Diagnostic accuracy of a novel lateral flow assay for histoplasmosis.

Antigen testing is an important diagnostic tool for histoplasmosis but has limited availability globally. We evaluated the OIDx urine lateral flow antigen assay among 204 persons suspected to have histoplasmosis. Among patients with proven histoplasmosis, sensitivity was 33.3% (3/9, 95% CI 7.5%-70.1%) and specificity 80.5% (157/195, 95% CI 74.3%-85.8%). The MiraVista urine antigen test had better specificity (96.9%) and equal sensitivity. The OIDx test demonstrated 33.3% (3/9) positive agreement and 84.0% (163/194) negative agreement with the MiraVista test. These results should be considered in the context of our low HIV prevalence population with a mixture of pulmonary and disseminated disease.

We evaluated a new lateral flow antigen test for the diagnosis of histoplasmosis. Proven/probable cases were mostly pulmonary disease making antigen tests likely to be less sensitive in this population. The test had similar sensitivity to the established antigen test but was less specific.

Skeletal muscle analysis of cancer patients reveals a potential role for carnosine in muscle wasting.

BACKGROUND: Muscle wasting during cancer cachexia is mediated by protein degradation via autophagy and ubiquitin-linked proteolysis. These processes are sensitive to changes in intracellular pH ([pH]i ) and reactive oxygen species, which in skeletal muscle are partly regulated by histidyl dipeptides, such as carnosine. These dipeptides, synthesized by the enzyme carnosine synthase (CARNS), remove lipid peroxidation-derived aldehydes, and buffer [pH]i . Nevertheless, their role in muscle wasting has not been studied. METHODS: Histidyl dipeptides in the rectus abdominis (RA) muscle and red blood cells (RBCs) of male and female controls (n = 37), weight stable (WS: n = 35), and weight losing (WL; n = 30) upper gastrointestinal cancer (UGIC) patients, were profiled by LC-MS/MS. Expression of enzymes and amino acid transporters, involved in carnosine homeostasis, was measured by Western blotting and RT-PCR. Skeletal muscle myotubes were treated with Lewis lung carcinoma conditioned medium (LLC CM), and ß-alanine to study the effects of enhancing carnosine production on muscle wasting. RESULTS: Carnosine was the predominant dipeptide present in the RA muscle. In controls, carnosine levels were higher in men (7.87 ± 1.98 nmol/mg tissue) compared with women (4.73 ± 1.26 nmol/mg tissue; P = 0.002). In men, carnosine was significantly reduced in both the WS (5.92 ± 2.04 nmol/mg tissue, P = 0.009) and WL (6.15 ± 1.90 nmol/mg tissue; P = 0.030) UGIC patients, compared with controls. In women, carnosine was decreased in the WL UGIC (3.42 ± 1.33 nmol/mg tissue; P = 0.050), compared with WS UGIC patients (4.58 ± 1.57 nmol/mg tissue), and controls (P = 0.025). Carnosine was significantly reduced in the combined WL UGIC patients (5.12 ± 2.15 nmol/mg tissue) compared with controls (6.21 ± 2.24 nmol/mg tissue; P = 0.045). Carnosine was also significantly reduced in the RBCs of WL UGIC patients (0.32 ± 0.24 pmol/mg protein), compared with controls (0.49 ± 0.31 pmol/mg protein, P = 0.037) and WS UGIC patients (0.51 ± 0.40 pmol/mg protein, P = 0.042). Depletion of carnosine diminished the aldehyde-removing ability in the muscle of WL UGIC patients. Carnosine levels were positively associated with decreases in skeletal muscle index in the WL UGIC patients. CARNS expression was decreased in the muscle of WL UGIC patients and myotubes treated with LLC-CM. Treatment with ß-alanine, a carnosine precursor, enhanced endogenous carnosine production and decreased ubiquitin-linked protein degradation in LLC-CM treated myotubes. CONCLUSIONS: Depletion of carnosine could contribute to muscle wasting in cancer patients by lowering the aldehyde quenching abilities. Synthesis of carnosine by CARNS in myotubes is particularly affected by tumour derived factors and could contribute to carnosine depletion in WL UGIC patients. Increasing carnosine in skeletal muscle may be an effective therapeutic intervention to prevent muscle wasting in cancer patients.

Aligning the Post Master's DNP with the 2021 AACN Essentials.

BACKGROUND: The Essentials: Core Competencies for Professional Nursing Education was published in 2021 to establish competency-based education on two levels; entry and advanced. Advanced level competencies are intended for doctorally prepared professionals. PURPOSE: The purpose of this initiative was to align a Post Master's Doctor of Nursing Practice (DNP) Program with the new 2021 American Association of Colleges of Nursing (AACN) Competency-Based Essentials. METHODS: Three DNP faculty met weekly, outlined a timeframe and approached the revision as a quality improvement plan to revise the curriculum based on our comprehensive review of the domains and concepts of the revised (2021) AACN Essentials. DNP Course Leads were interviewed to evaluate the course objectives, student learning objectives, assignments, and course content. RESULTS: Six new program outcomes (POs) were written. For each (PO), measurable student learning outcomes (SLOs) were articulated for each course. Several courses were combined or retired, and several new courses were added including an elective. The DNP project was reframed based on a 'systems' approach to implement quality improvement (QI) within the health care system in consideration of the concepts of diversity, equity, and inclusion (DEI) and the impact on patient outcomes. CONCLUSIONS: In keeping with the Mission, Vision and Values of the College and with the collaboration and support from the Dean, the graduate Chair, and faculty of the College, the post-master's DNP program was approved with an anticipated start date in Summer, 2023.

Sexual and Reproductive Health and Reproductive Coercion in Women Victim/Survivors Receiving Housing Support.

Housing instability and intimate partner violence (IPV) compromise women's sexual and reproductive health (SRH) through reduced contraceptive access and increased risk of unintended pregnancy. This study describes the reproductive health status and needs of IPV survivors receiving housing support and explores factors influencing their experience of reproductive coercion (RC), specifically. Cross-sectional baseline data from a quasi-experimental study of 70 IPV survivors enrolled in housing programs in the Baltimore, MD, metropolitan area from June 2019 through December 2020 were analyzed. Of the 70 women enrolled in the study, 70.3 percent (n = 45) desired to avoid pregnancy, but 57.4 percent were either using no contraceptive method (31.2%) or methods with low effectiveness (26.2%). Approximately, 1 in 6 women (16.4%, n = 11) experienced RC in the past 3 months, which was associated with frequency and severity of IPV (p = 0.001 to 0.005) and PTSD (p = 0.001), as well as not sharing children with the abusive partner (p = 0.002). This study highlights reproductive health risks in an important and under-studied population of women seeking housing due to IPV. Leaving an abusive relationship is a uniquely vulnerable time, and also a time of opportunity, as women are accessing services that can be tailored to their SRH needs. Significant results highlight vulnerability to and consequences of RC in this population. This study has implications for IPV support programs and housing programs that serve women.

20 Years of ICF-International Classification of Functioning, Disability and Health: Uses and Applications around the World.

The International Classification of Functioning Disability and Health (ICF) was approved in 2001 and, since then, several studies reported the increased interest about its use in different sectors. A recent overview that summarizes its applications is lacking. This study aims to provide an updated overview about 20 years of ICF application through an international online questionnaire, developed by the byline authors, and sent to each World Health Organization Collaborating Centers of the Family of International Classifications (WHO-FIC CCs). Data was collected during October 2020 and December 2021 and descriptive content analyses were used to report main results. Results show how, in most of the respondent countries represented by WHO-FIC CCs, ICF was mainly used in clinical practice, policy development and social policy, and in education areas. Despite its applications in different sectors, ICF use is not mandatory in most countries but, where used, it provides a biopsychosocial framework for policy development in health, functioning and disability. The study provides information about the needs related to ICF applications, that can be useful to organize targeted intervention plans. Furthermore, this survey methodology can be re-proposed periodically to monitor the use of the ICF in the future.

Safe and Stable Housing for Intimate Partner Violence Survivors, Maryland, 2019‒2020.

House of Ruth Maryland is a comprehensive intimate partner violence (IPV) service provider. Our academic‒practitioner partnership conducted a prospective, quasi-experimental evaluation (n = 70) of on-site transitional housing and community-based rapid rehousing to meet the safety and stability needs of individuals made homeless because of IPV. By 6-month follow-up, both IPV revictimization and housing instability significantly improved (P < .001). Housing supports through an IPV service provider advanced the dual goals of safety and housing stability for IPV survivors. Safe, affordable housing is an IPV prevention strategy. (Am J Public Health. 2022;112(6):865-870. https://doi.org/10.2105/AJPH.2022.306728).

Setting research priorities for management and treatment of hyperhidrosis: the results of the James Lind Alliance Priority Setting Partnership.

BACKGROUND: Hyperhidrosis is a common skin condition characterized by excessive sweating, which can negatively impact on quality of life. It is under-researched compared with other conditions of similar prevalence. AIM: To generate a Top 10 list of research priorities for the treatment and management of hyperhidrosis, with equal input from people with hyperhidrosis and healthcare professionals (HCPs). METHODS: A priority setting partnership (PSP) was established and processes from the James Lind Alliance Handbook were followed. An online survey asked participants what questions they would like research to answer. These questions were grouped into 'indicative questions', which were ranked in a second survey of 45 indicative questions. The top 23 questions were then taken to a final workshop event attended by key stakeholders, and ranked to generate the Top 10 list of research priorities. RESULTS: There were 592 questions submitted by 268 respondents for the first survey. For the second survey, 286 participants ranked the indicative questions in order of priority. At the final workshop, the Top 10 list was generated. The top three priorities were: (i) Are there any safe and effective permanent solutions for hyperhidrosis? (ii) What is the most effective and safe oral treatment (drugs taken by mouth) for hyperhidrosis? and (iii) What are the most effective and safe ways to reduce sweating in particular areas of the body? CONCLUSIONS: There are many unanswered research questions that both people with hyperhidrosis and HCPs would like to see answered. The results from this PSP will help to ensure future research funding can be directed to these areas of priority.

Defining Justice: Restorative and Retributive Justice Goals Among Intimate Partner Violence Survivors.

Intimate partner violence (IPV) and sexual violence (SV) are drivers of women's morbidity and mortality yet remain among the most underreported crimes in the United States. Understanding IPV/SV survivors' justice preferences and justice definitions can strengthen violence prevention and response systems. In-depth interviews were conducted with women who experienced past-year IPV (n = 26), to explore their justice preferences and recommendations. Primary themes included accountability, safety, and rehabilitation, with examples within and outside the current justice system, and across restorative and retributive justice frameworks. Women sought accountability through a variety of means. Retributive approaches like incarceration offered accountability as well as fleeting safety, but were critically limited in addressing the root causes of violence and, in some cases, were felt to exacerbate the problem. Women's expressed needs and preferences centered on restorative aspects of justice, including perpetrator's acknowledgment of harm, achieving physical safety and stability, and perpetrator rehabilitation through counseling. Paradoxically, women's safety-related justice goals both encouraged and discouraged their engagement in the formal justice system. The discordance between women's justice preferences and their perceptions and experiences within the current justice system illustrate complex and difficult trade-offs faced by survivors in achieving physical, social, and economic safety. Moreover, they likely contribute to the low levels of IPV/SV reporting to police. Women's goals were aligned with restorative justice principles, illustrating the value of this approach. In an era of unprecedented dialogue on justice reform, results provide direction for integrating restorative justice practices to strengthen the justice response to violence against women.

Organizational Readiness for Intimate Partner Violence Response among Supportive Housing Providers: A Capacity Assessment in Maryland.

Intimate partner violence (IPV) frequently leads to housing instability and homelessness among survivors. While the client populations of many housing support programs are likely to include IPV survivors who have unique safety needs, the organizational readiness of these housing providers to identify and support IPV survivors is not clear. This study assessed organizational readiness for IPV response among Rapid Re-Housing (RRH) and Transitional Housing (TH) providers in Maryland, whose client populations include women (n = 32). We adapted the Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS) to create the Housing provider Readiness to Manage IPV Survey (H-REMIS), inclusive of IPV-related perceptions, policies, staff training and capability, and resources. The 12-point H-REMIS demonstrated acceptable internal consistency reliability (Cronbach's α = 0.748). Descriptive and comparative analyses domains by IPV-specific (n = 4) and general (n = 28) housing providers assessed readiness and identified areas for improvement. IPV-specific providers had higher mean organizational readiness for IPV response scores relative to non-IPV specific providers (11.3 and 7.5, respectively). High readiness areas included perceiving the importance of IPV and staff having adequate time, space, and comfort level to address IPV. Areas of low readiness included development and use of IPV response policies as well as staff training on IPV. This assessment documents concerning gaps in organizational readiness for IPV response among supportive housing providers, and pinpoints areas where training and capacity building can be most valuable. The process of improving readiness in the supportive housing sector must involve capacity building and a systems-level approach in order to ensure that all supportive housing providers are prepared to meet the needs of IPV survivors among their client population.

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

BACKGROUND: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied. METHODS: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients. RESULTS: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group. CONCLUSIONS: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).

Development of a customised data management system for a COVID-19-adapted colorectal cancer pathway.

OBJECTIVES: A customised data management system was required for a rapidly implemented COVID-19-adapted colorectal cancer pathway in order to mitigate the risks of delayed and missed diagnoses during the pandemic. We assessed its performance and robustness. METHODS: A system was developed using Microsoft Excel (2007) to retain the spreadsheets' intuitiveness of direct data entry. Visual Basic for Applications (VBA) was used to construct a user-friendly interface to enhance efficiency of data entry and segregate the data for operational tasks. RESULTS: Large data segregation was possible using VBA macros. Data validation and conditional formatting minimised data entry errors. Computation by the COUNT function facilitated live data monitoring. CONCLUSION: It is possible to rapidly implement a makeshift database system with clinicians' regular input. Large-volume data management using a spreadsheet system is possible with appropriate data definition and VBA-programmed data segregation. The described concept is applicable to any data management system construction requiring speed and flexibility in a resource-limited situation.

Virtual pedagogical strategies and HESI student outcomes in response to COVID-19.

BACKGROUND: To maintain curricular integrity in response to COVID-19, nurse educators are increasingly required to transition from traditional (face-to-face) to virtual pedagogy. OBJECTIVES: The purpose of this analysis was to compare the HESI scores based on a traditional pedagogy with the HESI scores following implementation of virtual pedagogy during Spring 2020. METHODS: Student (n = 115; 81% female; mean age = 25.71 years) HESI scores were compared after each eight-week session using the Mann Whitney U test, permutation test and Wilcoxon rank test. Logistic regression was used to identify students achieving at least 850. Chi-square test was used to determine the relationship between pedagogy and students meeting 850 HESI scores. Fall 2019 Exit HESI scores were also compared with Spring 2020 Exit HESI scores. RESULTS: Students from diverse backgrounds (53.9% White; 27.8% Hispanic; 10.4% Asian; 5.2% Black; 1% Unknown) increased (p = 0.022) MHESI scores following virtual pedagogy in Fundamentals, although no difference was found in Maternity (p = 0.311), Psychiatric (p = 0.129) or Medical Surgical Nursing (p = 0.692). Wilcoxon rank test revealed significant differences in MHESI scores in same cohort of students between traditional (Psychiatric) and virtual strategies (Medical-Surgical) (p < 0.01); and traditional (Medical-Surgical) and virtual (Psychiatric) strategies (p = 0.023). White students' MHESI scores were higher than Asian students', as revealed by Logistic regression with no differences based on gender. Spring 2020 and Fall 2019 Exit HESI scores were comparable (p = 0.499). Chi-square analysis revealed no relationship between pedagogy and achieving at least 850 on HESI (χ2 = 0.027, p = 0.871). CONCLUSIONS: Based on the exit HESI scores, virtual pedagogy was as effective as traditional pedagogy for maintaining student competency in a community college associate degree nursing program. Future analyses of the effectiveness of virtual pedagogy in meeting curricular outcomes is warranted, regardless of exit degree option.

Terminal Schwann cells at the human neuromuscular junction.

Terminal Schwann cells are non-myelinating glial cells localized to the neuromuscular junction. They play an important role in regulating many aspects of neuromuscular junction form and function, in health and during disease. However, almost all previous studies of mammalian terminal Schwann cells have used rodent models. Despite a growing awareness of differences in the cellular and molecular anatomy of rodent and human neuromuscular junctions, it remains unclear as to whether these differences also extend to the terminal Schwann cells. Here, we have adapted immunohistochemical protocols to facilitate visualization and comparative morphometric analyses of terminal Schwann cells at the human and mouse neuromuscular junction. We labelled terminal Schwann cells in the peroneus brevis muscle in six adult mice and five humans with antibodies against S100 protein. All human neuromuscular junctions were associated with at least one terminal Schwann cell, consistent with findings from other species, with an average of ∼1.7 terminal Schwann cells per neuromuscular junction in both humans and mice. In contrast, human terminal Schwann cells were significantly smaller than those of mice (P ≤ 0.01), in keeping with differences in overall synaptic size. Human terminal Schwann cell cytoplasm extended significantly beyond the synaptic boundaries of the neuromuscular junction, whereas terminal Schwann cells in mice were largely restricted to the synapse. Moreover, there was a significant difference in the location of terminal Schwann cell nuclei (P ≤ 0.01), with human terminal Schwann cells having their nuclear compartment located beyond the perimeter of the synapse more than the mouse. Taken together, these findings demonstrate that terminal Schwann cells at the human neuromuscular junction have notable differences in their morphology and synaptic relationships compared to mice. These fundamental differences need to be considered when translating the findings of both neuromuscular junction biology and pathology from rodents to humans.

Examining the Neighborhood Attributes of Recently Housed Partner Violence Survivors in Rapid Rehousing.

Survivors' considerations for re-housing following intimate partner violence (IPV) are understudied despite likely neighborhood-level influences on women's safety. We assess housing priorities and predictors of re-housing location among recent IPV survivors (n = 54) in Rapid Re-housing (RRH) in the Baltimore-Washington Metropolitan Area. Choropleth maps depict residential location relative to census tract characteristics (neighborhood deprivation index (NDI) and residential segregation) derived from American Community Survey data (2013-2017). Linear regression measured associations between women's individual, economic, and social factors and NDI and segregation. In-depth interviews (n = 16) contextualize quantitative findings. Overall, survivors re-housed in significantly more deprived and racially segregated census tracts within their respective regions. In adjusted models, trouble securing housing (B = 0.74, 95% CI: 0.13, 1.34), comfortability with proximity to loved ones (B = 0.75, 95% CI: 0.02, 1.48), and being unsure (vs unlikely) about IPV risk (B = -0.76, 95% CI: -1.39, -0.14) were significantly associated with NDI. Economic dependence on an abusive partner (B = -0.31, 95% CI: -0.56, -0.06) predicted re-housing in segregated census tracts; occasional stress about housing affordability (B = 0.39, 95% CI: 0.04, 0.75) predicted re-housing in less segregated census tracts. Qualitative results contextualize economic (affordability), safety, and social (familiarity) re-housing considerations and process impacts (inspection delays). Structural racism, including discriminatory housing practices, intersect with gender, exacerbating challenges among survivors of severe IPV. This mixed-methods study further highlights the significant economic tradeoffs for safety and stability, where the prioritization of safety may exacerbate economic devastation for IPV survivors. Findings will inform programmatic policies for RRH practices among survivors.

Short-term outcomes of a COVID-adapted triage pathway for colorectal cancer detection.

AIM: The dramatic curtailment of endoscopy and CT colonography capacity during the coronavirus pandemic has adversely impacted timely diagnosis of colorectal cancer (CRC). We describe a rapidly implemented COVID-adapted diagnostic pathway to mitigate risk and maximize cancer diagnosis in patients referred with symptoms of suspected CRC. METHOD: The 'COVID-adapted pathway' integrated multiple quantitative faecal immunochemical tests (qFIT) to enrich for significant colorectal disease with judicious use of CT with oral contrast to detect gross pathology. Patients reporting 'high-risk' symptoms were triaged to qFIT+CT and the remainder underwent an initial qFIT to inform subsequent investigation. Demographic and clinical data were prospectively collected. Outcomes comprised cancer detection frequency. RESULTS: Overall, 422 patients (median age 64 years, 220 women) were triaged using this pathway. Most (84.6%) were referred as 'urgent suspicious of cancer'. Of the 422 patients, 202 (47.9%) were triaged to CT and qFIT, 211 (50.0%) to qFIT only, eight (1.9%) to outpatient clinic and one to colonoscopy. Fifteen (3.6%) declined investigation and seven (1.7%) were deemed unfit. We detected 13 cancers (3.1%), similar to the mean cancer detection rate from all referrals in 2017-2019 (3.3%). Compared with the period 1 April-31 May in 2017-2019, we observed a 43% reduction in all primary care referrals (1071 referrals expected reducing to 609). CONCLUSION: This COVID-adapted pathway mitigated the adverse effects on diagnostic capacity and detected cancer at the expected rate within those referred. However, the overall reduction in the number of referrals was substantial. The described risk-mitigating measures could be a useful adjunct whilst standard diagnostic services remain constrained due to the ongoing pandemic.

aNMJ-morph: a simple macro for rapid analysis of neuromuscular junction morphology.

Large-scale data analysis of synaptic morphology is becoming increasingly important to the field of neurobiological research (e.g. 'connectomics'). In particular, a detailed knowledge of neuromuscular junction (NMJ) morphology has proven to be important for understanding the form and function of synapses in both health and disease. The recent introduction of a standardized approach to the morphometric analysis of the NMJ-'NMJ-morph'-has provided the first common software platform with which to analyse and integrate NMJ data from different research laboratories. Here, we describe the design and development of a novel macro-'automated NMJ-morph' or 'aNMJ-morph'-to update and streamline the original NMJ-morph methodology. ImageJ macro language was used to encode the complete NMJ-morph workflow into seven navigation windows that generate robust data for 19 individual pre-/post-synaptic variables. The aNMJ-morph scripting was first validated against reference data generated by the parent workflow to confirm data reproducibility. aNMJ-morph was then compared with the parent workflow in large-scale data analysis of original NMJ images (240 NMJs) by multiple independent investigators. aNMJ-morph conferred a fourfold increase in data acquisition rate compared with the parent workflow, with average analysis times reduced to approximately 1 min per NMJ. Strong concordance was demonstrated between the two approaches for all 19 morphological variables, confirming the robust nature of aNMJ-morph. aNMJ-morph is a freely available and easy-to-use macro for the rapid and robust analysis of NMJ morphology and offers significant improvements in data acquisition and learning curve compared to the original NMJ-morph workflow.

Adipose depot gene expression and intelectin-1 in the metabolic response to cancer and cachexia.

BACKGROUND: Cancer cachexia is a poorly understood metabolic consequence of cancer. During cachexia, different adipose depots demonstrate differential wasting rates. Animal models suggest adipose tissue may be a key driver of muscle wasting through fat-muscle crosstalk, but human studies in this area are lacking. We performed global gene expression profiling of visceral (VAT) and subcutaneous (SAT) adipose from weight stable and cachectic cancer patients and healthy controls. METHODS: Cachexia was defined as >2% weight loss plus low computed tomography-muscularity. Biopsies of SAT and VAT were taken from patients undergoing resection for oesophago-gastric cancer, and healthy controls (n = 16 and 8 respectively). RNA was isolated and reverse transcribed. cDNA was hybridised to the Affymetrix Clariom S microarray and data analysed using R/Bioconductor. Differential expression of genes was assessed using empirical Bayes and moderated-t-statistic approaches. Category enrichment analysis was used with a tissue-specific background to examine the biological context of differentially expressed genes. Selected differentially regulated genes were validated by qPCR. Enzyme-linked immunosorbent assay (ELISA) for intelectin-1 was performed on all VAT samples. The previously-described cohort plus 12 additional patients from each group also had plasma I = intelectin-1 ELISA carried out. RESULTS: In VAT vs. SAT comparisons, there were 2101, 1722, and 1659 significantly regulated genes in the cachectic, weight stable, and control groups, respectively. There were 2200 significantly regulated genes from VAT in cachectic patients compared with controls. Genes involving inflammation were enriched in cancer and control VAT vs. SAT, although different genes contributed to enrichment in each group. Energy metabolism, fat browning (e.g. uncoupling protein 1), and adipogenesis genes were down-regulated in cancer VAT (P = 0.043, P = 5.4 × 10-6 and P = 1 × 10-6 respectively). The gene showing the largest difference in expression was ITLN1, the gene that encodes for intelectin-1 (false discovery rate-corrected P = 0.0001), a novel adipocytokine associated with weight loss in other contexts. CONCLUSIONS: SAT and VAT have unique gene expression signatures in cancer and cachexia. VAT is metabolically active in cancer, and intelectin-1 may be a target for therapeutic manipulation. VAT may play a fundamental role in cachexia, but the down-regulation of energy metabolism genes implies a limited role for fat browning in cachectic patients, in contrast to pre-clinical models.

Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program.

BACKGROUND: An intranasal formulation of esketamine, combined with an oral antidepressant, is approved in the USA and the European Union for adults with treatment-resistant depression (TRD). Transient cardiovascular stimulatory effects have been reported with ketamine. METHODS: Cardiovascular effects of esketamine nasal spray, combined with an oral antidepressant, were evaluated in 1708 esketamine-treated adults with TRD in six trials (five double-blind, placebo-controlled (486 placebo-treated patients); one open-label) of 4-52 weeks' duration. Patients with established cardiovascular disease, including uncontrolled hypertension (> 140/> 90 mmHg), history of hypertensive crisis, or clinically significant electrocardiogram (ECG) abnormalities, were excluded from enrollment. Effects on cardiac repolarization were assessed in a phase I randomized, positive- and active-controlled thorough corrected QT (QTc) interval study. For adverse events, odds ratio (OR) [95% confidence interval] for esketamine/antidepressant versus antidepressant/placebo was calculated. RESULTS: Adverse events related to increased BP were reported in 12.8% of all esketamine-treated patients (in double-blind trials: esketamine/antidepressant 11.6% vs. antidepressant/placebo 3.9%; OR 3.2 [1.9-5.8]). Among the patients without a history of hypertension, new antihypertensive medication was initiated by 2.1% (6/280) of patients in the esketamine/antidepressant group versus 1.2% (2/171) of patients in the antidepressant/placebo group, in the double-blinded studies. Adverse events related to abnormal heart rate were reported in 3.0% of all esketamine-treated patients (in double-blind trials: 1.6% vs. 0.8%; OR 1.9 [0.5-8.6]). Overall, three cardiovascular adverse events related to BP increase were reported as serious and severe, and there was one fatal event considered unrelated (acute cardiac failure). BP increases reached the maximum postdose value within ~ 40 min of esketamine dosing and returned to the predose range by ~ 1.5 h postdose. In two studies (4-week duration, age 18-64 years), the largest mean maximum systolic/diastolic postdose BP increases were 13.3/8.7 mmHg for esketamine/antidepressant and 6.1/4.9 mmHg for antidepressant/placebo, and in a short-term elderly study (age ≥ 65 years) were 16.0/9.5 and 11.1/6.8 mmHg, respectively. Across studies/study phases, < 2% of patients discontinued esketamine due to adverse events of increased BP and tachycardia. No clinically relevant effect on ECG parameters was observed. Therapeutic and supratherapeutic doses of esketamine did not prolong the QTcF (QT corrected by Fridericia's equation) interval (baseline-corrected values of - 2.02 to 2.16 ms, and - 3.51 to 4.89 ms, respectively). CONCLUSIONS: BP elevations following esketamine dosing are generally transient, asymptomatic, and not associated with serious cardiovascular safety sequalae. Further evaluation of long-term cardiovascular outcomes is warranted.