Effect of Sleep Restriction on Adolescent Cognition by Adiposity: A Randomized Crossover Trial.

Importance: Pediatric obesity is associated with impaired cognitive function; however, the mechanisms underlying this association demand assessment. Sleep may be a relevant moderator, as poor sleep predicts both increased adiposity and impaired cognitive function. Objective: To determine the effects of adiposity and sleep on adolescent cognitive function. Design, Setting, and Participants: This single-blind randomized crossover trial was conducted from September 2020 to October 2022. Parents or caregivers provided demographic information for adolescent participants. Body mass index percentile and bioelectrical impedance analysis assessed adiposity. Adolescents completed 2 actigraphy-confirmed sleep conditions, adequate and restricted, followed by in-person cognitive assessment. No additional follow-up was provided. Data collection for this population-based study took place in a behavioral medicine clinic in Birmingham, Alabama. A total of 323 participants were assessed for eligibility (ages 14-19 years and healthy). Of the 244 eligible adolescents, 157 declined participation. Eighty-seven were randomized and 26 dropped out postenrollment. The final sample included 61 adolescents, 31 with healthy weight and 30 with overweight or obesity. Data were analyzed from April to October 2023. Interventions: Following a 2-day washout period of adequate sleep, adolescents completed 2 sleep conditions: adequate (mean [SD] duration, 8 hours, 54 minutes [58.0 minutes]) and restricted (mean [SD] duration, 4 hours, 12 minutes [50.7 minutes]). Main Outcomes and Measures: The National Institutes of Health Cognitive Toolbox assessed global and fluid cognition, cognitive flexibility, working and episodic memory, attention, and processing speed. The Stroop Task assessed inhibition. Results: The final sample included 61 adolescents (mean [SD] age, 16.3 [1.6] years; 35 [57.4%] female). Restricted sleep predicted poorer global cognition scores (restricted mean [SD], 98.0 [2.8]; adequate mean [SD], 103.2 [2.9]), fluid cognition scores (restricted mean [SD], 94.5 [3.2]; adequate mean [SD], 102.0 [3.6]), and cognitive flexibility scores (restricted mean [SD], 84.8 [3.0]; adequate mean [SD], 92.8 [3.0]) for adolescents with overweight or obesity. No differences emerged for adolescents with healthy weight. Adolescents with overweight or obesity also had poorer attention scores (mean [SD], 80.0 [2.3]) compared to adolescents with healthy weight (mean [SD], 88.4 [SD, 2.3]) following restricted sleep. No differences emerged following adequate sleep. Findings were similar for total body fat percentage (TBF%); however, for adolescents with TBF% above 42, restricted sleep also predicted poorer processing speed, and the association between sleep and attention did not vary based on TBF%. Conclusions and Relevance: Adolescents with overweight or obesity may be more vulnerable to negative cognitive effects following sleep restriction. Improved sleep hygiene and duration in this group may positively impact their cognitive health. Trial Registration: ClinicalTrials.gov Identifier: NCT04346433.

Cataract surgery using two 3D visualization systems: Complication rates, surgical duration & comparison with traditional microscopes.

PURPOSE: To compare the complication rates and surgical duration of cataract surgery using two 3D visualization systems and a traditional binocular microscope among experienced and inexperienced surgeons. METHODS: This retrospective case series included 571 eyes that received cataract surgery using either heads up cataract surgery, via a 3D head mounted system (N = 148-Group 1) or a 3D display screen (N = 338 eyes-Group 2), or traditional binocular microscope (N = 85 eyes-Group 3). The surgical records of consecutive patients who underwent cataract surgery by two groups of surgeons (experienced and inexperienced) were reviewed. Patients in all groups received either femtosecond laser assisted cataract surgery (FLACS) or traditional phacoemulsification. Complication rate, as well as duration of cataract surgery were evaluated between all three visualization approaches, between experienced and inexperienced surgeons. RESULTS: There was no statistically significant difference in duration of surgery between all 3 visualization approaches for both experienced and inexperienced surgeons (p < 0.05). Furthermore, the type of surgical technique (manual or FLACS) did not affect the surgical duration for both experienced and inexperienced surgeons (p < 0.05). No intraoperative complications were demonstrated in the current cohort. CONCLUSIONS: The implementation of heads up-3D visualization either through a screen or a head mounted platform for cataract surgery seems to offer similar safety and efficiency as the traditional binocular microscope, and both experienced and inexperienced surgeons demonstrate the same outcomes in terms of safety and efficiency.

Sleep and Inflammation during COVID-19 Virtual Learning in Adolescents with Overweight or Obesity.

(1) Background: Adolescents present as a high-risk group for a range of adverse physical health outcomes during the pandemic, including sleep and C-reactive protein (CRP) levels. As adolescents with overweight or obesity (OWOB) present as an even higher risk group, the present study assessed relationships between sleep and CRP levels before and during COVID-19 in adolescents with OWOB. (2) Methods: Fourteen adolescents with OWOB participated in a pre-COVID1, pre-COVID2, and during-COVID-19 lab visit, measuring sleep and CRP levels. The sample size was limited by the number of participants who provided data before COVID-19 and who were enrolled in virtual school during the recruitment phase. However, our power analyses indicated needing a minimum of 10 participants to achieve adequate power. Pre-COVID1, pre-COVID2, and during-COVID-19 normative expected CRP levels were calculated based on age, sex, race, and body mass index percentile-matched data. Analyses compared pre-COVID1 and pre-COVID2 sleep with during-COVID-19 sleep, during-COVID-19 sleep and during-COVID-19 CRP levels, during-COVID-19 CRP levels with normative expected during-COVID-19 CRP levels, change in CRP levels from pre-COVID1 and pre-COVID2 to during-COVID-19 with normative expected CRP levels during those time periods, and change in CRP levels before COVID-19 with change in CRP levels during COVID-19. (3) Results. During COVID-19, participants experienced decreased sleep efficiency (p = 0.001), later wake time (p < 0.001), longer time in bed (p = 0.021), and onset latency (p = 0.004), compared to pre-COVID1, and decreased sleep efficiency (p = 0.002), longer onset latency (p = 0.006), and later wake time (p < 0.001) and bedtime (p = 0.016) compared with pre-COVID2. During-COVID-19 CRP levels were positively correlated with during-COVID-19 wake times (p = 0.01) and times in bed (p = 0.008). During-COVID-19 CRP levels were greater than normative expected CRP levels (p < 0.001). CRP levels increased more from pre-COVID1 and pre-COVID2 to during-COVID-19 than normative expected changes in CRP levels (p < 0.003). Changes in CRP levels before and during COVID-19 were not significantly different. (4) Conclusions. These findings highlight the consequential effects of COVID-19, including impairments in sleep, on adolescents with OWOB. CRP levels increased more (~5 mg/L) during COVID-19 than normative expected change.

Mutation rates and fitness consequences of mosaic chromosomal alterations in blood.

Mosaic chromosomal alterations (mCAs) are common in cancers and can arise decades before diagnosis. A quantitative understanding of the rate at which these events occur, and their functional consequences, could improve cancer risk prediction and our understanding of somatic evolution. Using mCA clone size estimates from the blood of approximately 500,000 UK Biobank participants, we estimate mutation rates and fitness consequences of acquired gain, loss and copy-neutral loss of heterozygosity events. Most mCAs have moderate to high fitness effects but occur at a low rate, being more than tenfold less common than equivalently fit single-nucleotide variants. Notable exceptions are mosaic loss of X and Y, which we estimate have roughly 1,000-fold higher mutation rates than autosomal mCAs. Although the way in which most mCAs increase in prevalence with age is consistent with constant growth rates, some mCAs exhibit different behavior, suggesting that their fitness may depend on inherited variants, extrinsic factors or distributions of fitness effects.

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aß42, tTau, and pTau181) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.

The Effects of COVID-19 Virtual Learning on Body Fat and Insulin Resistance in Adolescents with Overweight or Obesity.

(1) Background: COVID-19 virtual learning reduced structural supports for adolescent physical activity and diet, threatening metabolic health, especially in teens with overweight or obesity (OWOB). (2) Methods: Adolescents (N = 14) with OWOB completed fasting blood draws (measuring insulin resistance, IR) and Dual Energy X-Ray Absorptiometry (DXA, measuring total body fat percent, TBF%) pre-COVID-19 and during COVID-19. Changes in TBF% and IR were calculated (1) pre-COVID-19 and (2) from pre-COVID-19 to during COVID-19. Age and body mass index (BMI) percentile-matched data assessed normative changes across similar, non-COVID-19 time periods. Paired t-tests compared TBF% change pre- to during COVID-19 with (1) TBF% change pre-COVID19 and (2) TBF% normative change. Two ANCOVAs compared IR change pre- to during COVID-19 with (1) IR change pre-COVID-19 controlling for BMI z-score and difference in time between assessments and (2) normative change in IR controlling for sex/race. (3) Results: The TBF% change pre-COVID-19 and the normative change were similar. The TBF% increased more (~six percentage points) during COVID-19 compared to normative change (p < 0.01). During COVID-19, IR increased more (~2.5 units) than change pre-COVID-19 (p = 0.03) and increased more (~3.5 units) than normative change (p = 0.01). (4) Conclusions: TBF% and IR increased exponentially during COVID-19 in teens with OWOB compared to pre-COVID-19 and normative changes.

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease.

Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-ß (Aß) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aß plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aß plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aß and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aß and tau.

The Impact of Longitudinal Patterns of Adolescent Sleep Duration on Adult C-Reactive Protein (CRP), Waist-To-Height Ratio, and Body Mass Index (BMI) Among Black and White Individuals.

PURPOSE: To assess the impact of longitudinal adolescent sleep duration on adult C-reactive protein (CRP), waist-to-height ratio (WtHR), and body mass index (BMI) by race. METHODS: Participants (N = 2,399; Mage = 15.7; 40.2% male; 79.2% White, 20.8% Black; Grades 7-12 at Wave I) from the Add Health database provided self-reported sleep duration in Waves I-IV. During Wave V, CRP, WtHR, and BMI were objectively measured. Trajectory analysis was performed using a group-based modeling approach. Chi-square test determined racial differences between groups. General linear models determined relationships between trajectory group, race, and group/race interaction with Wave V CRP, WtHR, and BMI. RESULTS: Three sleep trajectories emerged: Group 1 "shortest" (24.4%), Group 2 "stable recommended" (67.6%), and Group 3 "varied" (8%). Black individuals and older individuals were more likely to be in Group 1 compared with Group 2. Regardless of race, individuals with patterns of sleep duration increasing to above what is recommended across waves (Group 3) had elevated CRP. Individuals with stable patterns of adequate sleep (Group 2) had lower WtHR. Black individuals with consistently stable patterns of adequate sleep duration had lower BMI compared to those with low sleep duration. DISCUSSION: Black individuals were more likely to obtain chronically short sleep during the transition from adolescence to adulthood, highlighting a significant health disparity. Poor longitudinal sleep predicted elevated CRP and WtHR. Sleep only impacted BMI for Black individuals. This may relate to racial differences in BMI measurement.

Quantitative proteomics of cerebrospinal fluid from African Americans and Caucasians reveals shared and divergent changes in Alzheimer's disease.

BACKGROUND: Despite being twice as likely to get Alzheimer's disease (AD), African Americans have been grossly underrepresented in AD research. While emerging evidence indicates that African Americans with AD have lower cerebrospinal fluid (CSF) levels of Tau compared to Caucasians, other differences in AD CSF biomarkers have not been fully elucidated. Here, we performed unbiased proteomic profiling of CSF from African Americans and Caucasians with and without AD to identify both common and divergent AD CSF biomarkers. METHODS: Multiplex tandem mass tag-based mass spectrometry (TMT-MS) quantified 1,840 proteins from 105 control and 98 AD patients of which 100 identified as Caucasian while 103 identified as African American. We used differential protein expression and co-expression approaches to assess how changes in the CSF proteome are related to race and AD. Co-expression network analysis organized the CSF proteome into 14 modules associated with brain cell-types and biological pathways. A targeted mass spectrometry method, selected reaction monitoring (SRM), with heavy labeled internal standards was used to measure a panel of CSF module proteins across a subset of African Americans and Caucasians with or without AD. A receiver operating characteristic (ROC) curve analysis assessed the performance of each protein biomarker in differentiating controls and AD by race. RESULTS: Consistent with previous findings, the increase of Tau levels in AD was greater in Caucasians than in African Americans by both immunoassay and TMT-MS measurements. CSF modules which included 14-3-3 proteins (YWHAZ and YWHAG) demonstrated equivalent disease-related elevations in both African Americans and Caucasians with AD, whereas other modules demonstrated more profound disease changes within race. Modules enriched with proteins involved with glycolysis and neuronal/cytoskeletal proteins, including Tau, were more increased in Caucasians than in African Americans with AD. In contrast, a module enriched with synaptic proteins including VGF, SCG2, and NPTX2 was significantly lower in African Americans than Caucasians with AD. Following SRM and ROC analysis, VGF, SCG2, and NPTX2 were significantly better at classifying African Americans than Caucasians with AD. CONCLUSIONS: Our findings provide insight into additional protein biomarkers and pathways reflecting underlying brain pathology that are shared or differ by race.

Quantitative Mass Spectrometry Analysis of Cerebrospinal Fluid Protein Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia, with cerebrospinal fluid (CSF) ß-amyloid (Aß), total Tau, and phosphorylated Tau (pTau) providing the most sensitive and specific biomarkers for diagnosis. However, these diagnostic biomarkers do not reflect the complex changes in AD brain beyond amyloid (A) and Tau (T) pathologies. Here, we report a selected reaction monitoring mass spectrometry (SRM-MS) method with isotopically labeled standards for relative protein quantification in CSF. Biomarker positive (AT+) and negative (AT-) CSF pools were used as quality controls (QCs) to assess assay precision. We detected 62 peptides (51 proteins) with an average coefficient of variation (CV) of ~13% across 30 QCs and 133 controls (cognitively normal, AT-), 127 asymptomatic (cognitively normal, AT+) and 130 symptomatic AD (cognitively impaired, AT+). Proteins that could distinguish AT+ from AT- individuals included SMOC1, GDA, 14-3-3 proteins, and those involved in glycolysis. Proteins that could distinguish cognitive impairment were mainly neuronal proteins (VGF, NPTX2, NPTXR, and SCG2). This demonstrates the utility of SRM-MS to quantify CSF protein biomarkers across stages of AD.

Predictors of Cognitive Decline in Healthy Middle-Aged Individuals with Asymptomatic Alzheimer's Disease.

Alzheimer's disease (AD) progresses through a lengthy asymptomatic period during which pathological changes accumulate prior to development of clinical symptoms. As disease-modifying treatments are developed, tools to stratify risk of clinical disease will be required to guide their use. In this study, we examine the relationship of AD biomarkers in healthy middle-aged individuals to health history, family history, and neuropsychological measures and identify cerebrospinal fluid (CSF) biomarkers to stratify risk of progression from asymptomatic to symptomatic AD. CSF from cognitively normal (CN) individuals (N=1149) in the Emory Healthy Brain Study were assayed for Aß42, total Tau (tTau), and phospho181-Tau (pTau), and a subset of 134 cognitively normal, but biomarker-positive, individuals were identified with asymptomatic AD (AsymAD) based on a locally-determined cutoff value for ratio of tTau to Aß42. These AsymAD cases were matched for demographic features with 134 biomarker-negative controls (CN/BM-) and compared for differences in medical comorbidities and family history. Dyslipidemia emerged as a distinguishing feature between AsymAD and CN/BM-groups with significant association with personal and family history of dyslipidemia. A weaker relationship was seen with diabetes, but there was no association with hypertension. Examination of the full cohort by median regression revealed a significant relationship of CSF Aß42 (but not tTau or pTau) with dyslipidemia and diabetes. On neuropsychological tests, CSF Aß42 was not correlated with performance on any measures, but tTau and pTau were strongly correlated with visuospatial perception and visual episodic memory. In addition to traditional CSF AD biomarkers, a panel of AD biomarker peptides derived from integrating brain and CSF proteomes were evaluated using machine learning strategies to identify a set of 8 peptides that accurately classified CN/BM- and symptomatic AD CSF samples with AUC of 0.982. Using these 8 peptides in a low dimensional t-distributed Stochastic Neighbor Embedding analysis and k-Nearest Neighbor (k=5) algorithm, AsymAD cases were stratified into "Control-like" and "AD-like" subgroups based on their proximity to CN/BM- or AD CSF profiles. Independent analysis of these cases using a Joint Mutual Information algorithm selected a set of 5 peptides with 81% accuracy in stratifying cases into AD-like and Control-like subgroups. Performance of both sets of peptides was evaluated and validated in an independent data set from the Alzheimer's Disease Neuroimaging Initiative. Based on our findings, we conclude that there is an important role of lipid metabolism in asymptomatic stages of AD. Visuospatial perception and visual episodic memory may be more sensitive than language-based abilities to earliest stages of cognitive decline in AD. Finally, candidate CSF peptides show promise as next generation biomarkers for predicting progression from asymptomatic to symptomatic stages of AD.

Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.

Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute myeloid leukemia development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease. SIGNIFICANCE: DNMT3A has emerged as the most important epigenetic regulator and tumor suppressor in the hematopoietic system. Our study represents a systematic and high-throughput method to characterize the molecular impact of DNMT3A missense mutations and the discovery of a regulated destruction mechanism of DNMT3A offering new prognostic and future therapeutic avenues.See related commentary by Ma and Will, p. 23.This article is highlighted in the In This Issue feature, p. 1.

Synonymous mutations reveal genome-wide levels of positive selection in healthy tissues.

Genetic alterations under positive selection in healthy tissues have implications for cancer risk. However, total levels of positive selection across the genome remain unknown. Passenger mutations are influenced by all driver mutations, regardless of type or location in the genome. Therefore, the total number of passengers can be used to estimate the total number of drivers-including unidentified drivers outside of cancer genes that are traditionally missed. Here we analyze the variant allele frequency spectrum of synonymous mutations from healthy blood and esophagus to quantify levels of missing positive selection. In blood, we find that only 30% of passengers can be explained by single-nucleotide variants in driver genes, suggesting high levels of positive selection for mutations elsewhere in the genome. In contrast, more than half of all passengers in the esophagus can be explained by just the two driver genes NOTCH1 and TP53, suggesting little positive selection elsewhere.

Cutaneous Branch of the Spinal Accessory Nerve: Case Report With Potential Relevance to Occipital Neuralgia.

We describe a case in which a cutaneous branch was found arising from the spinal accessory nerve, a nerve typically characterized as a purely motor nerve. Although reported anatomical variations of the lesser occipital and spinal accessory nerves are uncommon, rare variants have been reported. Such anatomy might result in unexpected patient presentations or rare complications following spinal accessory nerve injury.

Implementation Strategies for Creating Inclusive, All-Women HIV Care Environments: Perspectives From Trans and Cis Women.

INTRODUCTION: Transgender (trans) women in the United States have disproportionately high rates of HIV acquisition, yet there remains a dearth of culturally appropriate and gender affirming HIV care services for them. Trans women often are aggregated with men who have sex with men based on biological essentialism and behaviorally defined characteristics, even though they have more in common with cisgender (cis) women, such as gender identity and psychosocial factors that influence HIV risk. As a result, trans women often are rendered invisible and underserved in the HIV response. We explore the feasibility of constructing inclusive, all-women HIV care environments as a way to redress the dearth of appropriate services for trans women living with HIV and to affirm their gender identity as women. METHODS: Thirty-eight women living with HIV and five providers participated in a qualitative focus group and interview study between April 2016 and January 2017, exploring the desirability and practicality of including trans women in HIV treatment and support services traditionally focused on cis women. Transcripts were coded and template analysis was employed to discern key themes. RESULTS: Participants identified concrete strategies for implementation of inclusive, all-women HIV care related to representation and visibility of trans women, community input, education and training, aspects of the clinic environment, and flexibility and creativity. The impact of trauma and the need for safety and gender affirmation were emphasized throughout. CONCLUSIONS: Trans and cis women found the idea of inclusive, all-women's HIV care environments attractive and feasible, notwithstanding cultural and structural challenges to creating them.

Systems-based proteomics to resolve the biology of Alzheimer's disease beyond amyloid and tau.

The repeated failures of amyloid-targeting therapies have challenged our narrow understanding of Alzheimer's disease (AD) pathogenesis and inspired wide-ranging investigations into the underlying mechanisms of disease. Increasing evidence indicates that AD develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation. This growing recognition surrounding the diversity of AD pathophysiology underscores the need for holistic systems-based approaches to explore AD pathogenesis. Here we describe how network-based proteomics has emerged as a powerful tool and how its application to the AD brain has provided an informative framework for the complex protein pathophysiology underlying the disease. Furthermore, we outline how the AD brain network proteome can be leveraged to advance additional scientific and translational efforts, including the discovery of novel protein biomarkers of disease.

We Are All Women: Barriers and Facilitators to Inclusion of Transgender Women in HIV Treatment and Support Services Designed for Cisgender Women.

Transgender women share more in common with cisgender women, with respect to sociocultural context and factors influencing HIV risk and outcomes, than they do with "men who have sex with men", a behavioral risk category in which they often are included. However, it is not yet clear whether both transgender and cisgender women would find integrated, all-women HIV programs and services desirable and beneficial. We Are All Women was a qualitative study conducted in the San Francisco Bay Area from April 2016 to January 2017, using a conceptual framework based on gender affirmation and trauma-informed care, to explore barriers and facilitators to inclusion of transgender women in HIV treatment and support services traditionally focused on cisgender women. Thirty-eight women (10 trans, 25 cis, and 3 "other" gender) participated in six semistructured, facilitated focus groups. In addition, five HIV care providers participated in semistructured, in-depth interviews. Both trans and cis women identified the desire for gender affirmation, a feeling of safety (specifically space without men), and potential community building within a care and healing context as powerful facilitators of an inclusive all-women care environment. At the same time, they recognized that tensions do exist between idealized visions of such an environment, deep-seated sentiments and behaviors among some cis women toward trans women, and the practical realities of creating the optimal spaces for all women. Opportunities for dialog between trans and cis women to mitigate gender-associated phobias and misperceptions are a valuable first step in creating HIV care environments that serve all women.

The evolutionary dynamics and fitness landscape of clonal hematopoiesis.

Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.

Surgical anatomy of the internal carotid plexus branches to the abducens nerve in the cavernous sinus.

OBJECTIVE: Sympathetic branches to the abducens nerve derived from the internal carotid artery sympathetic plexus, while in the cavernous sinus, have been scantly described in the extant literature. Therefore, the present cadaveric study was performed to better elucidate this anatomy. PATIENTS AND METHODS: Eighteen cadaveric sides underwent dissection. RESULTS: The number of branches derived from the sympathetic plexus traveling with the internal carotid artery in the cavernous sinus was one on 11.1 %, two in 11.1 %, and three in 72.2 %. One side was found to have no branches (5.6 %). The mean diameter of the distance from the posterior border of the internal carotid artery, length, and diameter of the branches was 7.0 ±â€¯4.1 mm, 2.9 ±â€¯1.3 mm, and 0.4 ±â€¯0.1 mm, respectively. Of 44 of 45 sympathetic branches, 97.8 % originated from the lateral wall of the cavernous part of the internal carotid artery with only one from the medial wall. CONCLUSION: Based on our cadaveric findings, sympathetic connections between the internal carotid artery and the abducens nerve are common. Therefore, surgeons who operate in or near the cavernous sinus should be aware of such connections in order not to place unwanted tension on the cavernous part of the internal carotid artery or abducens nerve during dissection.