth analysis of all PET/CT studies from 1 January 2020 through 15 June 2020. The aims of this study were: (1) to determine temporal changes in PET/CT utilization during the COVID-19 pandemic; (2) to correlate PET/CT utilization and state-wide number of COVID-19 cases within the same period in the light of restrictive policy implementations; (3) to examine the impact of demographic and oncological factors on PET/CT utilization and (4) to examine the number of cases discussed in multidisciplinary tumor boards during the same period.

BackgroundCollaborative data sharing between research groups provides an opportunity to explore the basis for the heterogeneity in cognitive training outcomes reported in the schizophrenia literature. The current analyses focused on the contribution of site and participant characteristics to these heterogeneous outcomes.MethodsData from two independent studies, from New York (NY) and Los Angeles (LA), were combined to yield a sample of 132 outpatient adults with schizophrenia/schizoaffective disorder. While similar treatment doses, cognitive exercises and outcome measures were used, sites differed in use of coaching, group discussion and compensation. Between-site differences in participant demographic and baseline clinical characteristics were tested. Regression examined predictors of change in cognition (MCCB) and functional capacity (UPSA) which could explain site differences in treatment effects.ResultsMedium to large treatment effect size differences in MCCB and UPSA favored the NY site over LA. When the studies were combined, the effect of site was significant for both outcomes with a medium effect size difference. After controlling for background characteristics, the effect of site was reduced for both outcomes, but remained significant for cognition. Improvement in UPSA was associated with better baseline MCCB (p&nbsp

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy with a highly variable clinical presentation, course, and outcome. The factors that determine the clinical variation of GBS are poorly understood which complicates the care and treatment of individual patients. The protocol of the ongoing International GBS Outcome Study (IGOS), a prospective, observational, multicenter cohort study that aims to identify the clinical and biological determinants and predictors of disease onset, subtype, course and outcome of GBS is presented here. Patients fulfilling the diagnostic criteria for GBS, regardless of age, disease severity, variant forms, or treatment, can participate if included within 2 weeks after onset of weakness. Information about demography, preceding infections, clinical features, diagnostic findings, treatment, course, and outcome is collected. In addition, cerebrospinal fluid and serial blood samples for serum and DNA is collected at standard time points. The original aim was to include at least 1,000 patients with a follow-up of 1-3 years. Data are collected via a web-based data entry system and stored anonymously. IGOS started in May 2012 and by January 2017 included more than 1,400 participants from 143 active centers in 19 countries across 5 continents. The IGOS data/biobank is available for research projects conducted by expertise groups focusing on specific topics including epidemiology, diagnostic criteria, clinimetrics, electrophysiology, antecedent events, antibodies, genetics, prognostic modeling, treatment effects, and long-term outcome of GBS. The IGOS will help to standardize the international collection of data and biosamples for future research of GBS.

Tongue motility is an essential physiological component of human feeding from infancy through adulthood. At present, it is a challenge to distinguish among the many pathologies of swallowing due to the absence of quantitative tools. We objectively quantified tongue kinematics from ultrasound imaging during infant and adult feeding. The functional advantage of this method is presented in several subjects with swallowing difficulties. We demonstrated for the first time the differences in tongue kinematics during breast‐ and bottle‐feeding, showing the arrhythmic sucking pattern during bottle‐feeding as compared with breastfeeding in the same infant with torticollis. The method clearly displayed the improvement of tongue motility after frenotomy in infants with either tongue‐tie or restrictive labial frenulum. The analysis also revealed the absence of posterior tongue peristalsis required for safe swallowing in an infant with dysphagia. We also analyzed for the first time the tongue kinematics in an adult during water bolus swallowing demonstrating tongue peristaltic‐like movements in both anterior and posterior segments. First, the anterior segment undulates to close off the oral cavity and the posterior segment held the bolus, and then, the posterior tongue propelled the bolus to the pharynx. The present methodology of quantitative imaging revealed highly conserved patterns of tongue kinematics that can differentiate between swallowing pathologies and evaluate treatment interventions. The method is novel and objective and has the potential to advance knowledge about the normal swallowing and management of feeding disorders., Tongue kinematics was objectively quantified from ultrasound imaging during feeding. Tongue and palate contours were traced in each frame of the video; tongue outlines were registered with respect to the hard anterior palate; and tongue motility characteristics were determined from intersections with polar coordinates in subsequent frames. Differences in tongue kinematics during breast‐ and bottle‐feeding are demonstrate in the same infant. The method detected improvement of tongue motility after frenotomy interventions and revealed absence of posterior tongue peristalsis in infant with dysphagia. It demonstrated tongue peristaltic‐like movements in both anterior and posterior segments in an adult during water bolus swallowing.

Introduction The COVID-19 crisis and subsequent stay-at-home orders have produced unprecedented challenges to the dissemination of recovery oriented behavioral health services (RS) that support the treatment of those with complex psychosis (CP).This population has typically been managed with in-person pharmacotherapy and/or RS, with the goals of relieving symptoms, improving life satisfaction and increasing community engagement. COVID-19 related social distancing measures have required rapid shifts in care management, while easing of telehealth regulations has allowed for flexibility to approach RS differently. It is essential to learn from the RS telemedicine implementation experience, so that RSs can maintain care for this vulnerable and needy population. Method This paper describes the successful telehealth conversion of a NYC-based, university affiliated RS that serves adults with severe mental illnesses (SMI; n = 64). Results focus on the telehealth acceptance rates of the subset of participants with CP (n = 23). Results The RS continued providing services including intake, care coordination, group psychotherapies, skills training groups, individual skills coaching, and vocational/educational supports. The telehealth conversion rates of the CP subsample indicated that 90% of CP patients accepted telehealth sessions and maintained their specific treatment plans in the virtual format. Mean comparisons between session attendance and cancellations/no-shows during the six-week period before and after telehealth conversion showed no significant differences in service utilization. Discussion RSs play an essential role in the treatment of CP and telehealth may prove to be a viable format of care delivery even after the COVID-19 crisis subsides. The multiple factors in the inner and outer treatment setting that contributed to successful conversion to telehealth will be considered along with the challenges that clinicians and patients encountered.

Introduction:Improved diagnostics are needed to better inform the treatment of men with biochemically recurrent (BCR) prostate cancer (PCa). 18F-DCFPyL is a novel PET agent that selectively binds w...

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of “mast cell activation syndrome” (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a “consensus” (re-termed here as “consensus-1”). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as “consensus-2”), resembling “consensus-1” in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by “consensus-2” criteria has potential to be problematic, but underdiagnosis by “consensus-1” criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

Diabetes is a major public health issue affecting millions of people in the United States and worldwide.

Introduction Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). Methods We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting. Results There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. Discussion Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.

Purpose The purpose of this study was to assess the impact of Diabetes HealthSense on knowledge, attitudes, and behavior changes that prevent, delay, or manage diabetes among people at risk (PAR) for diabetes and people with diabetes (PWD). Methods Using a 2-group pretest-posttest design, 15 community sites were randomly assigned to either an intervention or comparison group. Intervention participants attended a group education session with a diabetes educator, followed by 4 weeks of independent use of the Diabetes HealthSense website. The comparison group received no intervention. A total of 311 adults (n = 135 intervention, n = 176 comparison) completed both a pretest and posttest. Outcome measures examined changes in self-reported knowledge, self-efficacy, and behaviors that support diabetes prevention or management. Results Statistically significant within-group pretest to posttest changes were found for almost all outcome measures in the intervention group, with no significant changes in the comparison group. Significant between-group differences were also found for almost all outcome measures at posttest, with the intervention group having more positive outcomes than the comparison group. Conclusions Patient referral to online tools is considered one key component of initial and ongoing diabetes self-management education and support (DSME/S) and is recommended as a way to enhance and extend the reach of in-person diabetes education. Positive outcomes were found for PWD/PAR who used Diabetes HealthSense following a guided education session. Study results suggested that with guided exploration, Diabetes HealthSense provided a valuable tool for educators to use with patients to support and extend the reach of DSME/S.

Hundreds of thousands of mobile phone apps intended to improve health and fitness are available for download across platforms and operating systems; however, few have been designed with people with physical disabilities in mind, ignoring a large population that may benefit from an effective tool to increase physical activity. : This study represents the first phase in the development process of a fitness tracking app for people with physical disabilities interested in nontraditional sport. The aim of this research was to explore user preferences for content, appearance, and operational features of a proposed physical activity app for people with physical disabilities to inform the design of a mobile phone app for increasing physical activity. : Four focus groups were conducted with 15 adults with physical disabilities who currently participate in nontraditional, non-Paralympic sport. Data collected from the focus group sessions centered on content, functionality, and appearance of apps currently used by participants as well as preferences for a future app. : Participants (mean age 35.7, SD 9.2 years) were mostly white (13/15, 87%), and all were currently participating in CrossFit and at least one other sport. Five main themes were identified. Themes included preferences for (1) workout-specific features that were tailored or searchable by disability, (2) user experience that was intuitive and accessible, (3) profile personalization options, (4) gamification features that allowed for competition with self and other users, and (5) social features that allowed increased interaction among users. Participants expressed a primary interest in having a fitness app that was designed for people with physical disabilities such that the features present in other fitness tracking apps were relevant to them and their community of adaptive athletes. : The results showed that features related to user experience, social engagement, and gamification are considered important to people with physical disabilities. Features highlighted by participants as most desired, from a consumer perspective, were in line with research identifying attributes of quality apps that use behavior change techniques to influence positive physical activity behavior change. Such insights should inform the development of any fitness app designed to integrate users with disabilities as a primary user base.

INTRODUCTION AND OBJECTIVES:Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed by prostate cancer (PCa) cells and can be targeted using the novel PET radiotr...

INTRODUCTION AND OBJECTIVES:99mTc-MIP-1404 (1404) is a small molecule SPECT imaging agent that binds to prostate-specific membrane antigen (PSMA) allowing for the detection of prostate cancer (PCa)...

Background Early auditory processing (EAP) has increasingly become a focus of efforts to identify biomarkers of treatment response in schizophrenia. EAP deficits lead to poor functional outcome via impaired cognition, and treatments that target EAP may drive downstream cognitive improvements. Assessment of baseline need provides an opportunity for cognitive remediation (CR) programs that give EAP training to personalize treatment and optimize its impact. This initial efficacy study examined the differential benefit of EAP training for those with and without baseline EAP deficits as defined by performance on the Tone Matching Test. Methods 103 outpatient adults diagnosed with schizophrenia or schizoaffective disorder were classified as having intact (48.5%) or impaired (51.5%) EAP and randomized to a CR program with restorative exercise plans that either included EAP training (N = 49) or did not (N = 54). Cognitive and functional outcomes were measured post-treatment and 3 months later. Results Only in EAP impaired participants was there a significant benefit from EAP training on verbal learning. Treatment condition did not significantly impact global cognitive or functional outcomes for either EAP group. Cognitive gains partially mediated the relationship between gains in EAP and functional capacity. Conclusion These findings support the importance of addressing basic auditory deficits when attempting to remediate higher order auditory impairments such as verbal learning. In addition, they highlight the need for routine assessment of EAP in cognitive remediation participants, as well as the need for more effective programs to reverse these impairments.

5023 Background: PSMA-targeted PET/CT is superior to conventional imaging modalities to localize biochemically recurrent (BCR) PCa after local therapy, particularly in pts with low PSA ( < 2 ng/mL). However, few studies have reported PSMA-targeted PET/CT accuracy compared to a pre-specified rigorous standard of truth (SOT) including histopathology, correlative imaging or treatment response in this population. Here, we report the CLR and PPV of PSMA-targeted 18F-DCFPyLPET/ CT, for each of the pre-defined SOT criteria for the CONDOR prospective phase 3 study. Methods: The study enrolled men with rising PSA after definitive therapy and negative or equivocal standard of care imaging (e.g., CT/MRI, bone scintigraphy, F-18 fluciclovine). A single 9 mCi (333 MBq) ± 20% dose of 18F-DCFPyL was injected, followed by PET/CT 1-2 hours later. Pts with positive 18F-DCFPyL-PET/CT scans based on local interpretation were scheduled for follow up within 60 days to verify suspected lesion(s) using a composite SOT. The primary endpoint was CLR defined as PPV with the requirement of anatomic lesion co-localization between 18F-DCFPyL-PET/CT and the SOT. The SOT consisted of, in descending priority: 1) histopathology, 2) subsequent correlative imaging findings determined by twocentral readers, or 3) post-radiation PSA response. The trial was successful if the lower bound of the 95% confidence interval for CLR exceeded 20% for at least two of three independent, blinded central 18F-DCFPyL-PET/CT reviewers. Results: 208 men (median PSA 0.8 ng/mL) underwent 18F-DCFPyL-PET/CT and the study achieved its primary endpoint: CLR was between 84.8% to 87.0% (lower bound of 95% CI: 77.8%-80.4%) among the three 18F-DCFPyL-PET/CT readers, against the composite SOT. The performance of 18F-DCFPyL-PET/CT by CLR (≥1 lesion co-localized) and PPV (≥1 lesion confirmed) was maintained through all 3 SOT categories. Histopathology (N = 31): 78.6-82.8% and 92.9-93.3% for CLR and PPV, respectively; correlative imaging (N = 100): 86.1-88.6% and 87.0-89.5% for CLR and PPV, respectively; and PSA response (N = 1): 100% for both CLR and PPV. Further analyses of the correlative imaging results showed CLR remained high across the different modalities used a) 18F-fluciclovine-PET/CT (N = 71): (86.8-90.9%); b) MRI (N = 23): (80.0-86.7%); and c) CT (n = 6): (80.0-100%). Conclusions: PSMA-targeted 18F-DCFPyL-PET/CT detected and localized metastatic lesions with high CLR and PPV regardless of which criterion defined CLR that was used, in men with BCR who had negative or equivocal baseline imaging. Clinicaltrials.gov: NCT03739684 Clinical trial information: NCT03739684.

Importance Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment’s sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration ClinicalTrials.gov Identifier:NCT02260388

We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.

Objective: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG). Methods: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody–positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living. Results: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4–12 prednisone AUDTC when compared to placebo (difference MTX − placebo: −488.0 mg, 95% confidence interval −2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%). Conclusions: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials. Classification of evidence: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

5501 Background: Current imaging modalities are inadequate for localizing and characterizing occult disease in men with BCR PCa, particularly in pts with low PSAs (18F-DCFPyL (PyL) is a novel PET imaging agent that binds selectively with high affinity to PSMA, which is overexpressed in PCa cells. Methods: Men ≥18 years- with rising PSA after definitive therapy and negative or equivocal standard of care imaging (e.g., CT/MRI, bone scintigraphy) were enrolled. A single 9 mCi (333 MBq) ± 20% dose of PyL was injected, followed by PET/CT 1-2 hours later. Primary endpoint was correct localization rate (CLR), defined as percentage of pts with a 1:1 correspondence between at least one lesion identified by PyL-PET/CT and the composite standard of truth: pathology, correlative imaging, or PSA response. The trial was successful if the lower bound of the 95% confidence interval (LLCI) for CLR exceeded 20% for two of three independent, blinded central PyL-PET/CT reviewers. The secondary endpoint, impact of PyL-PET/CT on clinical management of pts was based on the treating physician’s documented clinical plans before and after PyL-PET/CT. Results: 208 men (median PSA 0.8 [0.2 - 98.4] ng/mL) underwent PyL PET/CT. The study achieved its primary endpoint: CLR of 84.8% to 87.0% among the three PyL-PET/CT readers; the LLCI for CLR by all three reviewers was >77%. Here we report the clinical impact. Based on local radiology assessment, PSMA-avid lesion(s) were identified in 69.3% (142/208) of pts. 63.9% (131/205) had a change in intended management after PyL-PET/CT, of which 78.6% (103/131) were attributable to positive PyL finding(s) and 21.4% (28/131) to negative PyL scans. Changes included: salvage local therapy to systemic therapy (n=58); observation before initiating therapy (n=49); noncurative systemic therapy to salvage local therapy (n=43); and planned treatment to observation (n=9). PyL was well tolerated with one drug-related SAE (hypersensitivity) and the most common AE being headache (n=4; 1.9%). Conclusions: PSMA-targeted PyL-PET/CT detected and localized occult disease in most men with BCR presenting with negative or equivocal conventional imaging. PyL-PET/CT led to changed management plans in the majority of pts, thus providing evidence that clinicians find PSMA PET imaging useful in men with recurrent or suspected metastatic PCa. Clinical trial information: NCT03739684 .

9 Background: Current imaging modalities are suboptimal for the initial staging of men at risk of harboring occult metastatic prostate cancer (PCa). PSMA-based imaging is considered highly promising for PCa detection. 18F-DCFPyL is a novel PSMA-targeted radiopharmaceutical for positron emission tomography (PET) that may be useful in staging of pts with high risk PCa. The diagnostic performance of 18F-DCFPyL regarding regional and distant metastases has been previously reported. Here we report on detection rates and the resulting impact 18F-DCFPyL may have on staging of pts with high risk PCa. Methods: 18F-DCFPyL PET/CT was evaluated in 252 men with high-risk PCa who were planned for radical prostatectomy with lymphadenectomy (RP-PLND). 9 mCi (333 MBq) of 18F-DCFPyL was administered 1-2 hours prior to PET/CT. Based on TNM staging, 18F-DCFPyL PET/CT detection rates including lesion counts were systematically analyzed: prostatic (T), pelvic LN (N), extra-pelvic LN (M1a), bone (M1b) & other visceral organs/soft tissue (M1c). Three central, blinded, and independent readers evaluated the 18F-DCFPyL scans. Results: At study entry, 97% and 99% of all evaluable pts had no known nodal or metastatic disease, respectively, based on standard cross-sectional imaging. Of these, 18F-DCFPyL PET/CT staged 37 (14.7%) pts with N1 disease and 27 (10.7%) pts with M1 disease (1 [0.4%] M1a, 23 [9.1%] M1b, and 3 [1.2%] M1c). In total, 56 (22%) of patients were upstaged to N1 or M1 disease by 18F-DCFPyL. The positive predictive value of 18F-DCFPyL based on histopathologic validation for pelvic LNs was 86.7% (95% CI: 70, 95). Only one patient in Cohort A underwent a biopsy of their 18F-DCFPyL detected M1 finding; histopathology confirmed the metastatic lesion in the spine to be a true positive. Conclusions: A total of 22% of pts with high-risk PCa planned for RP-PLND had regional or distant metastatic lesions detected on 18F-DCFPyL PET/CT. These results suggest the potential utility of 18F-DCFPyL PET/CT in the staging of men with newly diagnosed high risk PCa to develop optimized treatment paradigms. Clinical trial information: NCT02981368.

BackgroundThis project is an effort to understand how orders for IV immunoglobulin (IVIg) are documented and prescribed by physicians, and subsequently, how they are reviewed by insurance companies for the treatment of immune neuropathies.MethodsA panel of neuromuscular specialists reviewed case records from 248 IVIg-naive patients whose in-home IVIg infusion treatment was submitted to insurance for authorization. After reviewing a case record, 1 panelist was asked to make a diagnosis and to answer several questions about the treatment. A second panelist reviewed the original record and follow-up records that were obtained for reauthorization of additional treatments and was asked to determine whether the patient had responded to the treatment.ResultsOur specialists believed that only 32.2% of 248 patients had an immune neuropathy and were appropriate candidates for IVIg therapy, whereas 46.4% had neuropathies that were not immune mediated. Only 15.3% of cases met electrodiagnostic criteria for a demyelinating neuropathy. Our specialists believed that 36.7% of 128 cases with follow-up records had responded to therapy. In cases in which the initial reviewer had predicted that there would be a response to IVIg, the second reviewer found that 54% had responded. This is compared with a 27% response rate when the first reviewer predicted that there would be no response (p = 0.019).ConclusionsOur expert review finds that the diagnosis of immune neuropathies made by providers, and subsequently approved for IVIg therapy by payers, is incorrect in a large percentage of cases. If payers include an expert in their review process, it would improve patient selection, appropriate use, and continuation of treatment with this expensive therapeutic agent.

Cyberbullying, defined as bullying that takes place using technology, includes similar tactics found in traditional bullying as well as unique approaches such as viral repetition. Nationally, prevalence rates for cyberbullying range from 10% to as high as 40% of school-aged children, depending on the definition and measurement tool applied. The current study examines public tweets with keywords and hashtags related to cyberbullying posted during May 2016, using both human evaluation and computer examination to answer the following research questions: (1) What is the sentiment of tweets using cyberbullying keywords/hashtags? (2) What is the thematic content of the tweets? (3) What is the relationship between coding by researchers versus automated coding by Linguistic Inquiry and Word Count (LIWC) software? and (4) What is the content of the URLs attached to the tweets? A unique aspect of this study is the examination of the content of URLs included in the tweets, with the finding that the majority of the accessible URL references were to material that was positively focused. The majority of sample tweets referred to a cyberbully situation, contributed to a negative atmosphere, included references to known individuals, and suggested ongoing cyberbullying events. Results from this study suggest an opportunity for researchers, educators, and public health practitioners to use discourse on social media to inform interventions, to educate and share information, and to promote social well-being and mental health.

Importance Geographic atrophy (GA) secondary to age-related macular degeneration is a leading cause of visual disability in older individuals. A phase 2 trial suggested that lampalizumab, a selective complement factor D inhibitor, reduced the rate of GA enlargement, warranting phase 3 trials. Objective To assess the safety and efficacy of lampalizumab vs sham procedure on enlargement of GA. Design, Setting, and Participants Two identically designed phase 3 double-masked, randomized, sham-controlled clinical trials, Chroma and Spectri, enrolled participants from August 28, 2014, to October 6, 2016, at 275 sites in 23 countries. Participants were aged 50 years or older, with bilateral GA and no prior or active choroidal neovascularization in either eye and GA lesions in the study eye measuring 2.54 to 17.78 mm 2 with diffuse or banded fundus autofluorescence patterns. Interventions Participants were randomized 2:1:2:1 to receive 10 mg of intravitreous lampalizumab every 4 weeks, sham procedure every 4 weeks, 10 mg of lampalizumab every 6 weeks, or sham procedure every 6 weeks, through 96 weeks. Main Outcomes and Measures Safety and efficacy assessed as mean change from baseline in GA lesion area at week 48 from centrally read fundus autofluorescence images of the lampalizumab arms vs pooled sham arms, in the intent-to-treat population and by complement factor I–profile genetic biomarker. Results A total of 906 participants (553 women and 353 men; mean [SD] age, 78.1 [8.1] years) were enrolled in Chroma and 975 participants (578 women and 397 men; mean [SD] age, 77.9 [8.1] years) were enrolled in Spectri; 1733 of the 1881 participants (92.1%) completed the studies through 48 weeks. The adjusted mean increases in GA lesion area from baseline at week 48 were 1.93 to 2.09 mm 2 across all groups in both studies. Differences in adjusted mean change in GA lesion area (lampalizumab minus sham) were −0.02 mm 2 (95% CI, −0.21 to 0.16 mm 2 ; P = .80) for lampalizumab every 4 weeks in Chroma, 0.16 mm 2 (95% CI, 0.00-0.31 mm 2 ; P = .048) for lampalizumab every 4 weeks in Spectri, 0.05 mm 2 (95% CI, −0.13 to 0.24 mm 2 ; P = .59) for lampalizumab every 6 weeks in Chroma, and 0.09 mm 2 (95% CI, −0.07 to 0.24 mm 2 ; P = .27) for lampalizumab every 6 weeks in Spectri. No benefit of lampalizumab was observed across prespecified subgroups, including by complement factor I–profile biomarker. Endophthalmitis occurred after 5 of 12 447 injections (0.04%) or in 5 of 1252 treated participants (0.4%) through week 48. Conclusions and Relevance In Chroma and Spectri, the largest studies of GA conducted to date, lampalizumab did not reduce GA enlargement vs sham during 48 weeks of treatment. Results highlight the substantial and consistent enlargement of GA, at a mean of approximately 2 mm 2 per year. Trial Registration ClinicalTrials.gov Identifier:NCT02247479andNCT02247531

Idiopathic inflammatory myopathies are rare autoimmune disorders characterized by proximal muscle weakness, elevation of muscle enzymes, abnormal electromyogram and imaging studies revealing areas of edema and inflammation. Initial approach to inflammatory myopathies includes steroids and immunosuppressive agents, with most individuals responding satisfactorily to therapy. However, treatment-refractory myopathies prompts clinicians to use second line agents to achieve remission. In this case series, we describe three patients with refractory idiopathic inflammatory myopathies who were treated with tacrolimus (TAC) added to mycophenolate mofetil (MMF) and steroid therapy, who achieved clinical and biochemical remission.

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by fibroproliferative alterations of the microvasculature leading to fibrosis and loss of function of the skin and internal organs. Gastrointestinal manifestations of SSc are the most commonly encountered complications of the disease affecting nearly 90% of the SSc population. Among these complications, the esophagus and the anorectum are the most commonly affected. However, this devastating disorder does not spare any part of the gastrointestinal tract (GIT), and includes the oral cavity, esophagus, stomach, small and large bowels as well as the liver and pancreas. In this review, we present the current understanding of the pathophysiologic mechanisms of SSc including vasculopathy, endothelial to mesenchymal transformation as well as the autoimmune pathogenetic pathways. We also discuss the clinical presentation and diagnosis of each part of the GIT affected by SSc. Finally, we highlight the latest developments in the management of this disease, addressing the severe malnutrition that affects this vulnerable patient population and ways to assess and improve the nutritional status of the patients.

Traumatic brain injury (TBI) affects 10 million people worldwide, annually. TBI is linked to increased risk of psychiatric disorders. TBI, induced by explosive devices, has a unique phenotype. Over one-third of people exposed to blast-induced TBI (bTBI) have prolonged neuroendocrine deficits, shown by anterior pituitary dysfunction. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is linked to increased risk for psychiatric disorders. Not only is there limited information on how the HPA axis responds to mild bTBI (mbTBI), sex differences are understudied. We examined central and peripheral HPA axis reactivity, 7 to 10 days after mbTBI in male and female mice. Males exposed to mbTBI had increased restraint-induced serum corticosterone (CORT), but attenuated restraint-induced corticotropin-releasing factor (CRF)/c-Fos-immunoreactivity (ir) in the paraventricular nucleus of the hypothalamus (PVN). Females displayed an opposite response, with attenuated restraint-induced CORT and enhanced restraint-induced PVN CRF/c-Fos-ir. We examined potential mechanisms underlying this dysregulation and found that mbTBI did not affect pituitary (pro-opiomelanocortin and CRF receptor subtype 1) or adrenal (11β-hydroxylase, 11β-dehydrogenase 1, and melanocortin 2 receptor) gene expression. mbTBI did not alter mineralocorticoid or glucocorticoid gene expression in the PVN or relevant limbic structures. In females, but not males, mbTBI decreased c-Fos-ir in non-neuroendocrine (presumably preautonomic) CRF neurons in the PVN. Whereas we demonstrated a sex-dependent link to stress dysregulation of preautonomic neurons in females, we hypothesize that mbTBI may disrupt limbic pathways involved in HPA axis coordination in males. Overall, mbTBI altered the HPA axis in a sex-dependent manner, highlighting the importance of developing therapies to target individual strategies that males and females use to cope with mbTBI.

Immunotherapy-induced hypophysitis presents with headache, fatigue, and visual disturbances. The diagnosis is supported by imaging findings of pituitary swelling, enhancement, and hypermetabolism and established by low levels of pituitary hormones. A 64-year-old man with metastatic melanoma on nivolumab presented with a severe headache, initially attributed to sinus disease. Contrast CT was interpreted as minor sinus disease and no pituitary abnormality. Hypophysitis was eventually diagnosed and successfully treated based on PET and laboratory findings. Our retrospective analysis demonstrated abnormal convex superior pituitary border visible on contrast and noncontrast CT and PET. This feature may aid diagnosis in the challenging cases.

The advent of hydroxyurea and advanced medical care, including immunizations has led to improved survival, among patients with Sickle Cell Disease (SCD). This prolonged survival however introduces, a chronic inflammatory disorder, Rheumatoid Arthritis (RA), which presents at a relatively older age and is rarely reported among SCD patients. In this review, we highlight the epidemiological association of SCD-RA and discuss the underlying common pathogenetic mechanisms, such as endothelial dysfunction, the role of inflammatory cytokines and oxidative stress. We also point to the difficulties in ascertaining the clinical diagnosis of RA in SCD patients. Finally, we provide rationale for therapeutic options available for RA and the challenges in the management of these patients with agents that are known to increase the risk of infection and immunosuppression such as steroids, disease modifying anti-rheumatic drugs and biologics.

Background and Objectives: The transition to clerkships is one of the most challenging times during medical school. To help students better cope, many schools have established transition-to-clerkship curricula. Such curricula may optimally prepare students through increasing their self-efficacy and response efficacy. We hypothesized that a small-group, near-peer-led format would be ideally suited to help students achieve these outcomes. Methods: During process improvement for a transition-to-clerkship curriculum, we conducted an informal focus group and subsequent survey of postclerkship students to guide curricular innovation, including incorporation of third- and fourth-year students as near-peer instructors in a seminar format. Seminars included three sequential small-group discussions focused on discrete topic areas and concluded with a large-group session highlighting salient discussion points. To evaluate the impact of this educational strategy, near-peer learners were surveyed before and after the seminars. Results: Junior student participants reported feeling more prepared to integrate into the health care team, develop a clerkship study plan, and access applicable, valuable study materials, both immediately following the seminars and 6 months later, demonstrating increased self-efficacy. These students placed equal or greater value on these topics as compared to students in previous year groups, demonstrating similar response efficacy. Conclusions: This study demonstrated an increase in student self-efficacy that persisted 6 months postintervention, in addition to similar response efficacy. Future research could be directed toward: (1) investigating whether improvements in self-efficacy among students transitioning to clerkships are associated with improved clerkship performance and (2) studying outcomes for near-peer teachers.

Background/Purpose: Accumulating evidence indicates a relationship between Cardiovascular Disease (CVD) and osteoporosis. Hypertension, a known risk factor for CVD is also associated with low Bone Mineral Density (BMD). We hypothesize that Pulse Pressure (PP); a CVD risk factor is associated with BMD. Methods: Data from two consecutive cycles of National Health and Nutritional Examination Survey (NHANES) from 2009–2010 and 2011–2012. Point estimates of demographic variables were calculated using descriptive methods. Study participants were divided into 4 groups based on quartile distribution of PP. Multivariate linear regression analysis was performed to assess the relationship between BMD and PP. Results: A total of 8,179 NHANES participants were included in the study (Tables 1–3). The cohort’s mean age (± SE) was 53.3 years 0.19, mean BMI (± SE) 29.6 kg/m2 ± 0.07. PP was significantly higher with increased age, among Blacks (57.4 ± 0.52) and Hispanics (57.5 ± 0.19) compared to whites (53.9 ± 0.29), and for men (57.2 ± 0.16) when compared to women (54.1 ± 0.17), p

Progressive muscular atrophy (PMA) is a rare, sporadic, adult-onset motor neuron disease, clinically characterized by isolated lower motor neuron features; however, clinically evident upper motor neuron signs may emerge in some patients. Subclinical upper motor neuron involvement is identified pathologically, radiologically, and neurophysiologically in a substantial number of patients with PMA. Patients with subclinical upper motor neuron involvement do not fulfill the revised El Escorial criteria to participate in amyotrophic lateral sclerosis clinical trials. Intravenous immunoglobulin therapy is only marginally beneficial in a small subgroup of patients with lower motor neuron syndrome without conduction block.

The literature on alcohol and alcoholism has long noted how the effects of alcohol are reported in early sources, including religious texts such as the Bible and Talmud. In that vein, we suggest that the Bible, as elucidated according to long-established rabbinic interpretation, contains the earliest recorded case of drug-dependent memory, in the account of Lot's alcohol-facilitated incestuous relationships with his daughters (Genesis 19:29-38). We posit that the Talmudic, Midrashic, and traditional rabbinic commentaries that support our reading of the Lot narrative convey keen understanding of the effects of alcohol on recall. These Jewish sources, written centuries ago, demonstrate insight into the nature of alcohol-influenced cognitive function, which was thought to have been unknown prior to contemporary times.