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BACKGROUND & AIMS: Systematic reviews, meta-analyses and Mendelian randomization studies suggest that cardiometabolic diseases may be associated with COVID-19 risk and prognosis, with evidence implicating insulin resistance (IR) as a common biological mechanism. As driving factors for IR, we examined body mass index (BMI) and waist circumference (WC) among postmenopausal women in association with COVID-19 outcomes (positivity and hospitalization), and the role of glucose homeostasis as a mediator of this relationship. METHODS: Associations of BMI and WC at baseline (1993-1998) with COVID-19 outcomes collected at Survey 1 (June-December, 2020) and/or Survey 2 (September-December, 2021) were evaluated among 42,770 Womens Health Initiative (WHI) participants (baseline age: 59.36 years) of whom 16,526 self-reported having taken ≥1 COVID-19 test, with 1242 reporting ≥1 positive COVID-19 test and 362 reporting ≥1 COVID-19 hospitalization. We applied logistic regression and causal mediation analyses to sub-samples with available fasting biomarkers of glucose homeostasis (glucose, insulin, Homeostatic Model Assessment for Insulin Resistance, Homeostasis Model Assessment for β-cell function, Quantitative Insulin-sensitivity Check Index, Triglyceride-Glucose index (TyG)) at baseline, whereby 57 of 759 reported COVID-19 test positivity and 23 of 1896 reported COVID-19 hospitalization. RESULTS: In fully adjusted models, higher BMI, WC and TyG were associated with COVID-19 test positivity and hospitalization. Glucose concentrations mediated associations of BMI and WC with COVID-19 positivity, whereas TyG mediated BMI and WCs associations with COVID-19 hospitalization. CONCLUSIONS: Obesity and central obesity markers collected an average of 24 years prior were associated with COVID-19 outcomes among postmenopausal women. Glucose concentration and TyG partly mediated these associations.

Background Cardiovascular disease (CVD) remains a leading cause of death for women in the United States, with veterans being at potentially higher risk than their nonveteran counterparts due to accelerated aging and distinct biopsychosocial mechanisms. We examined pathways between selected indicators of socioeconomic status (SES) such as education, occupation, household income, and neighborhood SES and major CVD events through lifestyle and health characteristics among veteran and nonveteran postmenopausal women. Methods and Results A total of 121 286 study‐eligible WHI (Women's Health Initiative) participants (3091 veterans and 118 195 nonveterans) were prospectively followed for an average of 17 years, during which 16 108 major CVD events were documented. Using generalized structural equations modeling coupled with survival analysis techniques, we estimated the effects of SES on major CVD events through smoking, body mass index, comorbidities, cardiometabolic risk factors, and self‐rated health, controlling for WHI component, region, age, race, ethnicity, marital status, and health care provider access. Among veterans, SES characteristics were indirectly related to major CVD events through body mass index, comorbidities, cardiometabolic risk factors, and self‐rated health. Among nonveterans, lower education (β= 0.2, P

KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line-derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.

It all started with the plastic chair, it is often found in Beirut’s urban settings without ever really being questioned. Inside the house, it’s an object you sit on. On the street, it prohibits parking. Like an unspoken and untaught language, everyone knows that if there’s a chair, you can’t park. Thinking about this specific urban phenomenon, it was about seeking instances in which the city creates solutions for itself. This collection of informalities formed a popular visual language worth being thought of, challenging the conventional ways we think of our own city. The plastic chair, the wheel, the concrete block, the fruit basket; those are a few ingredients of a creative recipe made of available, low-cost and repurposed materials, patched by a sense of utility. By considering those social occurrences, we attempt to reconsider our own cultural landscape, and by actually looking, we realize they are reflections of our times, struggles and daily obstacles. As urban artifacts, their whole is greater than the sum of their parts. The Beirut Street Museum is a conceptual museum that resists conventional forms of art and dismantles the exclusivity of museology. It operates on the ground, where every city walk becomes a museum walk. Rooted in concepts of the dérive, situationism and deconstructing museology, the BSM speaks the language of the street. It becomes a growing archive of collective evidence: people's marks on the space that surrounds them.

Abstract Objective This prospective study aimed to delineate the demographics, natural progression, and treatment response of patients newly diagnosed with epilepsy with generalized tonic–clonic seizures alone (EGTCA). Furthermore, our objective includes assessing the seizure recurrence rate post antiseizure medication (ASM) discontinuation within this cohort, alongside exploring predictive factors for seizure relapse. Methods The study cohort, derived from an ongoing, prospective, multicenter investigation on children and adults with new‐onset unprovoked seizures, included consecutive patients enrolled between March 2010 and March 2020, and meeting mandatory ILAE criteria for EGTCA diagnosis. Participants underwent a 3‐h sleep‐deprived video‐EEG recording along with an epilepsy protocol brain magnetic resonance imaging (MRI) with repeat EEG at each follow‐up. Cumulative time‐dependent probabilities of seizure recurrence were calculated using Kaplan–Meier survival analysis. Logistic regression identified variables associated with seizure recurrence following ASM taper. Results Eighty‐nine patients with a median age of 16 years were included, constituting 31% of those diagnosed with an idiopathic generalized epilepsy. Regarding the circadian distribution of seizures, 59.6% of patients exclusively experienced diurnal seizures, 12.4% exclusively nocturnal, and 28.1% experienced both diurnal and nocturnal seizures. Generalized spike–wave discharges (GSWD) were present in the initial EEG of 88% of patients. A GTC recurred in 14% of patients treated with ASM compared with 73% of untreated patients (p

ObjectiveThe WADA test is used to determine cerebral language dominance and assess the risk of postoperative amnesia following mesial temporal lobe resection. This study aims to explore the correlation between automated measures of hippocampal volume and WADA memory scores and to evaluate whether these volumetric measurements can reliably predict WADA memory scores.MethodsThis study included patients who underwent a comprehensive presurgical assessment along with bilateral WADA testing. Hippocampal volumes were measured from high-resolution brain MRIs using automated software (volBrain), which were harmonized and normalized to whole brain volume. These harmonized and normalized volumes were then correlated with ipsilateral WADA memory scores and stratified according to brain MRI findings. A similar analysis was conducted between hippocampal volume asymmetry and WADA memory score asymmetry (WMA). A Receiver Operating Characteristic (ROC) curve was generated to compare the sensitivity and specificity in predicting successful WADA outcomes based on ipsilateral harmonized normalized hippocampal volumes.ResultsIn patients with mesial temporal sclerosis (MTS), significant positive correlations were found between harmonized normalized hippocampal volumes and ipsilateral WADA memory scores, as well as between harmonized hippocampal volume asymmetries and WMA. However, no significant correlations were found in patients with epileptogenic lesions other than MTS or those with normal brain MRIs. A harmonized normalized hippocampal volume threshold of ≥ 28.94 units was identified as a predictor of a WADA memory score exceeding 50% following contralateral carotid artery injection, with a sensitivity of 62.1% and a specificity of 100%.SignificanceThis study indicates that hippocampal volumetry could potentially serve as an alternative to the WADA test in patients with MTS. Conversely, in individuals with normal MRI results or other types of epileptogenic lesions, hippocampal volumetry does not reliably predict memory deficits, necessitating the use of the WADA test or functional MRI for planning resections of mesial temporal structures in the dominant hemisphere.

OBJECTIVES: To evaluate sleep and affective (mood/anxiety) disorders as clinical predictors of incident Parkinsons disease (PD) among women ≥65 years of age. METHODS: We performed secondary analyses with available data from the Womens Health Initiative Clinical Trials and Observational Study linked to Medicare claims. Sleep, mood and anxiety disorders at baseline were defined using diagnostic codes. Incident PD was defined using self-reported PD, first PD diagnosis, use of PD medications, and/or deaths attributed to PD. Cox regression was applied to estimate hazard ratios (HR) with 95 % confidence intervals (CI), controlling for socio-demographic/lifestyle/health characteristics. Time-to-event was calculated from baseline (1993-1998) to year of PD event, loss to follow-up, death, or December 31, 2018, whichever came first. RESULTS: A total of 53,996 study-eligible WHI participants yielded 1756 (3.25 %) PD cases over ~14.39 (±6.18) years of follow-up. The relative risk for PD doubled among women with affective disorders (HR = 2.05, 95 % CI: 1.84, 2.27), mood disorders (HR = 2.18, 95 % CI: 1.97, 2.42) and anxiety disorders (HR = 1.97, 95 % CI: 1.75, 2.22). Sleep disorders alone (without affective) were not significantly associated with PD risk (HR = 0.85, 95 % CI: 0.69, 1.04), whereas affective disorders alone (without sleep) (HR = 1.93, 95 % CI: 1.72, 2.17) or in combination with sleep disorders (HR = 2.18, 95 % CI: 1.85, 2.56) were associated with twice the PD risk relative to no sleep/affective disorders. LIMITATIONS: Observational design; Selection bias; Information bias; Generalizability. CONCLUSIONS: Among older women, joint sleep/affective disorders and affective disorders alone are strong clinical predictors of incident PD over 14 years.

BackgroundAntiseizure medications (ASM) exhibit considerable interindividual variability in terms of efficacy and adverse events. Genetic variation is thought to contribute to these differences in clinical outcomes. Specifically, the response to valproic acid (VPA), a widely used ASM, is influenced by multiple pharmacogenetic factors. However, and in contrast to other ASMs such as phenytoin and carbamazepine, there is a paucity of data on the association between VPA and various gene variants. The aim of this study was hence to evaluate the influence of candidate pharmacogenetic variants on VPA efficacy, toxicity and serum concentrations in a homogeneous cohort of patients newly diagnosed with genetic generalized epilepsies (GGE).MethodsIn this prospective cohort study, demographic, clinical and treatment outcomes of GGE patients were retrieved from their medical records. Whole exome sequencing was performed in collaboration with Epi25. Gene variants associated with VPA efficacy, metabolism and toxicities were retrieved from PharmGKB. An analysis was then conducted to explore potential associations between these gene variants and VPA clinical outcomes.ResultsOf the 166 patients included, 60 (36.1%) experienced treatment failure while 106 (63.9%) achieved treatment success. After adjusting for VPA maintenance dose, carriers of the rs3892097 (CYP2D6) variant were 2.5 times more likely to experience treatment failure compared to wildtype (p = 0.026). The rs1057910 variant (CYP2C9*3) was associated with increased serum VPA concentrations (p = 0.034). Moreover, the rs1137101 variant (LEPR gene, a metabolism regulator) was significantly associated with a higher risk of weight gain (regression coefficient of 3.430 [0.674; 6.186], p = 0.015) and a higher frequency of hair loss (OR = 3.394 [1.157; 9.956], p = 0.026), while the rs4480 variant (SOD2 gene, encoding for a mitochondrial scavenging enzyme) was correlated with a lower frequency of hair loss (OR = 0.276 [0.089; 0.858], p = 0.026).ConclusionThese findings highlight the role of genetic factors in VPA treatment and underscore the potential for developing therapeutic strategies to enhance patient outcomes and minimize adverse effects.

IntroductionThe healthcare system in the United States relies heavily on physician-and house officer-driven initiation of billing and coding for collection of hospital payments and professional fees. Under the umbrella of practice management is the ever-changing and suboptimally taught concept of procedural billing and coding to house officers and faculty. Clinical providers and practitioners initiate billing and coding for performed services based on the procedural visit encounter, supported by the appropriate documentation. Correct charge capture is dependent on accurately linking CPT codes and J codes, including waste documentation, modifiers, and charge collection. We discuss a perspective regarding a new curricular methodology that teaches learners to apply an algorithmic approach for coding CPT codes, J codes, and modifiers for chemical denervation procedures involving high-cost botulinum toxin. We further recommend the use of visuals with algorithm development for other pertinent procedures that are specific to a department.MethodsWe developed a curriculum that includes algorithmic visuals, pre-and post-test questions, and reflections. It was implemented across various learner types.ResultsThis chemical denervation curriculum was well-received and impactful in meeting the objectives of the course. It further expanded a learner’s vision of practice management that can be applied to other procedural examples.DiscussionThe results demonstrate a clear gap in practice management education, with pre-education knowledge on applying appropriate codes being particularly low among resident physicians. Learners found the algorithm we developed especially valuable, as it serves as a practical tool for accurately accounting for all aspects of CPT codes, modifiers, and J-codes. The methodology of the algorithmic approach proved to be innovative for avoiding billing write-offs and loopbacks that were beneficial for the training process. Learners indicated that this approach can be applied to other procedural billing.

ObjectiveTo examine associations of antidepressant, anxiolytic and hypnotic use amongst older women (≥65 years) with incident Parkinson's Disease (PD), using data from Women's Health Initiative linked to Medicare claims.MethodsPD was defined using self-report, first diagnosis, medications and/or death certificates and psychotropic medications were ascertained at baseline and 3-year follow-up. Cox regression models were constructed to calculate adjusted hazard ratios (aHR) with 95% confidence intervals (CI), controlling for socio-demographic, lifestyle and health characteristics, overall and amongst women diagnosed with depression, anxiety and/or sleep disorders (DASD).ResultsA total of 53,996 WHI participants (1,756 PD cases)-including 27,631 women diagnosed with DASD (1,137 PD cases)-were followed up for ~14 years. Use of hypnotics was not significantly associated with PD risk (aHR = 0.98, 95% CI: 0.82, 1.16), whereas PD risk was increased amongst users of antidepressants (aHR = 1.75, 95% CI: 1.56, 1.96) and anxiolytics (aHR = 1.48, 95% CI: 1.25, 1.73). Compared to non-users of psychotropic medications, those who used 1 type had ~50% higher PD risk, whereas those who used ≥2 types had ~150% higher PD risk. Women who experienced transitions in psychotropic medication use ('use to non-use' or 'non-use to use') between baseline and 3-year follow-up had higher PD risk than those who did not. We obtained similar results with propensity scoring and amongst DASD-diagnosed women.InterpretationThe use of antidepressants, anxiolytics or multiple psychotropic medication types and transitions in psychotropic medication use was associated with increased PD risk, whereas the use of hypnotics was not associated with PD risk amongst older women.