Variability in COVID-19 Symptom Presentation During Pregnancy and its Impact on Maternal and Infant Outcomes Across the Pandemic.

BACKGROUND: With the dominance of different SARS-CoV-2 variants, the severity of COVID-19 has evolved. We aimed to investigate the difference in symptom prevalence and the association between symptoms and adverse pregnancy outcomes during the dominance of Wild-type/Alpha, Delta, and Omicron. METHODS: COVID-19 related symptom prevalence, maternal and specific neonatal outcomes of 5431 pregnant women registered in this prospective study were compared considering the dominant virus variant. Logistic regression models analyzed the association between specific symptoms and intensive care unit (ICU) admission or preterm birth. RESULTS: Infection with the Delta variant led to an increase in the symptom burden compared to the Wild-type/Alpha variant and the highest risk for respiratory tract symptoms, feeling of sickness, headache, and dizziness/drowsiness. An infection with the Omicron variant was associated with the lowest risk of dyspnea and changes in smell/taste but the highest risk for nasal obstruction, expectoration, headaches, myalgia, and fatigue compared to the Wild-type/Alpha and Delta variant dominant periods. With the progression of the Wild-type/Alpha to the Delta variant neonatal outcomes worsened. Dyspnea and fever were strong predictors for maternal ICU admission and preterm birth independent of vaccination status or trimester of infection onset. CONCLUSION: The symptom burden increased during the Delta period and was associated with worse pregnancy outcomes than in the Wild-type/Alpha area. During the Omicron dominance there still was a high prevalence of less severe symptoms. Dyspnea and fever can predict a severe maternal illness.

Amphiphilic Polyelectrolyte Complexes for Fouling-Resistant and Easily Tunable Membranes.

Commercial membranes today are manufactured from a handful of membrane materials. While these systems are well-optimized, their capabilities remain constrained by limited chemistries and manufacturing methods available. As a result, membranes cannot address many relevant separations where precise selectivity is needed, especially with complex feeds. This constraint requires the development of novel membrane materials that offer customizable features to provide specific selectivity and durability requirements for each application, enabled by incorporating different functional chemistries into confined nanopores in a scalable process. This study introduces a new class of membrane materials, amphiphilic polyelectrolyte complexes (APECs), comprised of a blend two distinct amphiphilic polyelectrolytes of opposite charge that self-assemble to form a polymer selective layer. When coated on a porous support from a mixture in a nonaqueous solvent, APECs self-assemble to create ionic nanodomains acting as water-conducting nanochannels, enveloped within hydrophobic nanodomains, ensuring structural integrity of the layer in water. Notably, this approach allows precise control over selectivity without compromising pore size, permeability, or fouling resistance. For example, using only one pair of amphiphilic copolymers, sodium sulfate rejections can be varied from >95% to <10% with no change in effective pore size and fouling resistance. Given the wide range of amphiphilic polyelectrolytes (i.e., combinations of different hydrophobic, anionic, and cationic monomers), APECs can create membranes with many diverse chemistries and selectivities. Resultant membranes can potentially address precision separations in many applications, from wastewater treatment to chemical and biological manufacturing.

Plasma metabolites are altered before and after diagnosis of preeclampsia or fetal growth restriction.

Metabolomics is the study of small molecules (metabolites), within cells, tissues and biofluids. Maternal metabolites can provide important insight into the health and development of both mother and fetus throughout pregnancy. This study assessed metabolic profiles in the maternal circulation prior to and at the time of diagnosis of preeclampsia and fetal growth restriction. Maternal plasma samples were collected from two independent cohorts: (1) Established disease cohort: 50 participants diagnosed with early-onset preeclampsia (< 34 weeks' gestation), 14 with early-onset fetal growth restriction, and 25 gestation-matched controls. (2) Prospective cohort, collected at 36 weeks' gestation before diagnosis: 17 participants later developed preeclampsia, 49 delivered infants with fetal growth restriction (birthweight < 5th centile), and 72 randomly selected controls. Metabolic evaluation was performed by Metabolomics Australia on the Agilent 6545 QTOF Mass Spectrometer. In the established disease cohort, 77 metabolites were altered in circulation from participants with preeclampsia - increased L-cysteine (3.73-fold), L-cystine (3.28-fold), L-acetylcarnitine (2.57-fold), and carnitine (1.53-fold) (p < 0.05). There were 53 metabolites dysregulated in participants who delivered a fetal growth restriction infant-including increased levulinic acid, citric acid (1.93-fold), and creatine (1.14-fold) (p < 0.05). In the prospective cohort, 30 metabolites were altered in participants who later developed preeclampsia at term - reduced glutaric acid (0.85-fold), porphobilinogen (0.77-fold) and amininohippuric acid (0.82-fold) (p < 0.05) was observed. There were 5 metabolites altered in participants who later delivered a fetal growth restriction infant - including reduced 3-methoxybenzenepropanoic acid (p < 0.05). Downstream pathway analysis revealed aminoacyl-tRNA biosynthesis to be most significantly altered in the established cohort in preeclampsia (13/48 hits, p < 0.001) and fetal growth restriction (7/48 hits, p < 0.001). The predictive cohort showed no significant pathway alterations. This study observed altered metabolites in maternal plasma collected before and after diagnosis of a preeclampsia or fetal growth restriction. While a significant number of metabolites were altered with established disease, few changes were observed in the predictive cohort. Thus, metabolites measured in this study may not be useful as predictors of preeclampsia or fetal growth restriction.

Leveraging existing data to improve antimicrobial resistance-related mortality estimates for Australia.

Antimicrobial resistance (AMR) is a global pandemic, however, estimating its burden is a complex process. As a result, many countries rely on global estimates to infer burden within their own setting. With a growing number of recent publications quantifying AMR burden in Australia, and an expansion of surveillance programs, enumerating AMR mortality for Australia is feasible. We aimed to leverage existing published data to assess methodological factors contributing to the considerable variation in AMR-related mortality and provide two reliable estimates of AMR mortality in Australia. This is a necessary step towards generating meaningful measures of AMR burden in Australia.

Selective Synthesis of 3-(1H-Tetrazol-5-yl)-indoles from 2H-Azirines and Arynes.

A new selective synthetic approach to indole derivatives bearing a tetrazole moiety has been developed. Arynes, generated in situ from o-(trimethylsilyl)aryl triflates and KF, reacted smoothly with 2-(2-benzyl-2H-tetrazol-5-yl)-2H-azirines to give 3-(2-benzyl-2H-tetrazol-5-yl)-indole derivatives with high selectivity. Deprotection of the tetrazole moiety gave 3-(1H-tetrazol-5-yl)-indole derivatives.

Prospective comparison of risk factors for firearm suicide and non-firearm suicide in a large population-based cohort of current and former US service members: findings from the Millennium Cohort Study.

Background: Suicide is a leading cause of death among service members and veterans. Among suicide methods, firearms are the most lethal and commonly used method among military populations. Limited research has compared risk factors for the various suicide methods. This study evaluated and compared risk factors for firearm versus non-firearm suicides using data from the Millennium Cohort Study, a large longitudinal military cohort. Methods: Using a competing risk approach, we identified factors associated with each suicide method. Risk factors included demographics, mental health diagnoses, mental health symptoms, military-specific characteristics, health behaviors, and psychosocial factors. Cause of death was assessed from July 1, 2001, through December 31, 2018. Findings: Among 201,565 eligible participants with a mean [SD] age of 29.0 [58.1] years, there were 139,789 (69.3%) male, 61,776 (30.7%) female, 15,927 (7.9%) Hispanic, 24,667 (12.3%) non-Hispanic Black, 14,138 (7.0%) Asian, Pacific Islander, American Indian or Multiracial, and 146,736 (72.8%) non-Hispanic White participants. During the study period, 330 died by firearm suicide and 168 died by non-firearm suicide. Overall, effect estimates for risk factors were similar across both methods of suicide. After adjustment, men (HR: 3.69, 95% CI: 2.59, 5.24) and those who screened positive for depression (HR: 1.97, 95% CI: 1.36, 2.87) had an elevated risk for firearm suicide. In contrast, those who self-reported a history of bipolar diagnosis (HR: 3.40, 95% CI: 1.76, 6.55) had significantly increased risk for non-firearm suicide. Interpretation: Findings suggest that prevention and intervention strategies overall may not need to be differentiated by specific demographic, military, or health factors. Targeted interventions that consider sex and mental health screens might have relative utility in preventing firearm related suicide risk compared with non-firearm suicide. Funding: Military Operational Medicine Research Program, Defense Health Program, and Department of Veterans Affairs.

Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations.

PURPOSE: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. METHODS: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. RESULTS: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). CONCLUSION: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.

A Rare Case of Left Main Coronary Artery Coronary Sinus Fistula in an 85-Year-Old Female.

Coronary arteriovenous fistulas (CAVFs) are congenital or acquired communications between the coronary arteries and coronary venous system, and they can also include other cardiac structures or vasculature. We discuss a case of a large fistula between the left main coronary artery and the right atrium in a geriatric patient with a history of gastrointestinal arteriovenous malformations (AVM). The occurrence of CAVFs, an uncommon cardiac irregularity, is particularly infrequent among older adults. Typically, it is discovered by chance when investigating symptoms such as shortness of breath or chest pain, where coronary angiography is necessary to determine the most effective treatment strategy. This case highlights the possible utility of evaluating CAVFs in patients with a history of gastrointestinal AVM who similarly present with clinical symptoms of high-output heart failure. Once identified, this could simplify the treatment approach and improve communication between healthcare providers to minimize the risk of harm to the patient.

Bias in Observed Assessments in Medical Education: A Scoping Review.

PURPOSE: Observed assessments are integral to medical education but may be biased against structurally marginalized communities. Current understanding of assessment bias is limited because studies have focused on single specialties, levels of training, or social identity characteristics (SIDCs). This scoping review maps studies investigating bias in observed assessments in medical education arising from trainees' observable SIDCs at different medical training levels, with consideration of medical specialties, assessment environments, and assessment tools. METHOD: MEDLINE, Embase, ERIC, PsycINFO, Scopus, Web of Science Core Collection, and Cochrane Library were searched for articles published between January 1, 2008, and March 15, 2023, on assessment bias related to 6 observable SIDCs: gender (binary), gender nonconformance, race and ethnicity, religious expression, visible disability, and age. Two authors reviewed the articles, with conflicts resolved by consensus or a third reviewer. Results were interpreted through group review and informed by consultation with experts and stakeholders. RESULTS: Sixty-six of 2,920 articles (2.3%) were included. These studies most frequently investigated graduate medical education (44 [66.7%]), used quantitative methods (52 [78.8%]), and explored gender bias (63 [95.5%]). No studies investigated gender nonconformance, religious expression, or visible disability. One evaluated intersectionality, with SIDCs described inconsistently. General surgery (16 [24.2%]) and internal medicine (12 [18.2%]) were the most studied specialties. Simulated environments (37 [56.0%]) were studied more frequently than clinical environments (29 [43.9%]). Bias favoring men was found more in assessments of intraoperative autonomy (5 of 9 [55.6%]), whereas clinical examination bias often favored women (15 of 19 [78.9%]). When race and ethnicity bias was identified, it consistently favored White students. CONCLUSIONS: This review mapped studies of gender, race, and ethnicity bias in the medical education assessment literature, finding limited studies on other SIDCs and intersectionality. These findings will guide future research by highlighting the importance of consistent terminology, unexplored SIDCs, and intersectionality.

Protocol for in vivo analysis of pre- and post-synaptic protein function in mice.

Studying synapses in vivo presents challenges due to the complexity of accurately targeting and visualizing specific synaptic proteins within the brain. Here, we present a protocol for in vivo analysis of pre- and post-synaptic protein function in mice. We describe steps for combining adeno-associated virus (AAV)-mediated gene transfer to manipulate specific neuron subtypes. We also describe immunofluorescence on artificial cerebrospinal fluid (ACSF)-perfused brain sections to enhance the visualization of synaptic proteins. For complete details on the use and execution of this protocol, please refer to Cramer et al.1.

Effectiveness of photodynamic therapy on treatment response and survival in patients with recurrent oral squamous cell carcinoma: A systematic review.

BACKGROUND: This systematic review assessed the effectiveness of photodynamic therapy (PDT) in patients with recurrent oral squamous cell carcinoma (OSCC). METHODS: Clinical studies on recurrent OSCC treated with PDT alone were included. Combined treatment strategies were excluded. The search was performed on Medline/Pubmed, Cochrane Library, Embase, Web of Science and ClinicalTrials.gov, manual search, and grey literature. RESULTS: The eleven included studies were observational. The risk of bias and methodological quality were evaluated using the Newcastle-Ottawa Quality Assessment Scale. The studies reported the use of hematoporphyrin derivative, PhotofrinⓇ, FoscanⓇ and 5-aminolevulinic acid. Data on treatment response and survival was collected. Secondarily, postoperative courses and patient's quality of life/acceptance were reported whenever available. PhotofrinⓇ and FoscanⓇ were the most used photosensitisers, with more complete responses. Lesions responding less favourably were on posterior regions or deep-seated in the tissue. CONCLUSIONS: Although treatment response differs between treatment protocols, PDT stands as a viable treatment option to be considered, as it can achieve therapeutic results and disease-free, long-lasting periods. Partial treatment responses may be of interest when achieving eligibility for other treatment strategies. Despite this study's limitations, which considered four photosensitisers, PhotofrinⓇ was the most used but more recent photosensitisers like FoscanⓇ have greater chemical stability, tissue penetration, and may be more efficacious on recurrent OSCC.

Shifting paradigms: A collective and structural strategy for addressing healthcare inequity.

Healthcare inequity is a persistent systemic problem, yet many solutions have historically focused on "debiasing" individuals. Individualistic strategies fit within a competency-based medical education and assessment paradigm, whereby professional values of social accountability, patient safety, and healthcare equity are linked to an individual clinician's competence. Unfortunately, efforts to realise the conceptual linkages between medical education curricula and goals to improve healthcare equity fail to address the institutional values, policies, and practices that enable structural racism. In this article, we explore alternative approaches that target collective and structural causes of health inequity. We first describe the structural basis of healthcare inequity by identifying the ways in which institutional culture, power and privilege erode patient-centred care and contribute to epistemic injustice. We then outline some reasons that stereotypes, which are a culturally supported foundation for discrimination, bias and racism in healthcare, cannot be modified effectively through individualistic strategies or education curricula. Finally, we propose a model that centres shared values for leadership by individuals and institutions with consistency in goal setting, knowledge translation, and talent development. Figure 1 summarises the key recommendations. We have provided cases to supplement this work and facilitate discussion about the model's application to practice.

Medicare Fee-For-Service Spending for Fall Injury and Nonfall Events: The Health, Aging, and Body Composition Study.

Background and Objectives: Fall injuries are prevalent in older adults, yet whether higher spending occurs after nonfracture (NFFI) and fracture is unknown. We examined whether incident fall injuries, including NFFI and fractures, were associated with higher Medicare spending in 12 months after incident events in older adults. Research Design and Methods: The Health, Aging, and Body Composition Study included 1 595 community-dwelling adults (53% women, 37% Black; 76.7 ±â€…2.9 years) with linked Medicare Fee-For-Service (FFS) claims at 2000/01 exam. Incident outpatient and inpatient fall injuries (N = 448) from 2000/01 exam to December 31, 2008 were identified using the first claim with a nonfracture injury diagnosis code with a fall E-code, or a fracture diagnosis code with/without an E-code. Up to 3 participants without fall injuries (N = 1 147) were matched on nonfall events to 448 participants in the fall injury month. We calculated the change in monthly FFS spending in 12 months before versus after index events in both groups. Generalized linear regression with centered outcomes and gamma distributions examined the association of prepost expenditure changes with fall injuries (including NFFI and fractures) adjusting for related covariates. Results: Monthly spending increased after versus before fall injuries (USD$2 261 vs $981), nonfracture (N = 105; USD$2 083 vs $1 277), and fracture (N = 343; USD$2 315 vs $890) injuries (all p < .0001). However, after adjusting for covariates in final models, fall injuries were not significantly associated with larger increases in spending/month versus nonfall events (differential increase: USD$399.58 [95% CI: -USD$44.95 to $844.11]). Fracture prepost change in monthly spending was similar versus NFFI (differential increase: USD$471.93 [95% CI: -USD$21.17 to $965.02]). Discussion and Implications: Although substantial increases occurred after injuries, with fracture and NFFI increasing similarly, changes in monthly spending after fall injury were not different compared to nonfall events. Our results contribute to the understanding of subsequent spending after fall injury that may inform further research on fall injury-related health care spending.

Remote Monitoring App for Endocrine Therapy Adherence Among Patients With Early-Stage Breast Cancer: A Randomized Clinical Trial.

Importance: Adjuvant endocrine therapy (AET) use among women with early-stage, hormone receptor-positive breast cancer reduces the risk of cancer recurrence, but its adverse symptoms contribute to lower adherence. Objective: To test whether remote monitoring of symptoms and treatment adherence with or without tailored text messages improves outcomes among women with breast cancer who are prescribed AET. Design, Setting, and Participants: This nonblinded, randomized clinical trial (RCT) following intention-to-treat principles included English-speaking women with early-stage breast cancer prescribed AET at a large cancer center with 14 clinics across 3 states from November 15, 2018, to June 11, 2021. All participants had a mobile device with a data plan and an email address and were asked to use an electronic pillbox to monitor AET adherence and to complete surveys at enrollment and 1 year. Interventions: Participants were randomized into 3 groups: (1) an app group, in which participants received instructions for and access to the study adherence and symptom monitoring app for 6 months; (2) an app plus feedback group, in which participants received additional weekly text messages about managing symptoms, adherence, and communication; or (3) an enhanced usual care (EUC) group. App-reported missed doses, increases in symptoms, and occurrence of severe symptoms triggered follow-ups from the oncology team. Main Outcomes and Measures: The primary outcome was 1-year, electronic pillbox-captured AET adherence. Secondary outcomes included symptom management abstracted from the medical record, as well as patient-reported health care utilization, symptom burden, quality of life, physician communication, and self-efficacy for managing symptoms. Results: Among 304 female participants randomized (app group, 98; app plus feedback group, 102; EUC group, 104), the mean (SD) age was 58.6 (10.8) years (median, 60 years; range, 31-83 years), and 60 (19.7%) had an educational level of high school diploma or less. The study completion rate was 87.5% (266 participants). There were no statistically significant differences by treatment group in AET adherence (primary outcome): 76.6% for EUC, 73.4% for the app group (difference vs EUC, -3.3%; 95% CI, -11.4% to 4.9%; P = .43), and 70.9% for the app plus feedback group (difference vs EUC, -5.7%; 95% CI, -13.8% to 2.4%; P = .17). At the 1-year follow-up, app plus feedback participants had fewer total health care encounters (adjusted difference, -1.23; 95% CI, -2.03 to -0.43; P = .003), including high-cost encounters (adjusted difference, -0.40; 95% CI, -0.67 to -0.14; P = .003), and office visits (adjusted difference, -0.82; 95% CI, -1.54 to -0.09; P = .03) over the previous 6 months compared with EUC participants. Conclusions and Relevance: This RCT found that a remote monitoring app with alerts to the patient's care team and tailored text messages to patients did not improve AET adherence among women with early-stage breast cancer; however, it reduced overall and high-cost health care encounters and office visits without affecting quality of life. Trial Registration: ClinicalTrials.gov Identifier: NCT03592771.

Antimicrobial Solid Starch-Iodine Complex via Reactive Extrusion and Its Application in PLA-PBAT Blown Films.

In this study, a solid masterbatch of starch-iodine complex with 6.7 wt.% iodine was prepared in pellet form using a ZSK-30 twin-screw extruder. Thermogravimetric (TGA) and isothermal TGA analysis of the pellets revealed that there was no significant loss of iodine due to sublimation during reactive extrusion. These solid pellets demonstrated antifungal properties when applied to strawberries via dip coating in an aqueous solution, extending their shelf life from two days to eight days, thereby reducing fungal growth and visual decay. Furthermore, the solid pellets displayed antibacterial activity against E. coli, as evidenced by the clear zone of inhibition observed in the Kirby-Bauer test. To enhance practical application, these pellets were further blended with PLA-PBAT film formulations at 10 and 18% by wt. to make blown films with effective iodine loadings of 0.7 and 1.3% by wt. These films showed superior antibacterial activity against E. coli compared with PLA control films and the commercial silver antimicrobial-containing films during direct inoculation tests as per ISO 22196. Tensile strength and elongation at break in machine direction (MD) for the starch-iodine-containing blown films were comparable to the control films in MD, but tensile strength was reduced to 37-40% in the transverse direction (TD). This was due to a non-uniform dispersion of the starch-iodine complex in the films, as confirmed by the visual and SEM analyses. Thus, this study illustrates the practical utility of the solid starch-iodine complex as a safe and efficient means of introducing iodine into an environment, mitigating the typical hazards associated with handling solid iodine.

3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance.

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331, exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596, a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598, a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.

Dynamic stereomutation of vinylcyclopropanes with metalloradicals.

The ever increasing demands for greater sustainability and lower energy usage in chemical processes call for fundamentally new approaches and reactivity principles. In this context, the pronounced prevalence of odd-oxidation states in less precious metals bears untapped potential for fundamentally distinct reactivity modes via metalloradical catalysis1-3. Contrary to the well-established reactivity paradigm that organic free radicals, upon addition to a vinylcyclopropane, lead to rapid ring opening under strain release-a transformation that serves widely as a mechanistic probe (radical clock)4 for the intermediacy of radicals5-we herein show that a metal-based radical, that is, a Ni(I) metalloradical, triggers reversible cis/trans isomerization instead of opening. The isomerization proceeds under chiral inversion and, depending on the substitution pattern, occurs at room temperature in less than 5 min, requiring solely the addition of the non-precious catalyst. Our combined computational and experimental mechanistic studies support metalloradical catalysis as origin of this profound reactivity, rationalize the observed stereoinversion and reveal key reactivity features of the process, including its reversibility. These insights enabled the iterative thermodynamic enrichment of enantiopure cis/trans mixtures towards a single diastereomer through multiple Ni(I) catalysis rounds and also extensions to divinylcyclopropanes, which constitute strategic motifs in natural product- and total syntheses6. While the trans-isomer usually requires heating at approximately 200 °C to trigger thermal isomerization under racemization to cis-divinylcyclopropane, which then undergoes facile Cope-type rearrangement, the analogous contra-thermodynamic process is herein shown to proceed under Ni(I) metalloradical catalysis under mild conditions without any loss of stereochemical integrity, enabling a mild and stereochemically pure access to seven-membered rings, fused ring systems and spirocycles.

Adolescent high fat diet alters the transcriptional response of microglia in the prefrontal cortex in response to stressors in both male and female mice.

Both obesity and high fat diets (HFD) have been associated with an increase in inflammatory gene expression within the brain. Microglia play an important role in early cortical development and may be responsive to HFD, particularly during sensitive windows, such as adolescence. We hypothesized that HFD during adolescence would increase proinflammatory gene expression in microglia at baseline and potentiate the microglial stress response. Two stressors were examined, a physiological stressor [lipopolysaccharide (LPS), IP] and a psychological stressor [15 min restraint (RST)]. From 3 to 7 weeks of age, male and female mice were fed standard control diet (SC, 20% energy from fat) or HFD (60% energy from fat). On P49, 1 h before sacrifice, mice were randomly assigned to either stressor exposure or control conditions. Microglia from the frontal cortex were enriched using a Percoll density gradient and isolated via fluorescence-activated cell sorting (FACS), followed by RNA expression analysis of 30 genes (27 target genes, three housekeeping genes) using Fluidigm, a medium throughput qPCR platform. We found that adolescent HFD induced sex-specific transcriptional response in cortical microglia, both at baseline and in response to a stressor. Contrary to our hypothesis, adolescent HFD did not potentiate the transcriptional response to stressors in males, but rather in some cases, resulted in a blunted or absent response to the stressor. This was most apparent in males treated with LPS. However, in females, potentiation of the LPS response was observed for select proinflammatory genes, including Tnfa and Socs3. Further, HFD increased the expression of Itgam, Ikbkb, and Apoe in cortical microglia of both sexes, while adrenergic receptor expression (Adrb1 and Adra2a) was changed in response to stressor exposure with no effect of diet. These data identify classes of genes that are uniquely affected by adolescent exposure to HFD and different stressor modalities in males and females.

Can blood-based markers predict RECIST progression in non-small cell lung cancer treated with immunotherapy?

PURPOSE: In this study, we aimed to evaluate the potential of routine blood markers, serum tumour markers and their combination in predicting RECIST-defined progression in patients with stage IV non-small cell lung cancer (NSCLC) undergoing treatment with immune checkpoint inhibitors. METHODS: We employed time-varying statistical models and machine learning classifiers in a Monte Carlo cross-validation approach to investigate the association between RECIST-defined progression and blood markers, serum tumour markers and their combination, in a retrospective cohort of 164 patients with NSCLC. RESULTS: The performance of the routine blood markers in the prediction of progression free survival was moderate. Serum tumour markers and their combination with routine blood markers generally improved performance compared to routine blood markers alone. Elevated levels of C-reactive protein (CRP) and alkaline phosphatase (ALP) ranked as the top predictive routine blood markers, and CYFRA 21.1 was consistently among the most predictive serum tumour markers. Using these classifiers to predict overall survival yielded moderate to high performance, even when cases of death-defined progression were excluded. Performance varied across the treatment journey. CONCLUSION: Routine blood tests, especially when combined with serum tumour markers, show moderate predictive value  of RECIST-defined progression in NSCLC patients receiving immune checkpoint inhibitors. The relationship between overall survival and RECIST-defined progression may be influenced by confounding factors.

Scrotal Cancer Incidence Rates and Trends-United States, 1999-2020.

OBJECTIVE: To examine population-level scrotal cancer incidence rates and trends among adult men in the United States. METHODS: Data from the United States Cancer Statistics, covering approximately 96% of the United States population, were analyzed to calculate age-standardized incidence rates of scrotal cancer among men aged 18 years and older from 1999 to 2020. Trends in incidence rates were evaluated by age, race and ethnicity, Census region, and histology using joinpoint regression. RESULTS: Overall, 4669 men were diagnosed with scrotal cancer (0.20 per 100,000). Incidence rates were highest among men aged 70 years and older (0.82 per 100,000). Rates were higher among non-Hispanic Asian or Pacific Islander men (0.31 per 100,000) compared to other race and ethnicity groups. The most common histologic subtypes were squamous cell carcinoma (35.9%), extramammary Paget disease (20.8%), and sarcoma (20.5%). Incidence rates decreased by 2.9% per year from 1999 to 2019 for non-Hispanic Asian or Pacific Islander men, decreased by 8.1% per year from 1999 to 2006 for basal cell carcinomas, and increased by 1.8% per year from 1999 to 2019 for extramammary Paget disease; otherwise, rates remained stable for all other variables examined. CONCLUSION: While scrotal cancer incidence rates were higher than previously reported, rates were still low and stable over time.