Background
Since 2017, women have made up over 50% of medical school matriculants; however, only 16% of department chairs are women—a number that has remained stagnant and demonstrates the ...underrepresentation of women in leadership positions in medicine.
Objective
To better understand the challenges women face in leadership positions and to inform how best to advance women leaders in Hospital Medicine.
Design, Setting, and Participants
Using hermeneutical phenomenological methods, we performed semi-structured qualitative interviews of ten female division heads from hospital medicine groups in the USA, transcribed verbatim, and coded for thematic saturation using Atlas.ti software.
Measurements
Qualitative themes and subthemes.
Key Results
Ten women hospitalist leaders were interviewed from September through November 2019. Participants identified four key challenges in their leadership journeys: lack of support to pursue leadership training, bullying, a sense of sacrifice in order to achieve balance, and the need for internal and external validation. Participants also suggested key interventions in order to support women leaders in the future: recommending a platform to share experiences, combat bullying, advocate for themselves, and bolster each other in sponsorship and mentorship roles. Finally, participants identified how they have unique strengths as women in leadership, and are transforming the culture of medicine with a focus on diversity and flexibility.
Conclusion
Women in leadership positions face unique challenges, but also have a unique perspective as to how to support the next generation of leaders.
Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin–kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density ...lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing.
The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran.
Participants with heterozygous familial hypercholesterolemia (ORION-9 Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol), or ASCVD and ASCVD risk equivalents (ORION-11 Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol) taking maximally tolerated statin therapy, with or without other LDL-C–lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed.
A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was −50.7% (95% confidence interval: −52.9% to −48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was −50.5% (95% confidence interval: −52.1% to −48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups.
These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.
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Protein biomarker discovery in blood plasma and serum is severely hampered by the vast dynamic range of the proteome. With protein concentrations spanning 12 orders of magnitude, conventional mass ...spectrometric analysis allows for detection of only a few low-abundance proteins. Prior depletion of high-abundant proteins from the sample can increase analytical depth considerably and has become a widely used practice. We describe in detail an affinity depletion method that selectively removes 14 of the most abundant proteins in plasma and serum.
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We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa ...multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.
Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% ± 9.3%; ...individuals with Parkinson disease, 52.3% ± 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease.
Restless Legs Syndrome (RLS) is a sensory-motor disorder which produces sleep disturbance. Using data from a large clinical trial of gabapentin enacarbil (GEn) we sought to assess the ability ...of baseline, and changes from baseline, in clinical trial endpoints to predict treatment response.
Data were derived from a randomized, double-blind, placebo-controlled, crossover polysomnography study of gabapentin enacarbil 1200 mg (n = 121) or placebo (n = 123). Efficacy evaluations included: sleep measures from polysomnography, subjective sleep measures, Suggested Immobilization Test (SIT) measures, and International Restless Legs Severity Scale (IRLS) and Clinical Global Impression-Improvement (CGI-I). Correlations were evaluated using Spearman's rank correlation coefficients. Predictors of treatment response were separately assessed for GEn and placebo using categorical IRLS and CGI-I outcomes. Stepwise logistic regression models ascertained which combination of baseline and change from baseline variables predicted response.
Moderate to large correlations were observed between changes in the IRLS and changes in subjective sleep for both GEn and placebo, substantially larger for GEn than placebo. Small to moderate correlations were present between the change in IRLS and the change in SIT-discomfort for both GEn and placebo. In the stepwise regression, for both GEn and placebo, baseline and change from baseline SIT discomfort, as well as change in sleep quality, were strong predictors of response.
Changes in sleep quality, and baseline and changes in SIT discomfort were prominent predictors of treatment response for GEn and placebo. Predictors of treatment response may allow for more targeted enrollment in future clinical trials and may provide insights into the efficacy of RLS treatments.
•Correlations between changes in IRLS and subjective sleep for GEn and placebo.•Correlations between change in IRLS and SIT-discomfort for GEn and placebo.•Changes in sleep quality and SIT-discomfort predictors of treatment response.
Today's optical networks are composed of thousands of kilometers of aging optical cables. Many of these cables are located in harsh environments, which contribute to induced birefringence of the ...fibers and a corresponding increase of polarization mode dispersion (PMD). This letter introduces derived statistics from the longest-known running evaluation of a PMD measuring campaign and an investigation into how higher optical power affects these aging systems. Results indicate strong seasonal dependence of PMD on temperature for an optical cable test bed exposed to atmospheric changes, leading to a 16% increase of a mean PMD value in summer. This fluctuation causes bit error rate limits to be exceeded for 10 and 40 Gbps non-return-to-zero signals, which is a critical issue for applications where high reliability is required. Moreover, due to the high optical power load within old optical infrastructures, a more than 0.15 dB increase of relative loss per year in tested routes, compared with reference routes, has been observed.
The differential mechanism of action of vamorolone compared to traditional corticosteroid anti-inflammatory drugs is attributed to the loss of gene transcriptional activities associated with ...glucocorticoid response element binding and activation, potent antagonist activity for the mineralocorticoid receptor, superior membrane stabilization properties, and retention of the distinct NFκB inhibitory (anti-inflammatory) activities 3,5–7). Safety endpoints (linear growth, body mass index) are also compared with data from a 12-month trial of daily prednisone (0.75 mg/kg group) in similar-aged boys with DMD 17. Methods Ethics statement All studies had appropriate approvals by ethics committees or institutional review boards, as required by the 11 participating international academic clinical recruitment sites: (Duke University, Durham, NC, US; Alberta Children’s Hospital, Calgary, AB, Canada; Nemours Children’s Hospital, Orlando, FL, US; John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Queen Silvia Children’s Hospital, Gothenburg, Sweden; Schneider Children’s Medical Center, Tel Aviv University, Petah Tikvah, Israel; Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, VIC, Australia; The Children’s Hospital at Westmead, Sydney, NSW, Australia; University of Texas Southwestern Medical Center, Dallas, TX, US; Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, US; University of California Davis, Davis, CA, US). ...the total duration of corticosteroid treatment was longer than 18 months for most participants.
We have investigated the extent and pattern of immunostaining for ubiquitin protein (UBQ) in 60 patients with frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions ...(FTLD-U), 37 of whom were ascertained in Manchester UK and 23 in Newcastle-Upon-Tyne, UK. There were three distinct histological patterns according to the form and distribution of the UBQ pathology. Histological type 1 was present in 19 patients (32%) and characterised by the presence of a moderate number, or numerous, UBQ immunoreactive neurites and intraneuronal cytoplasmic inclusions within layer II of the frontal and temporal cerebral cortex, and cytoplasmic inclusions within granule cells of the dentate gyrus; neuronal intranuclear inclusions (NII) of a "cat's eye" or "lentiform" appearance were present in 17 of these patients. In histological type 2 (16 patients, 27%), UBQ neurites were predominantly, or exclusively, present with few intraneuronal cytoplasmic inclusions within layer II of the cerebral cortex, while in histological type 3 (25 patients, 42%), UBQ intraneuronal cytoplasmic inclusions either within the cortical layer II or in the granule cells of the dentate gyrus, with few or no UBQ neurites, were seen. In neither of these latter two groups were NII present. The influence of histological type on clinical phenotype was highly significant with type 1 histology being associated clinically with cases of frontotemporal dementia (FTD) or progressive non-fluent aphasia (PNFA), type 2 histology with semantic dementia (SD), and type 3 histology with FTD, or FTD and motor neurone disease (MND).
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