N-SREBP2 Provides a Mechanism for Dynamic Control of Cellular Cholesterol Homeostasis.

Cholesterol is required to maintain the functional integrity of cellular membrane systems and signalling pathways, but its supply must be closely and dynamically regulated because excess cholesterol is toxic. Sterol regulatory element-binding protein 2 (SREBP2) and the ER-resident protein HMG-CoA reductase (HMGCR) are key regulators of cholesterol biosynthesis. Here, we assessed the mechanistic aspects of their regulation in hepatic cells. Unexpectedly, we found that the transcriptionally active fragment of SREBP2 (N-SREBP2) was produced constitutively. Moreover, in the absence of an exogenous cholesterol supply, nuclear N-SREBP2 became resistant to proteasome-mediated degradation. This resistance was paired with increased occupancy at the HMGCR promoter and HMGCR expression. Inhibiting nuclear N-SREBP2 degradation did not increase HMGCR RNA levels; this increase required cholesterol depletion. Our findings, combined with previous physiological and biophysical investigations, suggest a new model of SREBP2-mediated regulation of cholesterol biosynthesis in the organ that handles large and rapid fluctuations in the dietary supply of this key lipid. Specifically, in the nucleus, cholesterol and the ubiquitin-proteasome system provide a short-loop system that modulates the rate of cholesterol biosynthesis via regulation of nuclear N-SREBP2 turnover and HMGCR expression. Our findings have important implications for maintaining cellular cholesterol homeostasis and lowering blood cholesterol via the SREBP2-HMGCR axis.

Reprint of: Impact of altered mental status on antibiotic prescribing and outcomes in hospitalized patients presenting with pyuria.

BACKGROUND: Pyuria is nonspecific and may result in over-treatment of asymptomatic bacteriuria (ASB). The Infectious Diseases Society of America recommends against antibiotic treatment of ASB for most patients including those presenting with altered mental status (AMS). Close observation is recommended over treatment to avoid missing alternative causes of AMS and overuse of antibiotics resulting in adverse events and resistance. OBJECTIVES: The purpose of this study was to evaluate patient outcomes associated with antibiotic treatment of pyuria in patients presenting with AMS at hospital admission without specific urinary tract infection (UTI) symptoms. The primary objective was to compare 30-day readmission rates of patients with pyuria and AMS treated with antibiotics (AMS+Tx) versus those who were not treated (AMS-NoTx). Secondary outcomes included identifying risk factors for antibiotic treatment, comparing alternative diagnoses for AMS, and comparing safety outcomes. METHODS: This retrospective cohort study evaluated adult patients with AMS and pyuria (10 WBC/hpf) admitted between February 1, 2020 and October 1, 2021, in a 350-bed community teaching hospital. Patients with documented urinary symptoms were excluded. Additional exclusion criteria included admission to critical care, history of renal transplant, urological surgery, coinfections, pregnancy, and neutropenia. RESULTS: Two-hundred patients were included (AMS+Tx, n = 162; AMS-NoTx, n=38). There was no difference in 30-day hospital readmission rate for AMS between groups (AMS+Tx 16.7% vs AMS-NoTx 23.7%, P = 0.311). An alternative diagnosis of AMS occurred more frequently when antibiotics were withheld (AMS+Tx 66% vs. AMS-NoTx 86.8%, P = 0.012). Urinalyses showing bacteria (odds ratio 2.52; 95% CI, 1.11-5.731) and positive urine culture (OR 3.36; 95% CI, 1.46-7.711) were associated with antibiotic prescribing. CONCLUSIONS: Inappropriate antibiotic use is common among hospitalized patients presenting with AMS and pyuria; however, treatment of asymptomatic pyuria did not decrease rates of subsequent readmission for AMS or retreatment of symptomatic UTI. Patients who were monitored off antibiotics had higher rates of alternative AMS diagnosis.

Variation in Lip Shape and Aesthetics in the Young Female Population: A Statistical Atlas Study.

Background: The distribution of lip shapes in young females and how morphological variation relates to attractiveness are poorly defined. Objectives: We hypothesized that among young female lip images generated by a statistical atlas model, those with more full lips compared with those with less full lips would be perceived as more attractive as measured by anonymous survey participants. Method: A statistical atlas of lip morphology was created using photographs of 700 women aged 18-35 years. The average lip shape was determined by coregistering and averaging images. Morphological variation was analyzed using principal component analysis. The relationship between attractiveness and observed lip morphologies was assessed using publicly distributed surveys. Results: In total, 428 survey responses were obtained. We developed a statistical model of variation of lip shape in the population and its relationship to attractiveness. The most attractive lips were significantly fuller than the average shape in the population, with greater vertical height and surface area. Conclusion: A statistical atlas can provide a visual guide to variation in lip shape in the population. The most attractive lip shapes vary significantly from the population average, lending support to procedures that increase lip height and surface area.

Usability And Feasibility of an in-Home Remote Exam Device in Children with Medical Complexity During the COVID-19 Pandemic.

Background: Children with medical complexity (CMC) account for high health care utilization. Telemedicine holds significant potential in CMC, as it allows a provider to engage with CMC in their home environment and can alleviate both financial and transportation burdens. Remote exam devices that enable the performance of a physical exam could expand the ability of providers to clinically assess CMC during a telemedicine visit. In this pilot study, our goal was to develop a process for integrating an in-home remote exam device into a complex care clinic during the COVID-19 pandemic and evaluate the usability and feasibility of this device. Methods: The remote exam device was distributed to caregivers of CMC cared for at a complex care outpatient center. Using deliberate practice framework, our onboarding process provided opportunities for caregivers and providers to learn how to utilize the device. Surveys examining usability and feasibility were administered to both caregivers and providers after each telemedicine encounter. Results: A total of 43 caregivers participated in the onboarding process, which included a total of 83 practice visits. The remote exam device was rated as having excellent usability by caregivers; however, providers rated the device as having lower usability. Feasibility was notable for technology issues contributing to 15% of encounters being cancelled or ending early. Conclusions: The remote exam device was successfully integrated into a complex care clinic. Data from this pilot study supports the usability and feasibility of deploying a remote exam device across a telemedicine platform in a busy and complex outpatient academic practice.

Impact of an over-the-counter "sleep lotion" on human salivary melatonin levels and sleep quality: a randomized controlled trial.

OBJECTIVE: To compare the impact of a commercial "sleep lotion" versus a placebo control lotion on salivary melatonin and sleep quality. METHODS: The presence of melatonin in the lotion was confirmed and quantitated with High Performance Liquid Chromatography (HPLC). In this randomized, controlled, double-blind crossover trial, undergraduate student participants applied lotions on two separate nights and we quantitated melatonin in saliva samples with enzyme linked immunosorbent assays. We also assessed sleep quality with a modified Pittsburgh Sleep Quality Index. CLINICALTRIALS: gov ID NCT06053385. RESULTS: Sixty-three participants (age 20.5 ± 1.2 years; 81% female) enrolled in the study and provided at least one saliva sample. The sleep lotion contained 0.24 ± 0.01% melatonin (g/100 g lotion) which dramatically impacted salivary melatonin levels, increasing them up to ~1000 fold compared to the placebo lotion (n = 36 participants with all six timepoints). The lotion improved sleep quality in a subsample of the poor sleepers (n = 18). However, the sleep quality in the overall sample was not significantly different on the active versus placebo lotion nights. CONCLUSION: In a small undergraduate student sample, a commercial melatonin-containing lotion improved sleep in those with poor sleep quality. Caution should be taken by consumers using over-the-counter melatonin lotions because the undisclosed dosage can be high and well absorbed by the skin.

Using Ex Vivo Tonsil Organoids to Study Memory B Cells.

Tools to study memory B cell (MBC) development and function are needed to understand their role in supporting sustained protection against recurrent infections. While human MBCs are traditionally measured using blood, there is a growing interest in elucidating their behavior within lymphoid tissues, which are the main sites where adaptive immune responses are orchestrated. In this chapter, we introduce a high-throughput organoid system that is derived from primary human lymphoid tissues. The approach can recapitulate many hallmarks of successful adaptive immune responses and capture inter-individual variation in response to a variety of stimuli. Lymphoid tissue organoids enable characterization of pre-existing antigen-specific MBCs within an entirely human system and can provide valuable insights into MBC dynamics.

Skp1 is a conserved structural component of the meiotic synaptonemal complex.

The synaptonemal complex (SC) is a meiotic interface that assembles between parental chromosomes and is essential for the formation of gametes. While the dimensions and ultrastructure of the SC are conserved across eukaryotes, its protein components are highly divergent. Recently, an unexpected component of the SC has been described in the nematode C. elegans: the Skp1-related proteins SKR-1/2, which are components of the Skp1, Cullin, F-box (SCF) ubiquitin ligase. Here, we find that the role of SKR-1 in the SC is conserved in nematodes. The P. pacificus Skp1 ortholog, Ppa-SKR-1, colocalizes with other SC proteins throughout meiotic prophase, where it occupies the middle of the SC. Like in C. elegans, the dimerization interface of Ppa-SKR-1 is required for its SC function. A dimerization mutant, Ppa-skr-1 F105E , fails to assemble SC and is almost completely sterile. Interestingly, the evolutionary trajectory of SKR-1 contrasts with other SC proteins. Unlike most SC proteins, SKR-1 is highly conserved in nematodes. Our results suggest that the structural role of SKR-1 in the SC has been conserved since the common ancestor of C. elegans and P. pacificus, and that rapidly evolving SC proteins have maintained the ability to interact with SKR-1 for at least 100 million years.

Incidence of diabetes after SARS-CoV-2 infection in England and the implications of COVID-19 vaccination: a retrospective cohort study of 16 million people.

BACKGROUND: Some studies have shown that the incidence of type 2 diabetes increases after a diagnosis of COVID-19, although the evidence is not conclusive. However, the effects of the COVID-19 vaccine on this association, or the effect on other diabetes subtypes, are not clear. We aimed to investigate the association between COVID-19 and incidence of type 2, type 1, gestational and non-specific diabetes, and the effect of COVID- 19 vaccination, up to 52 weeks after diagnosis. METHODS: In this retrospective cohort study, we investigated the diagnoses of incident diabetes following COVID-19 diagnosis in England in a pre-vaccination, vaccinated, and unvaccinated cohort using linked electronic health records. People alive and aged between 18 years and 110 years, registered with a general practitioner for at least 6 months before baseline, and with available data for sex, region, and area deprivation were included. Those with a previous COVID-19 diagnosis were excluded. We estimated adjusted hazard ratios (aHRs) comparing diabetes incidence after COVID-19 diagnosis with diabetes incidence before or in the absence of COVID-19 up to 102 weeks after diagnosis. Results were stratified by COVID-19 severity (categorised as hospitalised or non-hospitalised) and diabetes type. FINDINGS: 16 669 943 people were included in the pre-vaccination cohort (Jan 1, 2020-Dec 14, 2021), 12 279 669 in the vaccinated cohort, and 3 076 953 in the unvaccinated cohort (both June 1-Dec 14, 2021). In the pre-vaccination cohort, aHRs for the incidence of type 2 diabetes after COVID-19 (compared with before or in the absence of diagnosis) declined from 4·30 (95% CI 4·06-4·55) in weeks 1-4 to 1·24 (1·14-1.35) in weeks 53-102. aHRs were higher in unvaccinated people (8·76 [7·49-10·25]) than in vaccinated people (1·66 [1·50-1·84]) in weeks 1-4 and in patients hospitalised with COVID-19 (pre-vaccination cohort 28·3 [26·2-30·5]) in weeks 1-4 declining to 2·04 [1·72-2·42] in weeks 53-102) than in those who were not hospitalised (1·95 [1·78-2·13] in weeks 1-4 declining to 1·11 [1·01-1·22] in weeks 53-102). Type 2 diabetes persisted for 4 months after COVID-19 in around 60% of those diagnosed. Patterns were similar for type 1 diabetes, although excess incidence did not persist beyond 1 year after a COVID-19 diagnosis. INTERPRETATION: Elevated incidence of type 2 diabetes after COVID-19 is greater, and persists for longer, in people who were hospitalised with COVID-19 than in those who were not, and is markedly less apparent in people who have been vaccinated against COVID-19. Testing for type 2 diabetes after severe COVID-19 and the promotion of vaccination are important tools in addressing this public health problem. FUNDING: UK National Institute for Health and Care Research, UK Research and Innovation (UKRI) Medical Research Council, UKRI Engineering and Physical Sciences Research Council, Health Data Research UK, Diabetes UK, British Heart Foundation, and the Stroke Association.

Continuous neural control of a bionic limb restores biomimetic gait after amputation.

For centuries scientists and technologists have sought artificial leg replacements that fully capture the versatility of their intact biological counterparts. However, biological gait requires coordinated volitional and reflexive motor control by complex afferent and efferent neural interplay, making its neuroprosthetic emulation challenging after limb amputation. Here we hypothesize that continuous neural control of a bionic limb can restore biomimetic gait after below-knee amputation when residual muscle afferents are augmented. To test this hypothesis, we present a neuroprosthetic interface consisting of surgically connected, agonist-antagonist muscles including muscle-sensing electrodes. In a cohort of seven leg amputees, the interface is shown to augment residual muscle afferents by 18% of biologically intact values. Compared with a matched amputee cohort without the afferent augmentation, the maximum neuroprosthetic walking speed is increased by 41%, enabling equivalent peak speeds to persons without leg amputation. Further, this level of afferent augmentation enables biomimetic adaptation to various walking speeds and real-world environments, including slopes, stairs and obstructed pathways. Our results suggest that even a small augmentation of residual muscle afferents restores biomimetic gait under continuous neuromodulation in individuals with leg amputation.

Chlamydia trachomatis Seroassays Used in Epidemiologic Research: A Narrative Review and Practical Considerations.

Chlamydia trachomatis (CT) is a sexually transmitted infection that can lead to adverse reproductive health outcomes. CT prevalence estimates are primarily derived from screening using nucleic acid amplification tests (NAATs). However, screening guidelines in the United States only include particular subpopulations, and NAATs only detect current infections. In contrast, seroassays identify past CT infections, which is important for understanding the public health impacts of CT, including pelvic inflammatory disease and tubal factor infertility. Older seroassays have been plagued by low sensitivity and specificity and have not been validated using a consistent reference measure, making it challenging to compare studies, define the epidemiology of CT, and determine the effectiveness of control programs. Newer seroassays have better performance characteristics. This narrative review summarizes the "state of the science" for CT seroassays that have been applied in epidemiologic studies and provides practical considerations for interpreting the literature and employing seroassays in future research.

Balancing Act: an Interdisciplinary Exploration of Trade-offs in Reproducing Females.

Trade-offs resulting from the high demand of offspring production are a central focus of many subdisciplines within the field of biology. Yet, despite the historical and current interest on this topic, large gaps in our understanding of whole-organism trade-offs that occur in reproducing individuals remain, particularly as it relates to the nuances associated with female reproduction. This volume of Integrative and Comparative Biology (ICB) contains a series of papers that focus on reviewing trade-offs from the female-centered perspective of biology (i.e., a perspective that places female reproductive biology at the center of the topic being investigated or discussed). These papers represent some of the work showcased during our symposium held at the 2024 meeting of the Society for Integrative and Comparative Biology (SICB) in Seattle, Washington. In this roundtable discussion, we use a question-and-answer format to capture the diverse perspectives and voices involved in our symposium. We hope that the dialogue featured in this discussion will be used to motivate researchers interested in understanding trade-offs in reproducing females and provide guidance on future research endeavors.

The Inflammation-Induced Dysregulation of Reelin Homeostasis Hypothesis of Alzheimer's Disease.

Alzheimer's disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation.

The sympathetic nervous system response to a Continuous Performance Task.

A Continuous Performance Task is an example of a mental stressor which requires vigilance, attention, and effort. We hypothesized that a sympathetic nervous system response would be evident from a resting baseline period to this attention test, and explored if physiological measures were correlated to state and trait anxiety, perceived stress, mindfulness, and performance on the task. In 20 undergraduates, blood pressure and skin conductance increased due to the attention test but heart rate variability did not change. The physiological variables did not correlate to psychological variables; there was a trend of higher perceived stress correlating to lower foil accuracy rate ( p = 0.09). ClinicalTrials.gov ID: NCT06098352.

Sustained human outbreak of a new MPXV clade I lineage in eastern Democratic Republic of the Congo.

Outbreaks of monkeypox (mpox) have historically resulted from zoonotic spillover of clade I monkeypox virus (MPXV) in Central Africa and clade II MPXV in West Africa. In 2022, subclade IIb caused a global epidemic linked to transmission through sexual contact. Here we describe the epidemiological and genomic features of an mpox outbreak in a mining region in eastern Democratic Republic of the Congo, caused by clade I MPXV. Surveillance data collected between September 2023 and January 2024 identified 241 suspected cases. Genomic analysis demonstrates a distinct clade I lineage divergent from previously circulating strains in the Democratic Republic of the Congo. Of the 108 polymerase chain reaction-confirmed mpox cases, the median age of individuals was 22 years, 51.9% were female and 29% were sex workers, suggesting a potential role for sexual transmission. The predominance of APOBEC3-type mutations and the estimated emergence time around mid-September 2023 imply recent sustained human-to-human transmission.

Uptake and Persistent Use of HIV Preexposure Prophylaxis Among Key Populations: Results From Ukraine's Scaled National Preexposure Prophylaxis Program.

BACKGROUND: Ukraine has implemented ambitious HIV-prevention programs since 1999 and began offering preexposure prophylaxis (PrEP) in 2017. Little is known about PrEP uptake and persistence in this setting. SETTING: We analyzed data from 40 facilities providing PrEP in 11 oblasts (regions) of Ukraine between October 2020 and February 2022. METHODS: We estimated the time between PrEP visits and conducted Kaplan-Meier analyses to estimate retention on PrEP stratified by sex, age, and key populations (KPs): men who have sex with men (MSM), people who inject drugs (PWID), sex workers (SW), discordant couples, and others vulnerable to HIV acquisition (DC/other). We used Cox regression to estimate the risk of PrEP discontinuation by KP group and sex, adjusting for age. RESULTS: Overall, 2033 clients initiated PrEP across regions; the majority (51%) were DC/other, 22% were MSM, 22% were PWID, and 5% were SW. The overall 3-month persistence was 52.3% (95% confidence interval [CI]: 49.9% to 54.8%) and was lowest among MSM (46.7%; 95% CI: 41.9% to 52.2%) and SW (25.9%; 95% CI: 18.2% to 36.9%) (P < 0.05 for differences by KP group). After adjusting for age, PrEP discontinuation was not statistically significantly different across groups, although female PWID tended to have the lowest discontinuation risk (adjusted hazard ratio [aHR] 0.59; 95% CI: 0.31 to 1.11) while male SW tended to have the highest risk (aHR 1.87, 95% CI: 0.57 to 6.11) compared with females in the DC/other group. CONCLUSION: Three-month PrEP persistence was low across KP groups, especially in SW. Further research examining the barriers and enablers of persistence by KPs is needed.

Systematic review and meta-analysis of the association between Mycoplasma genitalium and Pelvic inflammatory disease (PID).

BACKGROUND: Differences in opinion concerning the contribution of M. genitalium to pelvic inflammatory disease (PID) has resulted in inconsistencies across global testing and treatment guidelines. We conducted a systematic review and meta-analysis to determine the association between M. genitalium and PID and M. genitalium positivity within PID cases to provide a contemporary evidence base to inform clinical practice (PROSPERO registration: CRD42022382156). METHODS: PubMed, Embase, Medline and Web of Science were searched to Dec 1, 2023 for studies that assessed women for PID using established clinical criteria and used nucleic acid amplification tests to detect M. genitalium. We calculated summary estimates of the 1) association of M. genitalium with PID (pooled odds ratio [OR]) and 2) proportion of PID cases with M. genitalium detected (pooled M. genitalium positivity in PID), using random-effects meta-analyses, with 95% confidence intervals (CI). RESULTS: Nineteen studies were included: 10 estimated M. genitalium association with PID, and 19 estimated M. genitalium positivity in PID. M. genitalium infection was significantly associated with PID (pooled OR=1.67 [95%CI: 1.24-2.24]). The pooled positivity of M. genitalium in PID was 10.3% [95%CI: 5.63-15.99]. Subgroup and meta-regression analyses showed that M. genitalium positivity in PID was highest in the Americas, in studies conducted in both inpatient and outpatient clinic settings, and in populations at high risk of sexually transmitted infections. CONCLUSIONS: M. genitalium was associated with a 67% increase in odds of PID and was detected in about one in ten clinical diagnoses of PID. These data support testing women for M. genitalium at initial PID diagnosis.

Counseling Women About Sexual Health Effects of Contraceptives.

Background: Choosing a contraceptive method is a pivotal decision for patients, whereas health care professionals (HCPs) face challenges in providing suitable recommendations. Adverse sexual effects often lead to dissatisfaction and discontinuation of contraceptives, underscoring the importance of thorough counseling and shared decision making between HCPs and patients. Objective: This article aims to investigate the relationship between contraceptive methods and female sexual function through a comprehensive review of available literature, emphasizing the importance of considering sexual health in contraceptive prescription and management. Methods: A systematic analysis of existing literature, incorporating studies utilizing validated sexual health questionnaires, was conducted to elucidate the intricate interplay between contraceptives and female sexual function. Results: The review encompasses various contraceptive methods, including combined hormonal contraceptives, progestin-only pills, depot medroxyprogesterone acetate, subdermal contraceptive implants, hormonal intrauterine devices, permanent sterilization, and barrier methods. Insights gleaned from the analysis shed light on the impact of these methods on female sexual health. Conclusion: Comprehensive understanding of the effects of contraceptives on female sexual function is crucial for both HCPs and patients. By integrating sexual health considerations into contraceptive surveillance, compliance can be improved, contraceptive efficacy optimized, and the risk of unwanted pregnancies minimized. This review underscores the significance of tailored counseling and shared decision making in contraceptive management, particularly for cisgender women.

A Retrospective Cohort Analysis of Analgosedation Requirements in COVID-19 Compared to Non-COVID-19 Extracorporeal Membrane Oxygenation Patients.

BACKGROUND: Reports have described increased sedation requirements in patients with acute respiratory distress syndrome (ARDS) while on extracorporeal membrane oxygenation (ECMO) and for intubated COVID-19 patients. Thus, the objective of this study was to assess the analgosedation requirements of COVID-19 patients receiving ECMO compared to non-COVID-19 ECMO patients. METHODS: This retrospective, observational cohort study included adult patients with ARDS requiring venovenous or venopulmonary arterial ECMO admitted to a single intensive care unit from January 2017 to December 2021. Patients were categorized as COVID-19 ECMO or non-COVID-19 ECMO. The primary outcome was median daily dosing of parenteral analgosedative medications. Pertinent secondary outcomes included incidence of extubation or tracheostomy and change in sedation following tracheostomy or addition of oral agents. RESULTS: A total of 109 patients were evaluated; 63 COVID-19 ECMO patients and 46 non-COVID ECMO patients. The primary outcome was statistically higher in the COVID-19 compared to non-COVID-19 patients for propofol (4131.0 mg vs 2704.8 mg, P < .001), dexmedetomidine (1581.4 mcg vs 1081.3 mcg, P = .016), and parenteral morphine equivalents ([PME], 209.3 mg vs 154.1 mg, P = .027), but only propofol remained significant after adjustment for weight (31.1 mcg/kg/day vs 37.7 mcg/kg/day, P = .014). COVID-19 was significantly associated with increased propofol and PME requirements after adjustment for confounders on linear regression analysis. COVID-19 patients had more days with non-zero dose for propofol (8 days vs 7 days), dexmedetomidine (13 days vs 8.5 days), and PME (17 days vs 8.5 days). The only interventions that were associated with reductions in propofol dose were tracheostomy and antipsychotics. CONCLUSIONS: COVID-19 patients on ECMO had significantly longer durations and higher doses of propofol, dexmedetomidine, and parenteral opioids over the first 28 days of cannulation. The only interventions that were associated with statistical reductions in propofol were antipsychotics and tracheostomy.

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer.

PURPOSE: Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy. METHODS: Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC. RESULTS: One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). CONCLUSION: One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Pectus Disorders: Excavatum, Carinatum and Arcuatum.

This article reviews pectus excavatum, carinatum, and arcuatum. Topics covered include etiology, epidemiology, associated syndromes, physiologic impact, workup, indications for treatment, surgical and nonsurgical therapy, results, complications, and emerging therapies. Pectus excavatum is an inward deformation of the sternum and/or anterior chest wall. Pectus carinatum is ether an outward protrusion or tilt of the sternum with potential psychological impact, but no demonstrated physiologic impact. Nonoperative compression bracing is successful in carinatum patients with chest wall flexibility who are compliant with a bracing program. Pectus arcuatum is an abnormally short, fully fused sternum with a high anterior protrusion.