Late-Stage C-H Functionalization of Azines.

Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite of physiochemical properties that match key criteria in drug design and is tunable by varying their substituents. Developments in synthetic chemistry, therefore, directly impact these efforts, and methods that can install various groups from azine C-H bonds are particularly valuable. Furthermore, there is a growing interest in late-stage functionalization (LSF) reactions that focus on advanced candidate compounds that are often complex structures with multiple heterocycles, functional groups, and reactive sites. Because of factors such as their electron-deficient nature and the effects of the Lewis basic N atom, azine C-H functionalization reactions are often distinct from their arene counterparts, and the application of these reactions in LSF contexts is difficult. However, there have been many significant advances in azine LSF reactions, and this review will describe this progress, much of which has occurred over the past decade. It is possible to categorize these reactions as radical addition processes, metal-catalyzed C-H activation reactions, and transformations occurring via dearomatized intermediates. Substantial variation in reaction design within each category indicates both the rich reactivity of these heterocycles and the creativity of the approaches involved.

Synthesis of 15N-Pyridines and Higher Mass Isotopologs via Zincke Imine Intermediates.

Methods to incorporate stable radioisotopes are integral to pharmaceutical and agrochemical development. However, despite the prevalence of pyridines in candidate compounds, methods to incorporate 15N atoms within their structures are limited. Here, we present a general approach to pyridine 15N-labeling that proceeds via ring-opening to NTf-Zincke imines and then ring-closure with commercially available 15NH4Cl salts. This process functions on a range of substituted pyridines, from simple building block-type compounds to late-stage labeling of complex pharmaceuticals, and 15N-incorporation is >95% in most cases. The reactivity of the Zincke imine intermediates also enables deuteration of the pyridine C3- and C5-positions, resulting in higher mass isotopologs required for LCMS analysis of biological fluids during drug development.

Predicting multilingual effects on executive function and individual connectomes in children: An ABCD study.

While there is a substantial amount of work studying multilingualism's effect on cognitive functions, little is known about how the multilingual experience modulates the brain as a whole. In this study, we analyzed data of over 1,000 children from the Adolescent Brain Cognitive Development (ABCD) Study to examine whether monolinguals and multilinguals differ in executive function, functional brain connectivity, and brain-behavior associations. We observed significantly better performance from multilingual children than monolinguals in working-memory tasks. In one finding, we were able to classify multilinguals from monolinguals using only their whole-brain functional connectome at rest and during an emotional n-back task. Compared to monolinguals, the multilingual group had different functional connectivity mainly in the occipital lobe and subcortical areas during the emotional n-back task and in the occipital lobe and prefrontal cortex at rest. In contrast, we did not find any differences in behavioral performance and functional connectivity when performing a stop-signal task. As a second finding, we investigated the degree to which behavior is reflected in the brain by implementing a connectome-based behavior prediction approach. The multilingual group showed a significant correlation between observed and connectome-predicted individual working-memory performance scores, while the monolingual group did not show any correlations. Overall, our observations suggest that multilingualism enhances executive function and reliably modulates the corresponding brain functional connectome, distinguishing multilinguals from monolinguals even at the developmental stage.

Hazard of Failed Nonoperative Management for Symptomatic Accessory Navicular in Children and Adolescents: A Population-Based Case-Cohort Study.

BACKGROUND: The accessory navicular (AN) is an idiopathic condition of the foot present in 4% to 21% of the population. Most ANs remain asymptomatic, but children and adolescents who develop symptoms can have remarkably reduced quality of life. Although many respond to conservative measures, surgery is occasionally needed. Our purpose was to determine factors associated with the failure of nonoperative management. METHODS: This single-institution retrospective case-cohort study included patients up to age 19 years presenting between 2000 and 2021 with symptomatic AN and treated with standard-of-care. All 298 surgical cases, indicating failed nonoperative treatment, were included. For the subcohort, 299 patients were randomly sampled from all eligible patients, regardless of treatment. Baseline characteristics were summarized for the surgical cases and subcohort. Proportional hazards assumptions were checked and stratification implemented when necessary. Marginal structural proportional hazard modeling was used to estimate hazard ratios with 95% confidence intervals via inverse probability and LinYing weighting methods. RESULTS: The 298 surgical cases failed nonoperative management at a median of 5.2 months (IQR, 2.0-11.6 mo). In the subcohort, 86 failures of nonoperative management and 213 nonfailures constituted a 28.8% surgery rate. In both cohorts, nearly all patients played sports. Univariate proportional hazard modeling found older age ( P =0.02) and activity limitation ( P <0.001) at presentation, female sex ( P =0.002), higher BMI ( P =0.01), AN on the right ( P <0.001), and bone marrow edema of the AN ( P <0.001) and navicular body ( P <0.001) on MRI were associated with increased hazard of nonoperative failure. Nearly all of the surgical cohort reported improvement in pain (278/296, 94%) and returned to their primary sport (236/253, 93%) after surgery. Most also experienced full resolution of symptoms (187/281, 67%). CONCLUSIONS: Symptomatic AN predominantly affects female athletes, leading to surgery in 28.8% of our subcohort. Conservative treatment may be less successful-and therefore surgery could be more strongly considered-in older age, activity limitation at presentation, female sex, higher BMI, right-sided AN, and bone marrow edema on MRI. Surgery is effective for symptomatic and functional improvement. LEVEL OF EVIDENCE: Case-cohort-Level III.

The Effect of Prosthetic Joint Infection on Work Status and Quality of Life: A Multicenter, International Study.

BACKGROUND: Periprosthetic joint infection (PJI) and subsequent revision surgeries may affect patients' social and physical health, ability to complete daily activities, and disability status. This study sought to determine how PJI affects patients' quality of life through patient-reported outcome measures with minimum 1-year follow-up. METHODS: Patients who suffered PJI following primary total joint arthroplasty (TJA) from 2012 to 2021 were retrospectively reviewed. Patients met Musculoskeletal Infection Society criteria for acute or chronic PJI, underwent revision TJA surgery, and had at least 1 year of follow-up. Patients were surveyed regarding how PJI affected their work and disability status, as well as their mental and physical health. Outcome measures were compared between acute and chronic PJIs. In total, 318 patients (48.4% total knee arthroplasty and 51.6% total hip arthroplasty) met inclusion criteria. RESULTS: Following surgical treatment for knee and hip PJI, a substantial proportion of patients reported that they were unable to negotiate stairs (20.5%), had worse physical health (39.6%), and suffered worse mental health (25.2%). A high proportion of patients reported worse quality of life (38.5%) and social satisfaction (35.3%) following PJI. Worse reported patient-reported outcome measures including patients' ability to complete daily physical activities were found among patients undergoing treatment for chronic PJI, and also, 23% of patients regretted their initial decision to pursue primary TJA. CONCLUSIONS: A PJI negatively affects patients' ability to carry out everyday activities. This patient population is prone to report challenges overcoming disability and returning to work. Patients should be adequately educated regarding the risk of PJI to decrease later potential regrets. LEVEL OF EVIDENCE: Case series (IV).

Incidence and Outcomes of Registry-Based Acute Myocardial Infarction After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Acute myocardial infarction (AMI) is the rarest and least studied cardiac complication of aneurysmal subarachnoid hemorrhage (aSAH). Precise estimates of the incidence of AMI after aSAH are unavailable. Our goal was to estimate the incidence of registry-based AMI (rb-AMI) after aSAH and determine its association with clinical outcomes. METHODS: Adult patients with aSAH in the National Inpatient Samples from 2002 to 2014 were included in the study. We evaluated risk factors for rb-AMI using univariate and multivariate regression models. Clinical outcomes that were assessed included functional status at discharge, in-patient mortality, length of stay, and total hospitalization cost, adjusting for patient demographics and cardiovascular risk factors through an inverse probability weighted analysis. Subgroup analyses were further performed stratified by rb-AMI type (ST-segment elevation myocardial infarction [STEMI] vs. non-STEMI [NSTEMI]). RESULTS: A total of 139,734 patients with aSAH were identified, 3.6% of whom had rb-AMI. NSTEMI was the most common type of rb-AMI occurring after aSAH (71% vs. 29% for NSTEMI vs. STEMI, respectively). Patient characteristics associated with higher odds of rb-AMI included age, female sex, poor aSAH grade, and various cardiovascular risk factors. Rb-AMI was also associated with poor functional status at discharge, higher in-hospital mortality, and a longer and more costly hospital stay. CONCLUSIONS: Rb-AMI occurs in 3.6% of patients with aSAH and is associated with poor functional status at discharge, higher in-patient mortality, and a longer and more costly hospitalization. Differentiating between different types of rb-AMI would be important in optimizing the management of patients with aSAH. Our definition of rb-AMI likely includes patients with neurogenic stress cardiomyopathy, which may confound the results.

Dynamic Kinetic Resolution of Aldehydes by Hydroacylation.

We report a dynamic kinetic resolution (DKR) of chiral 4-pentenals by olefin hydroacylation. A primary amine racemizes the aldehyde substrate via enamine formation and hydrolysis. Then, a cationic rhodium catalyst promotes hydroacylation to generate α,γ-disubstituted cyclopentanones with high enantio- and diastereoselectivities.

Gender-Affirming Hormone Use in Transgender Individuals: Impact on Behavioral Health and Cognition.

PURPOSE OF REVIEW: With increasing numbers of transgender and gender non-binary individuals presenting for care, knowing how to elucidate the mental health and cognitive outcomes of gender-affirming hormone therapy (GAHT) is necessary. This article reviews the present literature covering GAHT effects on mood, behavioral health, and cognition in these individuals and offers research priorities to address knowledge gaps. RECENT FINDINGS: Although there are some conflicting data, GAHT overwhelmingly seems to have positive psychological effects in both adolescents and adults. Research tends to support that GAHT reduces symptoms of anxiety and depression, lowers perceived and social distress, and improves quality of life and self-esteem in both male-to-female and female-to-male transgender individuals. Clinically, prescribing GAHT can help with gender dysphoria-related mental distress. Thus, timely hormonal intervention represents a crucial tool for improving behavioral wellness in transgender individuals, though effects on cognitive processes fundamental for daily living are unknown. Future research should prioritize better understanding of how GAHT may affect executive functioning.

Extent of alignment between the Australian Dietary Guidelines and the NOVA classification system across the Australian packaged food supply.

AIMS: The Australian Dietary Guidelines are currently being revised and ultra-processed foods have been identified as a high priority action area. To better understand how well the current Dietary Guidelines align with level of processing classifications, the aim of this study was to assess the alignment between the Australian Dietary Guidelines and the NOVA classification system for classifying the healthiness of packaged foods. METHODS: Data were sourced from the Australian FoodSwitch dataset, which included 28 071 packaged food and beverage products available in major Australian supermarkets in 2022. Products were classified as (i) core or discretionary (Australian Dietary Guidelines) and (ii) non-ultra-processed or ultra-processed (NOVA). Agreement between the two systems (core vs. non-ultra-processed and discretionary vs. ultra-processed) was evaluated using the kappa statistic. RESULTS: There was 'moderate' agreement (κ = 0.41, 95% CI: 0.40-0.42) between the Australian Dietary Guidelines and the NOVA system, with 69.8% of products aligned across the two systems. Alignment was more common for discretionary foods (80.6% were ultra-processed) than core foods (59.9% aligned were not-ultra-processed). Food categories exhibiting the strongest levels of alignment included confectionary, foods for specific dietary use, and egg and egg products. Discordance was most common for convenience foods, sugars, honey and related products, and cereal and grain products. CONCLUSIONS: Despite moderate alignment between the Australian Dietary Guidelines and NOVA, the discordance observed for almost one-third of products highlights the opportunity to develop recommendations for ultra-processed foods within the guidelines to advise Australians how these foods should be considered as part of a healthy diet.

Validation of Patient-Reported Outcome Measurement Information System for Detection of Posttraumatic Stress in Children and Adolescents Following Procedures for Acute Orthopaedic Trauma.

OBJECTIVES: The efficiency and validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) surveys were determined for pediatric orthopaedic trauma patients with posttraumatic stress disorder (PTSD) symptoms in a clinic setting. DESIGN: Prospective cohort study. SETTING: Single-institution, Level I trauma center. PATIENT SELECTION CRITERIA: All consecutive children aged 8-18 years undergoing procedures or surgery for orthopaedic trauma. OUTCOME MEASURES AND COMPARISONS: The convergent, divergent, and discriminant validity of the PROMIS Anger and Anxiety computerized adaptive tests (CATs) were evaluated and compared with the previously validated Child PTSD Symptom Scale (CPSS). The efficiency in time to completion of the outcome measures was compared between the CPSS and PROMIS surveys. Cutoffs for increased likelihood of PTSD were established for the PROMIS questionnaires. RESULTS: A total of 233 subjects were included in this study (mean age 13.1 years with SD 2.8 years, 71% male). The majority (51%) of injuries were related to sports, and most (60%) involved the upper extremity. Of those included, 41 patients had high levels of PTSD symptoms on the CPSS (18%; 95% CI, 13.1-23.2%). The CPSS took 182 (interquartile range [IQR] 141-228) seconds versus 52 (IQR 36-84) and 52 (IQR 36-70) seconds for PROMIS Anger and Anxiety CATs, respectively. Convergent validity showed patient scores on both PROMIS instruments significantly correlated with CPSS scores (Anger: P < 0.001, r = 0.51; Anxiety: P < 0.001, r = 0.41). Neither PROMIS score correlated with University of California Los Angeles Activity Score (Anger: r = -0.26; Anxiety: r = -0.22), a functional outcome measure, demonstrating divergent validity. Both PROMIS instruments sufficiently discriminated across PTSD risk groups (Anger P < 0.001; Anxiety P < 0.001). A score of at least 53 on PROMIS Anger or at least 48 on PROMIS Anxiety indicated an increased likelihood of PTSD risk. CONCLUSIONS: PROMIS Anger and Anxiety CATs are efficient and valid for evaluating posttraumatic stress in children following orthopaedic trauma procedures. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Randomized Clinical Trials in Cerebrovascular Neurosurgery From 2018 to 2022.

There has been an exponential increase in randomized controlled trials (RCTs) on cerebrovascular disease within neurosurgery. The goal of this study was to review, outline the scope, and summarize all phase 2b and phase 3 RCTs impacting cerebrovascular neurosurgery practice since 2018. We searched PubMed, MEDLINE, Embase, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases for relevant RCTs published between January 1, 2018, and July 1, 2022. We searched for studies related to eight major cerebrovascular disorders relevant to neurosurgery, including acute ischemic stroke, cerebral aneurysms and subarachnoid hemorrhage, intracerebral hemorrhage, subdural hematomas, cerebral venous thrombosis, arteriovenous malformations, Moyamoya disease and extracranial-intracranial bypass, and carotid and intracranial atherosclerosis. We limited our search to phase 2b or 3 RCTs related to cerebrovascular disorders published during the study period. The titles and abstracts of all relevant studies meeting our search criteria were included. Pediatric studies, stroke studies related to rehabilitation or cardiovascular disease, study protocols without published results, prospective cohort studies, registry studies, cluster randomized trials, and nonrandomized pivotal trials were excluded.  From an initial total of 2,797 records retrieved from the database searches, 1,641 records were screened after duplicates and studies outside of our time period were removed. After screening, 511 available reports within our time period of interest were assessed for eligibility. Pediatric studies, stroke studies related to rehabilitation or cardiovascular disease, study protocols without published results, prospective cohort studies, registry studies, cluster randomized trials, and nonrandomized pivotal trials were excluded. We found 80 unique phase 2b or 3 RCTs that fit our criteria, with 165 topic-relevant articles published within the study period.  Numerous RCTs in cerebrovascular neurosurgery have been published since 2018. Ischemic stroke, including mechanical thrombectomy and thrombolysis, accounted for a majority of publications, but there were large trials in intracerebral hemorrhage, subdural hemorrhage, aneurysms, subarachnoid hemorrhage, and cerebral venous thrombosis, among others. This review helps define the scope of the large RCTs published in the last four years to guide future research and clinical care.

See, seek, support: a policy framework to uplift first-generation low-income medical professionals.

The First-Generation and/or Low-Income (FGLI) identity is not readily visible, encapsulating those who are the first in their families to complete a 4-year college degree and/or those living near or below the poverty line. In the backdrop of unprecedented levels of socioeconomic inequality in a country where household income predicts educational attainment, we explore the current state of U.S. society regarding socioeconomic status and health care. We describe challenges in diversifying the health care workforce and present a multi-pronged policy approach for visibilizing, recruiting, supporting, and retaining FGLI trainees in medicine, with the promise of improving the quality of health care delivery altogether. Through this work, we aim to render the field of medicine more equitable for trainees, physicians, and patients alike.

The Impact of COVID-19 on Multidisciplinary Care Delivery to Children with Cerebral Palsy and Other Neuromuscular Complex Chronic Conditions.

The COVID-19 pandemic has caused unprecedented challenges in the care of children with cerebral palsy (CP) and other neuromuscular complex chronic conditions (NCCCs). The purpose of this study is to explore the direct impact of the COVID-19 pandemic on healthcare delivery. From May to August 2020, medical professionals caring for CP and NCCC patients across multiple countries and disciplines completed a self-administered cross-sectional survey comparing practices before and during the COVID-19 pandemic. Of the 79 healthcare workers from eight countries who participated-predominantly pediatric orthopedic surgeons (32%), pediatricians (30%), and pediatric physiatrists (23%)-most of them felt that caring for NCCC patients during the pandemic presented unique difficulties, and they reported a significant decrease in the in-person NCCC clinic volume (p < 0.001), multidisciplinary appointments (p < 0.001), surgical cases (p = 0.008), and botulinum toxin/phenol injections. Most providers affirmed that institutional guidelines for perioperative emergent/urgent and elective procedures, workplace settings, and technology were modified to accommodate the ongoing public health crisis. The usage of telemedicine significantly increased for NCCC patient visits (p < 0.001). During the COVID-19 pandemic, many children with NCCCs lost access to routine, multidisciplinary care. Telemedicine became an integral part of communication and management. In the setting of the COVID-19 pandemic and with the threat of future healthcare disruptions, these data lay the foundation for trending the evolution of healthcare delivery and accelerating best practice guidelines for children with CP and NCCCs.

What has sex got to do with it? The role of hormones in the transgender brain.

Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female "characteristics" in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.

The association between infant and young child feeding practices and diarrhoea in Tanzanian children.

BACKGROUND: Diarrhoea is a leading cause of child mortality in Tanzania. The association between optimal infant feeding practices and diarrhoea has been reported elsewhere, but the evidence has been limited to promote and advocate for strategic interventions in Tanzania. This study examined the association between infant and young child feeding (IYCF) practices and diarrhoea in Tanzanian children under 24 months. METHODS: The study used the Tanzania Demographic and Health Survey data to estimate the prevalence of diarrhoea stratified by IYCF practices. Using multivariable logistic regression modelling that adjusted for confounding factors and cluster variability, the association between IYCF practices and diarrhoea among Tanzanian children was investigated. RESULTS: Diarrhoea prevalence was lower in infants aged 0-5 months whose mothers engaged in exclusive breastfeeding (EBF) and predominant breastfeeding (PBF) compared to those who were not exclusively and predominantly breastfed. Infants aged 6-8 months who were introduced to complementary foods had a higher prevalence of diarrhoea compared to those who received no complementary foods, that is, infants who were exclusively breastfed at 6-8 months. Infants who were exclusively and predominantly breastfed were less likely to experience diarrhoea compared to those who were not exclusively and predominantly breastfed [adjusted odds ratio (AOR) 0.31, 95% confidence interval (CI) 0.16-0.59, P < 0.001 for EBF and AOR = 0.30, 95% CI 0.10-0.89, P = 0.031 for PBF]. In contrast, infants aged 6-8 months who were introduced to complementary foods were more likely to experience diarrhoea compared to those who received no complementary foods (AOR = 2.91, 95% CI 1.99-4.27, P < 0.001). CONCLUSIONS: The study suggests that EBF and PBF were protective against diarrhoeal illness in Tanzanian children, while the introduction of complementary foods was associated with the onset of diarrhoea. Strengthening IYCF (facility- and community-based) programmes would help to improve feeding behaviours of Tanzanian women and reduce diarrhoea burden in children under 2 years.