Conditional frequency spectra as a tool for studying selection on complex traits in biobanks.

Natural selection on complex traits is difficult to study in part due to the ascertainment inherent to genome-wide association studies (GWAS). The power to detect a trait-associated variant in GWAS is a function of frequency and effect size - but for traits under selection, the effect size of a variant determines the strength of selection against it, constraining its frequency. To account for GWAS ascertainment, we propose studying the joint distribution of allele frequencies across populations, conditional on the frequencies in the GWAS cohort. Before considering these conditional frequency spectra, we first characterized the impact of selection and non-equilibrium demography on allele frequency dynamics forwards and backwards in time. We then used these results to understand conditional frequency spectra under realistic human demography. Finally, we investigated empirical conditional frequency spectra for GWAS variants associated with 106 complex traits, finding compelling evidence for either stabilizing or purifying selection. Our results provide insight into polygenic score portability and other properties of variants ascertained with GWAS, highlighting the utility of conditional frequency spectra.

Incidentally Discovered Giant Benign Ovarian Serous Cystadenoma in Elective Bariatric Surgery.

Ovarian cystadenomas are benign epithelial neoplasms, many of which are of the serous subtype. Most patients present with symptoms such as abdominal pain, bloating, and bladder issues. This patient, who had a BMI of 45, presented with a giant ovarian serous cystadenoma identified during an elective bariatric surgery; interestingly, she was completely asymptomatic at the time of discovery. A large, predominantly cystic pelvic mass with internal septations and soft tissue components, suspicious for ovarian neoplasm, was discovered on a CT abdomen and pelvis with IV contrast. She underwent an exploratory laparotomy with complete resection, right oophorectomy, and ovarian cystectomy. Her postoperative pathology report revealed the mass to be a benign serous cystadenoma. This case serves as an example of how a massive tumor can potentially get overlooked for many years, only to be detected unintentionally in an asymptomatic patient. Healthcare quality is often negatively impacted by the inherent prejudice that many healthcare providers have toward their obese patients. Providers may mistakenly over-attribute a patient's symptoms to their obesity, failing to effectively evaluate the patient's concerns, which could lead to overlooking potentially harmful diagnoses. A comprehensive history and physical exam in all patients, especially those who are obese, is vital in ensuring timely diagnosis and management to improve patient outcomes.

Assessing the information provided regarding oral cancer by dental practice websites within the Greater Manchester area.

INTRODUCTION: With increasing numbers of oral cancer diagnoses and guidance recommending that patients approach their doctors or dentists for assessments, when searching for information regarding mouth cancer, patients may first look to their dental practice website. This study aimed to evaluate the variance of patient information provided regarding oral cancer on dental practice websites. MATERIALS AND METHODS: Dental practices within the Manchester area with an active website were included with assessment of whether there was any information provided regarding reducing oral cancer risk factors, signs to look out for and if oral cancer screening was included as part of the general check-up, using a three-point score based on the joint statement from the British and Irish Society for Oral Medicine (BISOM) and Cancer Research UK (CRUK) regarding oral cancer diagnosis and prevention. RESULTS: In total, 66.6% (n=60) of practices provided no accessible information regarding oral cancer screening and prevention on their websites. Only 12.2% (n=11) discussed all three factors of oral screening, symptoms and reducing risk factors. Screening as part of routine examination was most frequently mentioned at 27% (n=24), risk factors were discussed by 23% (n=21) of practices and symptoms to be aware of by 13% (n=12). DISCUSSION: There is a lack of information available to patients on dental practice websites regarding oral cancer. To overcome lack of quality assurance on the internet, dentists can provide factual information via their dental practice websites. This could help with improving patient awareness and therefore aiding in early detection, improving patient outcomes.

ATF4 as a Prognostic Marker and Modulator of Glutamine Metabolism in Estrogen Receptor Positive Breast Cancer.

PURPOSE: ATF4, a stress-responsive transcription factor that upregulates adaptive genes, is a potential prognostic marker and modulator of glutamine metabolism in breast cancer. However, its exact role remains to be elucidated. METHODS: ATF4 expression was evaluated at genomic and transcriptomic levels using METABRIC (n=1980), GeneMiner (n=4712) and KM-Plotter datasets. Proteomic expression was assessed via immunohistochemistry (n=2225) in the Nottingham Primary Breast Carcinoma Series. ATF4 genomic copy number (CN) variation and mRNA/protein in association with clinicopathological parameters, amino acid transporters (AATs), and patient outcome was investigated. RESULTS: Genomic, transcriptomic, and proteomic overexpression of ATF4 was associated with more aggressive ER-negative tumours. ATF4 mRNA and protein expression were significantly associated with increased expression of glutamine related AATs including SLC1A5 (p<0.01) and SLC7A11 (p<0.02). High ATF4 and SLC1A5 protein expression was significantly associated with shorter breast cancer-specific survival (p<0.01), especially in ER+ tumours (p<0.01), while high ATF4 and SLC7A11 protein expression was associated with shorter survival (p<0.01). CONCLUSION: These findings suggest a complex interplay between ATF4 and AATs in breast cancer biology and underscore the potential role for ATF4 as a prognostic marker in ER+ breast cancer, offering a unique opportunity for risk stratification and personalised treatment strategies.

Increasing equity in science requires better ethics training: A course by trainees, for trainees.

Despite the profound impacts of scientific research, few scientists have received the necessary training to productively discuss the ethical and societal implications of their work. To address this critical gap, we-a group of predominantly human genetics trainees-developed a course on genetics, ethics, and society. We intend for this course to serve as a template for other institutions and scientific disciplines. Our curriculum positions human genetics within its historical and societal context and encourages students to evaluate how societal norms and structures impact the conduct of scientific research. We demonstrate the utility of this course via surveys of enrolled students and provide resources and strategies for others hoping to teach a similar course. We conclude by arguing that if we are to work toward rectifying the inequities and injustices produced by our field, we must first learn to view our own research as impacting and being impacted by society.

In Vitro Lipolysis Model to Predict Food Effect of Poorly Water-Soluble Drugs Itraconazole, Rivaroxaban, and Ritonavir.

It is desirable to predict positive food effect of oral formulations due to food mediated dissolution enhancement of lipophilic drugs. The objective was to assess the ability of in vitro lipolysis to anticipate a positive food effect. Tested formulations included rivaroxaban and itraconazole, where some formulations, but not all, exhibit a positive food effect in vivo in humans. Amorphous solid dispersion formulations of ritonavir, which exhibit a negative food effect in vivo in humans, were also studied. Fe-lipolysis and Fa-lipolysis media representing fed and fasted intestinal conditions were used. Results show frequent agreement between in vitro lipolysis predictions and in vivo human outcomes. For rivaroxaban, food effect of unformulated active pharmaceutical ingredient (API) and products were correctly predicted where 2.5 mg and 10 mg strengths did not show any food effect; however, 20 mg did show a positive food effect. For itraconazole, all four products were correctly predicted, with Sporanox, Sempera, and generic capsules having a food effect, but Tolsura not having a positive food effect. For ritonavir, lipolysis predicted a positive food effect for API and Norvir tablet and powder, but Norvir products have negative food effect in vivo in humans. Overall, the lipolysis model showed favorable predictability and merits additional evaluation.

Thauera sp. for efficient nitrate removal in continuous denitrifying moving bed biofilm reactor.

Thauera is the most widely found dominant denitrifying genus in wastewater. In earlier study, MBBR augmented with a specially developed denitrifying five-membered bacterial consortium (DC5) where Thauera was found to be the most abundant and persistent genus. Therefore, to check the functional potential of Thauera in the removal of nitrate-containing wastewater in the present study Thauera sp.V14 one of the member of the consortium DC5 was used as the model organism. Thauera sp.V14 exhibited strong hydrophobicity, auto-aggregation ability, biofilm formation and denitrification ability, which indicated its robust adaptability short colonization and nitrate removal efficiency. Continuous reactor studies with Thauera sp.V14 in 10 L dMBBR showed 91% of denitrification efficiency with an initial nitrate concentration of 620 mg L-1 within 3 h of HRT. Thus, it revealed that Thauera can be employed as an effective microorganism for nitrate removal from wastewater based on its performance in the present studies.

Neurological care for LGBT+ people.

Sexual and gender minority (LGBT+) people face unique health disparities that must be considered by health-care providers to ensure equitable and inclusive care. Although traditionally LGBT+ health has not been integrated into neurology training, sexual orientation and gender identity have direct relevance to neurological health, driven by both systemic and interpersonal factors. In this Review, we summarize the evidence for associations between sexual orientation and gender identity with the prevalence and outcomes of various neurological conditions, including neurodegenerative diseases, epilepsy, stroke and neurodevelopmental disorders, among others. We describe important clinical considerations pertaining to LGBT+ people and recommend language and practices to promote inclusive care, as well as highlight gaps in need of further research and possible strategies to minimize these, including systematic collection of sexual orientation and gender identity and use of inclusive language.

A Qualitative Study of Drivers for Use of the Primary Care Exception Among Internal Medicine Teaching Faculty.

BACKGROUND: The Primary Care Exception (PCE) is a billing rule from the Centers for Medicare and Medicaid Services (CMS) that allows supervising physicians to bill for ambulatory care provided by a resident without their direct supervision. There has been increased focus on entrustment as a method to assess readiness for unsupervised practice. OBJECTIVE: To understand the factors influencing attending physicians' use of the PCE in ambulatory settings and identify common themes defining what motivates faculty preceptors to use the PCE. APPROACH: This was a qualitative exploratory study. Participants were interviewed one-on-one using a semi-structured template informed by the entrustment literature. Analysis was conducted using a thematically framed, grounded theory-based approach to identify major themes and subthemes. PARTICIPANTS: Twenty-seven internal medicine teaching faculty took part in a multi-institutional study representing four residency training programs across two academic medical centers in Connecticut. KEY RESULTS: Four predominant categories of themes influencing PCE use were identified: (1) clinical environment factors, (2) attending attitudes, (3) resident characteristics, and (4) patient attributes. An attending's "internal rules" drawn from prior experiences served as a significant driver of PCE non-use regardless of the trainee, patient, or clinical context. A common conflict existed between using the PCE to promote resident autonomy versus waiving the PCE to promote safety. CONCLUSIONS: The PCE can serve as a tool to support resident autonomy, confidence, and overall clinical efficiency. Choice of PCE use by attendings involved complex internal decision-making schema balancing internal, patient, resident, and environmental-related factors. The lack of standardized processes in competency evaluation may increase susceptibility to biases, which could be mitigated by applying standardized modes of assessment that encompass shared principles.

The early determinants of career choices for medical students following an obstetrics and gynaecology placement: Mixed methods study.

OBJECTIVE: To explore the impact of attending a clinical placement in considering a career in obstetrics and gynaecology. DESIGN: Mixed methods study. SETTING: London Medical School. POPULATION: Fifth year medical students attending a clinical placement in obstetrics and gynaecology. METHODS: Between January 2021 and January 2022, questionnaires were used and semi-structured focus groups conducted, which were audio-recorded. Descriptive statistics were conducted and a framework analysis on transcribed focus groups. MAIN OUTCOME MEASURE: The impact of the clinical placement on career choice. RESULTS: Six main themes were identified from the analysis; three contributing to considering a career in obstetrics and gynaecology; pregnancy is not an illness, extraordinary experience of observing childbirth and variable specialty and three themes emerged contributing to not considering a career; lack of work-life balance, high stakes specialty and the emotional toll. Even at an undergraduate level, medical students exhibited concerns about the long-term feasibility of achieving work-life balance and avoiding professional burnout, which was partly attributed to the responsibility of looking after both the woman and their baby. CONCLUSIONS: Obstetrics and gynaecology is perceived as an exciting and variable speciality by medical students. Students' experiences on the labour ward during a clinical placement appear to contribute to the consideration of a career in obstetrics and gynaecology. Students should be given opportunities to discuss their concerns about obstetrics, particularly over the potential psychological impact of adverse/traumatic birth events. It is crucial to provide a realistic introduction to obstetrics, to recruit enthusiastic junior doctors who will be resilient to the pressures of the speciality, to avoid burnout and minimise attrition rates.

Drug Dissolution in Oral Drug Absorption: Workshop Report.

The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of "dissolved drug," particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.

Medicaid policy data for evaluating eligibility and programmatic changes.

OBJECTIVES: Medicaid and the Children's Health Insurance Program (CHIP) provide health insurance coverage to more than 90 million Americans as of early 2023. There is substantial variation in eligibility criteria, application procedures, premiums, and other programmatic characteristics across states and over time. Analyzing changes in Medicaid policies is important for state and federal agencies and other stakeholders, but such analysis requires data on historical programmatic characteristics that are often not available in a form ready for quantitative analysis. Our objective is to fill this gap by synthesizing existing qualitative policy data to create a new data resource that facilitates Medicaid policy research. DATA DESCRIPTION: Our source data were the 50-state surveys of Medicaid and CHIP eligibility, enrollment, and cost-sharing policies, and budgets conducted near annually by KFF since 2000, which we coded through 2020. These reports are a rich source of point-in-time information but not operationalized for quantitative analysis. Through a review of the measures captured in the KFF surveys, we developed five Medicaid policy domains with 122 measures in total, each coded by state-quarter-1) eligibility (28 measures), 2) enrollment and renewal processes (39 measures), 3) premiums (16 measures), 4) cost-sharing (26 measures), and 5) managed care (13 measures).

Pitfalls and biases in neuroepidemiological studies of COVID-19 and the nervous system: a critical appraisal of the current evidence and future directions.

BACKGROUND: Neurological manifestations frequently occur in individuals with COVID-19, manifesting during the acute phase, persisting beyond the resolution of acute symptoms, and appearing days or weeks after the initial onset of COVID-19 symptoms. However, predicting the incidence, course, and outcome of these neurological manifestations at the individual patient level remains challenging. Biases in study design and limitations in data collection may contribute to the inconsistency and limited validity of the reported findings. Herein, we focused on critically appraising pitfalls and biases of prior reports and provide guidance for improving the quality and standardization of future research. Patients with COVID-19 exhibit diverse demographic features, sociocultural backgrounds, lifestyle habits, and comorbidities, all of which can influence the severity and progression of the infection and its impact on other organ systems. Overlooked or undocumented comorbidities and related treatments may contribute to neurological sequelae, which may not solely be attributable to COVID-19. It is crucial to consider the potential side effects of vaccines in relation to neurological manifestations. CONCLUSION: To investigate neurological manifestations of COVID-19, it is essential to employ valid and reliable diagnostic criteria and standard definitions of the factors of interest. Although population-based studies are lacking, well-defined inception cohorts, including hospitalized individuals, outpatients, and community residents, can serve as valuable compromises. These cohorts should be evaluated for the presence of common comorbidities, alongside documenting the primary non-neurological manifestations of the infectious disease. Lastly, patients with COVID-19 should be followed beyond the acute phase to assess the persistence, duration, and severity of neurological symptoms, signs, or diseases.

Characterisation of the treatment provided for children with unilateral hearing loss.

Background: Children with permanent unilateral hearing loss (UHL) are an understudied population, with limited data to inform the guidelines on clinical management. There is a funding gap in healthcare provision for the children with UHL in the United Kingdom, where genetic screening, support services, and devices are not consistently provided or fully funded in all areas. They are a disparate population with regard to aetiology and their degree of hearing loss, and hence their device choice and use. Despite having one "good ear", some children with UHL can have similar outcomes, socially, behaviourally, and academically, to children with bilateral hearing loss, highlighting the importance of understanding this population. In this longitudinal cohort study, we aimed to characterise the management of the children with UHL and the gaps in the support services that are provided for the children in Nottingham, United Kingdom. Methods: A cohort study was conducted collecting longitudinal data over 17 years (2002-2019) for 63 children with permanent congenital confirmed UHL in a large tertiary regional referral centre for hearing loss in Nottingham, United Kingdom. The cases of UHL include permanent congenital, conductive, mixed, or sensorineural hearing loss, and the degree of hearing loss ranges from mild to profound. The data were taken from their diagnostic auditory brainstem responses and their two most recent hearing assessments. Descriptors were recorded of the devices trialled and used and the diagnoses including aetiology of UHL, age of first fit, degree of hearing loss, when and which type of device was used, why a device was not used, the support services provided, concerns raised, and who raised them. Results: Most children (45/63; 71%) trialled a device, and the remaining 18 children had no device trial on record. Most children (20/45; 44%) trialled a bone-conduction device, followed by contralateral routing of signal aid (15/45; 33%) and conventional hearing aids (9/45; 20%). Most children (36/45; 80%) who had a device indicated that they wore their device "all day" or every day in school. Few children (8/45; 18%) reported that they wore their device rarely, and the reasons for this included bullying (3/8), feedback from the device (2/8), and discomfort from the device (2/8). Only one child reported that the device was not helping with their hearing. The age that the children were first fitted with their hearing device varied a median of 2.5 years for hearing aids and bone-conduction devices and 7 years for a contralateral routing of signal aid. The length of time that the children had the device also varied widely (median of 26 months, range 3-135 months); the children had their bone-conduction hearing aid for the longest period of time (median of 32.5 months). There was a significant trend where more recent device fittings were happening for children at a younger age. Fifty-one children were referred by the paediatric audiologist to a support service, 72.5% (37/51) were subsequently followed up by the referred service with no issue, whilst the remaining 27.5% (14/51) encountered an issue leading to an unsuccessful provision of support. Overall, most children (65%, 41/63) had no reported concerns, and 28.5% (18/63) of the children went on to have a documented concern at some point during their audiological care: five with hearing aid difficulties, five with speech issues, four with no improvement in hearing, three facing self-image or bullying issues, and one case of a child struggling to interact socially with friends. Three of these children had not trialled a device. We documented every concern reported from the parents, clinicians, teachers of the deaf, and from the children themselves. Where concerns were raised, more than half (58.6%, 10/18) were by schools and teachers, the remaining four concerns were raised by the family, and further four concerns were raised by the children themselves. Conclusion: To discover what management will most benefit which children with permanent UHL, we first must characterise their treatment, their concerns, and the support services available for them. Despite the children with UHL being a highly disparate population-in terms of their aetiology, their device use, the degree of hearing loss, and the age at which they trial a device-the majority report they use their device mostly in school. In lieu of available data and in consideration of the devices that are available to them, it could be useful to support families and clinicians in understanding the devices which are most used and where they are used. Considering the reasons for cessation of regular device use counselling and support services would be vital to support the children with UHL.

The effect of botulinum toxin on anxiety in cervical dystonia: A prospective, observational study.

INTRODUCTION: Anxiety is present in 30-40% of patients with cervical dystonia (CD). It has been ascribed to a direct effect of the state of motor symptoms on related pain, disability, and disfigurement. Accordingly, any reported benefit of botulinum toxin (BoNT) on anxiety is thought to be secondary to its effect on the same. We sought to evaluate the distinctive impact of botulinum toxin (BoNT) on anxiety in cervical dystonia (CD). METHODS: In this prospective observational study, 60 participants with idiopathic isolated CD were recruited from clinic. We assessed motor and anxiety burden using Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) parts I-III and State-Trait Anxiety Inventory (STAI). Assessments were done at time of BoNT (baseline) and at 6 weeks post-injection. RESULTS: STAI and motor severity TWSTRS scores poorly correlated at the baseline visit (rho = -0.30, p = 0.411). Both, motor TWSTRS (Mdifference = -1.46, p < 0.024) and STAI (Mdifference = -10.37, p = 0.007) improved from baseline to 6 weeks (peak effect). The change in motor TWSTRS poorly correlated with change in anxiety scores from baseline visit to 6 weeks (rho = -0.14, p > 0.999). Of these measures of anxiety, improvement in STAI-T had the largest effect size (rank biserial = 0.52). CONCLUSION: BoNT improves both motor severity and anxiety in CD. Poor correlation between motor severity and anxiety at both the time of injection and during the time of peak effect, and improvement in trait anxiety suggests that BoNT has a direct beneficial effect on anxiety.

Pregnancy in women with congenital heart disease: a focus on management and preventing the risk of complications.

INTRODUCTION: Congenital heart disease (CHD) is the most common cardiac disorder in pregnancy in the western world (around 80%). Due to improvements in surgical interventions more women with CHD are surviving to adulthood and choosing to become pregnant. AREAS COVERED: Preconception counseling, antenatal management of CHDs and strategies to prevent maternal and fetal complications.Preconception counseling should start early, before the transition to adult care and be offered to both men and women. It should include the choice of contraception, lifestyle modifications, pre-pregnancy optimization of cardiac state, the chance of the child inheriting a similar cardiac lesion, the risks to the mother, and long-term prognosis. Pregnancy induces marked physiological changes in the cardiovascular system that may precipitate cardiac complications. Risk stratification is based on the underlying cardiac disease and data from studies including CARPREG, ZAHARA, and ROPAC. EXPERT OPINION: Women with left to right shunts, regurgitant lesions, and most corrected CHDs are at lower risk and can be managed in secondary care. Complex CHD, including systemic right ventricle need expert counseling in a tertiary center. Those with severe stenotic lesions, pulmonary artery hypertension, and Eisenmenger's syndrome should avoid pregnancy, be given effective contraception and managed in a tertiary center if pregnancy does happen.

The labels and models used to describe problematic substance use impact discrete elements of stigma: A registered report.

OBJECTIVES: Problematic substance use is one of the most stigmatized health conditions leading research to examine how the labels and models used to describe it influence public stigma. Two recent studies examine whether beliefs in a disease model of addiction influence public stigma but result in equivocal findings-in line with the mixed-blessings model, Kelly et al. (2021) found that while the label "chronically relapsing brain disease" reduced blame attribution, it decreased prognostic optimism and increased perceived danger and need for continued care; however, Rundle et al. (2021) conclude absence of evidence. This study isolates the different factors used in these two studies to assess whether health condition (drug use vs. health concern), etiological label (brain disease vs. problem), and attributional judgment (low vs. high treatment stability) influence public stigma toward problematic substance use. METHOD: Overall, 1,613 participants were assigned randomly to one of the eight vignette conditions that manipulated these factors. They completed self-report measures of discrete and general public stigma and an indirect measure of discrimination. RESULTS: Greater social distance, danger, and public stigma but lower blame were ascribed to drug use relative to a health concern. Greater (genetic) blame was reported when drug use was labeled as a "chronically relapsing brain disease" relative to a "problem." Findings for attributional judgment were either inconclusive or statistically equivalent. DISCUSSION: The labels used to describe problematic substance use appear to impact discrete elements of stigma. We suggest that addiction is a functional attribution, which may explain the mixed literature on the impact of etiological labels on stigma to date. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A systemic review and meta-analysis of Aflibercept plus FOLFIRI regimen as a second-line treatment for metastatic colorectal cancer: A PRISMA compliant pooled analysis of randomized controlled trials and single arm studies to assess efficacy and safety.

BACKGROUND AND OBJECTIVE: Aflibercept; a decoy receptor for vascular endothelial growth factors (VEGFs) and placental growth factor (PLGF), in combination with FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride) chemotherapy regime, was FDA approved in 2012 as second-line salvage chemotherapy for metastatic colorectal cancer (mCRC). This is the first systematic review, and meta-analysis-based evidence to determine the efficacy and safety of Aflibercept plus FOLFIRI regimen pooling randomized controlled trials and single-arm studies. METHOD: PubMed, Cochrane library, Embase, and Clinical trial.gov were systematically searched for published randomized controlled trials, single-arm studies, and national patient programs on aflibercept plus FOLFIRI chemotherapy for the treatment of mCRC till 11/10/2022. RESULT: Ten studies met the inclusion criteria comprising 1075 patients for efficacy studies and 2027 patients for safety studies. The pooled prevalences were 18% (95% CI, 5%-37%, p = 0.00) for 12 m PFS and 61% (95% CI, 53-68%, p = 0.00) for 12 m OS. The pooled prevalences were 69% (95% CI, 55-82%, p = 0.00) for any grade 3-4 toxicities, 10% (95% CI, 5-16%, p = 0.00) for grade 3-4 diarrhea, 13% (95% CI, 5-24%, p = 0.00) for grade 3-4 hypertension, 31% (95% CI, 22-40%, p = 0.00) for grade 3-4 neutropenia and 5% (95% CI, 2-7%, p = 0.00) for grade 3-4 venous thromboembolic event. CONCLUSION: Our meta-analysis shows that the aflibercept plus FOLFIRI combination shows better survival efficacies however; it is also associated with more high-grade adverse events.

Sex and Gender Differences in Parkinson's Disease.

The lower prevalence of Parkinson disease (PD) in females is not well understood but may be partially explained by sex differences in nigrostriatal circuitry and possible neuroprotective effects of estrogen. PD motor and nonmotor symptoms differ between sexes, and women experience disparities in care including undertreatment with DBS and less access to caregiving. Our knowledge about PD in gender diverse individuals is limited. Future studies should improve our understanding of the role of hormone replacement therapy in PD, address gender-based inequities in PD care and expand our understanding of PD in SGM and marginalized communities.