Certain women develop depression with fluctuations in hormone levels whereas other women do not; this hormonally driven depression has been termed reproductive depression. The pathophysiology of reproductive depression differs from that of major depressive disorder, and this distinction has important clinical-including treatment-implications. Recent advances have revealed that the neurosteroid, allopregnanolone, plays a central role in reproductive depression. Appreciation of allopregnanolone's role in reproductive depression aids in selecting targeted treatments and in predicting symptom worsening during subsequent reproductive stages, and it can be used to reduce risk of relapse. This knowledge is also guiding the development of new pharmacologic treatments for reproductive depression.
Objective: The purpose of this review is to explore the breadth of research conducted on SDM in the care of Black patients. Methods: We conducted a scoping review following the methodological framework outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. We searched articles related to original research on SDM in the care of Black patients in October 2022 using PubMed, Embase, and Google Scholar databases. Articles of all study designs (quantitative and qualitative), published or translated into English, were included. A standardized data extraction form and thematic analysis were used to facilitate data extraction by two independent reviewers. Results: After removal of duplicates and screening, 30 articles were included in the final analysis. Black patients and clinician were found to not share the same understanding of SDM, and patients highly valued SDM in their care. Interventions to improve SDM yielded mixed results to enhance intent, participation in SDM, as well as health outcomes. Decision aids were the most effective form of intervention to enhance SDM. The most common barrier to SDM was patient-clinician communication, and was exacerbated by racial discordance, clinician mistrust, past experiences, and paternalistic clinician-patient dynamics. Conclusions: SDM has the potential to improve health outcomes in Black patients when implemented contextually within Black patients' experiences and concerns. Significant barriers such as clinician mistrust exist, and the overall perception in the Black community is that SDM does not occur sufficiently. Barriers to SDM seem to be most pronounced when there is patient-clinician racial discordance. Several interventions aimed at improving SDM with Black patients have shown mixed results. Future studies should evaluate larger-scale interventions with longer follow-up. Practice implications Shared decision making (SDM) has been proposed as a useful tool for improving quality and equity in Black patients' care. However, Black patients experience lower rates of SDM compared to other populations. SDM has the potential to improve health outcomes in Black patients when implemented contextually within Black patients' experiences and concerns.
To fight antimicrobial resistance (AMR), we must recognize and target all its manifestations. In this review, we briefly summarize the history that led to recognition of the various manifestations of AMR in bacterial pathogens and the ways in which they interrelate. We emphasize the importance of distinguishing between AMR arising from genetic alterations versus induction of endogenous machinery in response to environmental triggers, including — paradoxically — stresses from host immunity and antimicrobial therapy. We present an integrated view of AMR by reframing it as a spectrum of phenotypes within a continuous three-dimensional space defined by the growth rate, prevalence, and kill rate of cells displaying AMR. Finally, we reflect on strategies that may help stem the emergence of AMR.
Background We recently reveal that anti-CD4 autoantibodies contribute to blunted CD4+ T cell reconstitution in HIV+ individuals on antiretroviral therapy (ART). Cocaine use is common among HIV+ individuals and is associated with accelerated disease progression. However, the mechanisms underlying cocaine-induced immune perturbations remain obscure. Methods We evaluated plasma levels of anti-CD4 IgG and markers of microbial translocation, as well as B-cell gene expression profiles and activation in HIV+ chronic cocaine users and non-users on suppressive ART, as well as uninfected controls. Plasma purified anti-CD4 IgGs were assessed for antibody-dependent cytotoxicity (ADCC). Results HIV+ cocaine users had increased plasma levels of anti-CD4 IgGs, lipopolysaccharide (LPS), and soluble CD14 (sCD14) versus non-users. An inverse correlation was observed in cocaine users, but not non-drug users. Anti-CD4 IgGs from HIV+ cocaine users mediated CD4+ T cell death through ADCC in vitro . B cells from HIV+ cocaine users exhibited activation signaling pathways and activation (cycling and TLR4 expression) related to microbial translocation versus non-users. Conclusions This study improves our understanding of cocaine associated B cell perturbations and immune failure and the new appreciation for autoreactive B cells as novel therapeutic targets.
Women with antiphospholipid syndrome (APS) have an increased risk of adverse pregnancy outcomes. To define clinical, serologic, and treatment factors that can predict outcomes in pregnant women with APS. Retrospective cohort study of pregnant women with APS evaluated at a university medical center between January 2006 and August 2021. Demographics, personal and family history of thrombosis, autoimmune disease, antithrombotic use, pregnancy outcomes, maternal and fetal complications were collected. We compared pregnancy outcomes in the presence or absence of lupus anticoagulant (LA), systemic lupus erythematosus (SLE), prior thrombosis or pregnancy losses, and antithrombotic use. There were 169 pregnancies in 50 women; 79 (46.7%) occurred after maternal diagnosis of APS. The most common antithrombotic regimen was aspirin and low molecular weight heparin (LMWH) in 26.6% of pregnancies; 55.0% of all pregnancies and 68.4% of pregnancies post-APS diagnosis resulted in a live birth. In age-adjusted analyses, aspirin plus LMWH regardless of dosage was associated with significantly higher odds of live birth compared with no antithrombotic use (OR = 7.5, p < 0.001) and compared with aspirin alone (OR = 13.2, p = 0.026). SLE increased the risk for preterm birth and preeclampsia. A positive LA did not impact the outcomes evaluated and anticardiolipin IgM decreased the risk of pre-eclampsia. The presence of SLE is a significant risk factor for adverse outcomes in pregnant women with APS. Treatment with LMWH and aspirin was superior to aspirin alone. The creation of a global registry may be useful in improving the management of these patients.
Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children’s Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. We report the study design and some elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy (NEHI), with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). This Registry is the largest longitudinal chILD cohort in the U.S. to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.
Assessing cognitive function – especially language processing – in severely brain-injured patients is critical for prognostication, care, and development of communication devices (e.g., brain-computer interfaces). In patients with diminished motor function, language processing has been probed using EEG measures of command following in motor imagery tasks. While such tests eliminate the need for a motor response, they require sustained attention. However, passive listening tasks, with an EEG response measure can reduce both motor and attentional demands. These considerations motivated the development of two assays of low-level language processing – identification of differential phoneme-class responses and tracking of the natural speech envelope. This cross-sectional study looks at a cohort of 26 severely brain-injured patient subjects and 10 healthy controls. Patients’ level of function was assessed via the Coma Recovery Scale–Revised at bedside. Patients were also tested for command following via EEG and/or MRI assays of motor imagery. For the present investigation, EEG was recorded while presenting a 148 s audio clip of Alice in Wonderland. Time-locked EEG responses to phoneme classes were extracted and compared to determine a differential phoneme-class response. Tracking of natural speech envelope was assessed from the same recordings by cross-correlating the EEG response with the speech envelope. In healthy controls, the dynamics of the two measures were temporally similar but spatially different: a central parieto-occipital component of differential phoneme-class response was absent in the natural speech envelope response. The differential phoneme-class response was present in all patient subjects, including the six classified as vegetative state/unresponsive wakefulness syndrome by behavioral assessment. However, patient subjects with evidence of language processing either by behavioral assessment or motor imagery tests had an early bilateral response in the first 50 ms that was lacking in patient subjects without any evidence of language processing. The natural speech envelope tracking response was also present in all patient subjects, and responses in the first 100 ms distinguished patient subjects with evidence of language processing. Specifically, patient subjects with evidence of language processing had a more global response in the first 100 ms whereas those without evidence of language processing had a frontopolar response in that period. In summary, we developed two passive EEG-based methods to probe low-level language processing in severely brain-injured patients. In our cohort, both assays showed a difference between patient subjects with evidence of command following and those with no evidence of command following: a more prominent early bilateral response component.
Background: The ability of vibration controlled transient elastography (VCTE) to reliably exclude significant steatosis in living donor candidates could obviate the need for invasive liver biopsies, expedite the donor approval process, and reduce recipient wait time. We therefore aimed to determine whether VCTE controlled attenuation parameter (CAP) could be used to detect steatosis in potential living donors. Methods: Living donor candidates who presented for evaluation between 2016 and 2019 underwent standard donor workup, VCTE, and liver biopsy if indicated. CAP scores were compared with MRI-Fat Fraction and, when available, histologic fat fraction from liver biopsy. Receiver operating characteristic curves were used to identify cutoffs with appropriate sensitivity and specificity for screening. Statistical analysis was conducted using R (version 3.6.0). Results: Seventy-nine candidate living donors presented during the study period, of whom 71 were included in the final analysis and of whom 20 underwent liver biopsy. There was a positive correlation between MRI-Fat Fraction and CAP scores with an observed Spearman correlation coefficient of 0.424 (P < 0.01). A CAP score of 271.5 dB/m or less was determined to have 89.8% sensitivity and 75% specificity for detecting <5% steatosis on MRI. The correlation between CAP and steatosis of available histologic samples had a Pearson correlation coefficient of 0.603 (P = 0.005). A CAP cutoff of 276.0 dB/m demonstrated 66.7% sensitivity and 85.7% specificity for detecting <15% histopathologic steatosis and positive and negative predictive values of 71.5% and 82.7%, respectively. Conclusions: VCTE can be integrated into living donor evaluation to accurately screen for hepatic steatosis.
Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.
Background: Targeted radionuclide therapy with Actinium-225-labeled prostate-specific membrane antigen ligands (225Ac-PSMA) is currently being studied in clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC). Compared to β-emitting therapeutic radionuclides, alpha-emitters (e.g., 225Ac) have a significantly higher linear energy transfer and significantly shorter range. As a result, alphas could be expected to improve efficacy and reduce bystander toxicity. This systematic literature review was conducted to evaluate the impact of sequencing of 177Lu-PSMA and 225Ac-PSMA radioligand therapy (RLT) in mCRPC. Methods: The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The searches were made using relevant keywords in the PubMed, Scopus and Web of Science databases, and articles up to Aug 22, 2022, were included. Publications were excluded if they were duplicate publications, wrong study or publication format or discussing a topic out of scope. Data on efficacy, toxicity and health-related quality of life were extracted from the individual articles. The I2 index was used to measure the extent of heterogeneity amongst studies. In the studies that reported subgroup outcomes according to the prior status on 177Lu-PSMA RLT, pooled estimates of the main outcomes were generated through descriptive analysis. Quality assessment was performed using the Newark-Ottawa-Scale. Results: The study included 12 articles; one series was performed prospectively. In total, data of 329 patients were analyzed. About 33% (n=132) of the included men were pretreated with 177Lu-PSMA RLT. Seven studies, including data of 212 individuals, were eligible for quantitative analysis based on reporting outcomes of the subgroups according to their prior status on 177Lu-PSMA RLT. >25% PSA decline after 225Ac-PSMA RLT was lower in individuals who received prior 177Lu-PSMA RLT (pooled median 42.7%) compared to those who did not (pooled median 15.4%). The pooled medians of the reported median PFS and OS for pretreated vs. not pretreated individuals was 4.3 vs. 14.3 months and 11.1 vs. 9.2 months, respectively. However, the outcomes for each individual study were reported inconsistently (I2 =99.9%). None of the included studies stratified the report of adverse events or changes in health-related quality of life for the subgroups. Conclusions: 225Ac-PSMA RLT is an experimental treatment for men with mCRPC. There is limited data available from high-quality trials but so far PSMA-targeted RLT has demonstrated a low morbidity profile. Our review revealed that there is a possible decrease in efficacy of targeted alpha-particle therapy if individuals previously were exposed to 177Lu-PSMA RLT. However, the level of evidence is low. The underlying mechanism by which 177Lu-PSMA RLT might trigger possible radioresistance as well as randomized controlled trials are required to establish the therapeutic efficacy and safety of 225-Ac-PSMA RLT in men refractory to 177Lu-PSMA RLT. This article is protected by copyright. All rights reserved.
Guidelines for Qualifications of Neurodiagnostic Personnel: A Joint Position Statement of the American Clinical Neurophysiology Society, the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Society of Neurophysiological Monitoring, and ASET-The Neurodiagnostic Society
The Guidelines for Qualifications of Neurodiagnostic Personnel (QNP) document has been created through the collaboration of the American Clinical Neurophysiology Society (ACNS), the American Society of Neurophysiological Monitoring (ASNM), the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), and ASET-The Neurodiagnostic Society (ASET). The quality of patient care is optimized when neurophysiological procedures are performed and interpreted by appropriately trained and qualified practitioners at every level. These societies recognize that neurodiagnostics is a large field with practitioners who have entered the field through a variety of training paths. This document suggests job titles, associated job responsibilities, and the recommended levels of education, certification, experience, and ongoing education appropriate for each job. This is important because of the growth and development of standardized training programs, board certifications, and continuing education in recent years. This document matches training, education, and credentials to the various tasks required for performing and interpreting neurodiagnostic procedures. This document does not intend to restrict the practice of those already working in neurodiagnostics. It represents recommendations of these societies with the understanding that federal, state, and local regulations, as well as individual hospital bylaws, supersede these recommendations. Because neurodiagnostics is a growing and dynamic field, the authors fully intend this document to change over time.
Aim: Best-practice in audiological rehabilitation takes a holistic client- and family-centred approach and considers hearing care in the context of personal well-being. Hearing loss not only impairs the ability to hear, but can also compromise the ability to communicate, thus negatively impacting both social and emotional well-being. Hearing care professionals play a key role in fostering their client’s well-being. This paper aims to provide evidence-based recommendations to ensure inclusion of social-emotional well-being in audiologic rehabilitation clinical practice. Methods: A review of current research and expert opinion. Results: This guide proposes a 5-step plan which includes: identifying the client’s social-emotional well-being; including family members in audiological rehabilitation; incorporating social-emotional needs and goals in an individualized management plan; relating identified hearing needs and goals to rehabilitation recommendations; and using counselling skills and techniques to explore and monitor social-emotional well-being. Each component of the 5-step plan is discussed and clinical considerations are presented. Conclusion: These comprehensive recommendations provide guidance to hearing care professionals looking to ensure clients’ social-emotional well-being are considered throughout the rehabilitation journey.
While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor 3 (TLR3)-dependent mechanism that is not driven by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms elicited by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling was found to have independent prognostic value on relapse-free survival and overall survival in a cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML.
Background Twelve ocular surface disease experts convened to achieve consensus about Demodex blepharitis (DB) using a modified Delphi panel process. Methods Online surveys were administered using scaled, open-ended, true/false, and multiple-choice questions. Consensus for questions using a 1 to 9 Likert scale was predefined as median scores of 7–9 and 1–3. For other question types, consensus was achieved when 8 of 12 panellists agreed. Questions were randomized, and results of each survey informed the following survey. Results Twelve practitioners comprised the D emodex E xpert P anel on T reatment and Eyelid H ealth (DEPTH). Following 3 surveys, experts agreed that DB is chronic ( n = 11) and recurrent ( n = 12) and is often misdiagnosed. Consensus was achieved regarding inflammation driving symptoms (median = 7; range 7–9), collarettes as the most common sign ( n = 10) and pathognomonic for DB (median = 9; range 8–9), and itching as the most common symptom ( n = 12). Panellists agreed that DB may be diagnosed based on collarettes, mites, and/or patient symptoms ( n = 10) and felt that patients unresponsive to typical therapies should be evaluated for DB ( n = 12). Consensus about the most effective currently available OTC treatment was not reached. Conclusions The Delphi methodology proved effective in establishing consensus about DB, including signs, symptoms, and diagnosis. Consensus was not reached about the best treatment or how to grade severity. With increased awareness, eyecare practitioners can offer DB patients better clinical outcomes. A follow-up Delphi panel is planned to obtain further consensus surrounding DB treatment.
Glucose control continues to be challenging for intensivists, in particular in high-risk neonates. Many factors play a role in glucose regulation including intrinsic and extrinsic factors. Optimal targets for euglycemia are debatable with uncertain short and long-term effects. Glucose measurement technology has continued to advance over the past decade; unfortunately, the availability of these advanced devices outside of research continues to be problematic. Treatment approaches should be individualized depending on etiology, symptoms, and neonatal conditions. Glucose infusions should be titrated based upon variations in organ glucose uptake, co-morbidities and postnatal development. In this article we summarize the most common dilemmas encountered in the NICU: ranges for euglycemia, physiological differences, approach for glucose measurements, monitoring and best strategies to control parenteral glucose delivery.
Background: Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. Methods: This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n = 370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. Results: Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2 months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3 months; 95% CI, 6-20.1 months) (p < .001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p < .001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p = .01). Conclusions: These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.
Structural variants (SVs) are a major driver of genetic diversity and disease in the human genome and their discovery is imperative to advances in precision medicine. Existing SV callers rely on hand-engineered features and heuristics to model SVs, which cannot scale to the vast diversity of SVs nor fully harness the information available in sequencing datasets. Here we propose an extensible deep-learning framework, Cue, to call and genotype SVs that can learn complex SV abstractions directly from the data. At a high level, Cue converts alignments to images that encode SV-informative signals and uses a stacked hourglass convolutional neural network to predict the type, genotype and genomic locus of the SVs captured in each image. We show that Cue outperforms the state of the art in the detection of several classes of SVs on synthetic and real short-read data and that it can be easily extended to other sequencing platforms, while achieving competitive performance.
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