Gender differences in illicit drug access, use and use disorder: Analysis of National Survey on Drug Use and Health data.

Although gender differences in the prevalence of substance use disorders (SUD) have been well-characterized, little is known about when gender differences emerge along the continuum of substance use. Understanding the contribution of gender to risk at key transition points across this continuum is needed to identify potential mechanisms underlying gender differences and to inform improved gender-responsive interventions. To characterize gender differences in the progression of cannabis, cocaine, and heroin use, the current study used data from the United States-based 2015-2019 National Survey on Drug Use and Health to quantify gender differences in: (1) perceived access to drugs, (2) lifetime drug use among individuals with at least some access, and (3) past-year SUD among those who had ever used each drug. Logistic regressions were conducted for each drug to examine gender differences across all three stages, controlling for sociodemographic factors and survey year. Compared to women, men had higher odds of reporting access to and lifetime use of all three drug types. Men also had higher odds of past-year cannabis and cocaine use disorders compared to women. Results suggest gender differences emerge in the earliest stage of drug use (access) and may accumulate across the stages of use. The magnitude of gender differences varied across stages, with the largest differences observed for odds of drug initiation among those with perceived access to each drug. Longitudinal data will be needed to confirm these findings and to provide insight into potential contributors to gender-specific risk and intervention targets across the continuum of drug use severity.

Irregular Cycles, Ovulatory Disorders, and Cardiometabolic Conditions in a US-Based Digital Cohort.

Importance: Polycystic ovary syndrome (PCOS), characterized by irregular menstrual cycles and hyperandrogenism, is a common ovulatory disorder. Having an irregular cycle is a potential marker for cardiometabolic conditions, but data are limited on whether the associations differ by PCOS status or potential interventions. Objective: To evaluate the association of PCOS, time to regularity since menarche (adolescence), and irregular cycles (adulthood) with cardiometabolic conditions. Design, Setting, and Participants: This cross-sectional study used a large, US-based digital cohort of users of the Apple Research application on their iPhone. Eligibility criteria were having ever menstruated, living in the US, being at age of consent of at least 18 years (or 19 years in Alabama and Nebraska or 21 years in Puerto Rico), and being able to communicate in English. Participants were enrolled between November 14, 2019, and December 13, 2022, and completed relevant surveys. Exposures: Self-reported PCOS diagnosis, prolonged time to regularity (not spontaneously establishing regularity within 5 years of menarche), and irregular cycles. Main Outcomes and Measures: The primary outcome was self-reported cardiometabolic conditions, including obesity, prediabetes, type 1 and 2 diabetes, high cholesterol, hypertension, metabolic syndrome, arrhythmia, congestive heart failure, coronary artery disease, heart attack, heart valve disease, stroke, transient ischemic attack (TIA), deep vein thrombosis, and pulmonary embolism measured using descriptive statistics and logistic regression to estimate prevalence odds ratios (PORs) and 95% CIs. Effect modification by lifestyle factors was also estimated. Results: The study sample (N = 60 789) had a mean (SD) age of 34.5 (11.1) years, with 12.3% having PCOS and 26.3% having prolonged time to regularity. Among a subset of 25 399 participants who completed the hormonal symptoms survey, 25.6% reported irregular cycles. In covariate-adjusted logistic regression models, PCOS was associated with a higher prevalence of all metabolic and several cardiovascular conditions, eg, arrhythmia (POR, 1.37; 95% CI, 1.20-1.55), coronary artery disease (POR, 2.92; 95% CI, 1.95-4.29), heart attack (POR, 1.79; 95% CI, 1.23-2.54), and stroke (POR, 1.66; 95% CI, 1.21-2.24). Among participants without PCOS, prolonged time to regularity was associated with type 2 diabetes (POR, 1.24; 95% CI, 1.05-1.46), hypertension (POR, 1.09; 95% CI, 1.01-1.19), arrhythmia (POR, 1.20; 95% CI, 1.06-1.35), and TIA (POR, 1.33; 95% CI, 1.01-1.73), and having irregular cycles was associated with type 2 diabetes (POR, 1.36; 95% CI, 1.08-1.69), high cholesterol (POR, 1.17; 95% CI, 1.05-1.30), arrhythmia (POR, 1.21; 95% CI, 1.02-1.43), and TIA (POR, 1.56; 95% CI, 1.06-2.26). Some of these associations were modified by high vs low body mass index or low vs high physical activity. Conclusions and Relevance: These findings suggest that PCOS and irregular cycles may be independent markers for cardiometabolic conditions. Early screening and intervention among individuals with irregular menstrual cycles may be beneficial.

IL-13 protects from C. difficile Colitis.

OBJECTIVES: Clostridioides difficile infection (CDI) is the leading hospital-acquired infection in North America. We have previously discovered that antibiotic disruption of the gut microbiota decreases intestinal IL-33 and IL-25 and increases susceptibility to CDI. We further found that IL-33 promotes protection through type 2 Innate Lymphoid Cells (ILC2s), which produce IL-13. However, the contribution of IL-13 to disease has never been explored. METHODS: We used a validated model of CDI in mice, in which we neutralized via blocking antibodies, or administered recombinant protein, IL-13 to assess the role of this cytokine during infection using weight and clinical scores. Fluorescent activated cell sorting (FACS) was used to characterize myeloid cell population changes in response to IL-13 manipulation. RESULTS: We found that administration of IL-13 protected, and anti-IL-13 exacerbated CDI. Additionally, we observe alterations to the monocyte/macrophage cells following neutralization of IL-13 as early as day three post infection. We also observed elevated accumulation of myeloid cells by day four post-infection following IL-13 neutralization. Neutralization of the decoy receptor, IL-13Rα2, resulted in protection from disease, likely through increased available endogenous IL-13. CONCLUSIONS: Our data highlight the protective role of IL-13 in protecting from more severe CDI and the association of poor responses with a dysregulated monocyte-macrophage compartment. These results increase our understanding of type 2 immunity in CDI and may have implications for treating disease in patients.

Measurement invariance of the Revised-Green Paranoid Thought Scale across Black and White Americans.

Given the culturally diverse landscape of mental healthcare and research, ensuring that our psychological constructs are measured equivalently across diverse populations is critical. One construct for which there is significant potential for inequitable assessment is paranoia, a prominent feature in psychotic disorders that can also be driven by culture and racial marginalization. This study examined measurement invariance-an analytic technique to rigorously investigate whether a given construct is being measured similarly across groups-of the Revised-Green Paranoid Thought Scale (R-GPTS; Freeman et al., 2021) across Black and White Americans in the general population. Racial group differences in self-reported paranoia were also examined. The analytic sample consisted of 480 non-Hispanic White and 459 non-Hispanic Black Americans. Analyses demonstrated full invariance (i.e., configural, metric, and scalar invariance) of the R-GPTS across groups, indicating that the R-GPTS appropriately captures self-reported paranoia between Black and White Americans. Accordingly, it is reasonable to compare group endorsement: Black participants endorsed significantly higher scores on both the ideas of reference and ideas of persecution subscales of the R-GPTS (Mean ± SD = 10.91 ± 7.12 versus 8.21 ± 7.17 and Mean ± SD = 10.18 ± 10.03 versus 6.35 ± 8.35, for these subscales respectively). Generalized linear modeling revealed that race remained a large and statistically significant predictor of R-GPTS total score (ß = -0.38756, p < 0.001) after controlling for relevant demographic factors (e.g., sex, age). This study addresses a critical gap within the existing literature as it establishes that elevations in paranoia exhibited by Black Americans in the R-GPTS reflect actual differences between groups rather than measurement artifacts.

MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.

Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo.

Novel RAB39B loss-of-function mutation in patient with typical early-onset Parkinson's disease.

RAB39B mutations have been identified in X-linked developmental delays. Recently, RAB39B mutations were identified in males with early-onset parkinsonism and intellectual disability. A novel loss-of-function RAB39B mutation was found in a female patient with typical early-onset Parkinson's disease (EOPD). RAB39B mutations may cause EOPD, potentially due to a-synuclein homeostasis disruption.

Relationship between FEV1/FVC and age in children with asthma.

INTRODUCTION: Forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) normally decreases through childhood, increases briefly during early adolescence, and then declines throughout life. The physiology behind this temporary increase during early adolescence is not well understood. The objective of this study was to determine if this pattern occurs in children with asthma. DESIGN: Single-center, cross-sectional, retrospective analysis of pulmonary function tests obtained over a 5-year period in children 5-18 years of age with persistent asthma. RESULTS: A total of 1793 patients satisfied all inclusion and exclusion criteria. The mean age (±SD) was 10.4 ± 3.8 years. Forty-eight percent were female. Mean FEV1/FVC was 0.83 ± 0.09. FEV1/FVC was lower at 5 years of age than in healthy children, declined from age 5 to 11 by 5.7% compared to 7.3% in healthy girls, and 5.8% compared to 9.4% in healthy boys. FEV1/FVC increased in early adolescence, but at age 16, was 5.6% lower in male children compared to healthy children, and 5.4% lower in females. The ratio was lower in obese children at all ages but demonstrated the same curvilinear shape as healthy children. In absolute terms, FEV1 grew proportionately more than FVC during early adolescence, so the ratio of FEV1/FVC increased during that period. The curvilinear shape of the curve remained in postbronchodilator testing, though significantly blunted. CONCLUSIONS: FEV1/FVC is lower in children with persistent asthma than healthy children, but the "Shepherd's Hook" pattern is preserved. This was true in obese patients with asthma, although their FEV1/FVC ratios were lower throughout all stages of childhood and adolescence.

Protocol for harmonization of randomized trials testing the addition of behavioral therapy to buprenorphine for opioid use disorder.

Background: Although buprenorphine is an effective treatment for opioid use disorder (OUD), much remains to be understood about treatment non-response and methods for improving treatment retention. The addition of behavioral therapies to buprenorphine has not yielded consistent benefits for opioid outcomes, on average. However, several studies suggest that certain subgroups may benefit from the combination of buprenorphine and behavioral therapy, highlighting the potential for personalized approaches to treatment. Furthermore, little is known about whether behavioral therapies improve buprenorphine retention or non-opioid (e.g., functional) outcomes. Methods: The objective of this project is to harmonize four previously conducted clinical trials testing the addition of behavioral therapy to buprenorphine maintenance for OUD and to use this larger dataset to answer critical clinical questions about the role of behavioral therapy in this population. Study aims include identifying potential moderators of the effect of the addition of behavioral therapy and quantifying the effect of behavioral therapy on buprenorphine retention and functional outcomes. Results: Analyses will consider outcomes of weeks of opioid use, weeks of retention in buprenorphine treatment, and functional outcomes as measured by the Addiction Severity Index. Analyses will include an indicator for each study to account for heterogeneity of samples and design. Conclusion: Results will help to inform clinical and research efforts to optimize the use of behavioral therapies in the treatment of OUD.

Association of Demographic Characteristics and Laboratory Values in Diabetic Foot Infections Leading to Lower-Extremity Amputation.

BACKGROUND: Lower-extremity amputations are a common complication of poorly controlled diabetes and contribute to significant morbidity and mortality in diabetic patients. We sought to determine whether objective data points obtained on presentation or hospital admission, including white blood cell (WBC) count, hemoglobin A1c (HbA1c), C-reactive protein (CRP), and descriptive patient demographics allow for the ability to predict optimal amputation levels and outcomes of lower-extremity amputation in the diabetic population. METHODS: A retrospective analysis of 162 patients was performed evaluating laboratory and descriptive values on hospital presentation for lower-extremity infection during a 16-year period. Occurrence of multiple amputations and level of amputation were assessed against laboratory values to determine whether these objective values would provide clinicians with a better understanding of amputations in the diabetic patient. RESULTS: The mean patient age was 60.6 years. A significantly higher percentage of patients who underwent amputations through the tibia and fibula or of the foot midtarsal were male compared with patients who underwent amputations of the thigh through femur. Patients who had amputations through the tibia and fibula had a significantly higher WBC count compared with patients who had a transmetatarsal amputation (P = .03). There was no significant difference in type or quantity of amputations when analyzing HbA1c and CRP levels. CONCLUSIONS: An admission WBC count may be used as a predictor of lower-extremity amputation level and outcomes in diabetic infections. Although a statistically significant difference was not found for CRP or HbA1c levels between amputation procedures and number of procedures performed, these values remain useful in managing lower-extremity infections in diabetic patients.

Description of the first species of gall wasp (Hym., Cynipidae: Cynipini) on Quercus grahamii (Fagaceae).

A new species of oak gall wasp, Andricus coombesi Pujade-Villar & Prez-Torres n. sp. from Mexico, known only from its asexual generation that induces galls on acorns of Quercus grahamii Benth., (section Lobatae) is described. Its presence causes the complete disappearance of the acorn. Diagnosis, distribution and biological data of the new species are given. Andricus coombesi Pujade-Villar & Prez-Torres n. sp. represents the first gall wasp species mentioned from this host.

An association between Dnmt1 and Wnt in the production of oocytes in the whitefly Bemisia tabaci.

The function of DNA methylation in insects and the DNA methyltransferase (Dnmt) genes that influence methylation remains uncertain. We used RNA interference to reduce the gene expression of Dnmt1 within the whitefly Bemisia tabaci (Hemiptera:Aleyrodidae; Gennadius), a hemipteran species that relies on Dnmt1 for proper gametogenesis. We then used RNA-seq to test an a priori hypothesis that meiosis-related genetic pathways would be perturbed. We generally did not find an overall effect on meiosis-related pathways. However, we found that genes in the Wnt pathway, genes associated with the entry into meiosis in vertebrates, were differentially expressed. Our results are consistent with Dnmt1 knockdown influencing specific pathways and not causing general transcriptional response. This is a finding that is also seen with other insect species. We also characterised the methylome of B. tabaci and assessed the influence of Dnmt1 knockdown on cytosine methylation. This species has methylome characteristics comparable to other hemipterans regarding overall level, enrichment within gene bodies, and a bimodal distribution of methylated/non-methylated genes. Very little differential methylation was observed, and difference in methylation were not associated with differences in gene expression. The effect on Wnt presents an interesting new candidate pathway for future studies.

Pregnancy History at 40 Years of Age as a Marker of Cardiovascular Risk.

BACKGROUND: Individual pregnancy complications are associated with increased maternal risk of cardiovascular disease. We assessed the link between a woman's total pregnancy history at 40 years of age and her relative risk of dying from atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: This population-based prospective study combined several Norwegian registries covering the period 1967 to 2020. We identified 854 442 women born after 1944 or registered with a pregnancy in 1967 or later, and surviving to 40 years of age. The main outcome was the time to ASCVD mortality through age 69 years. The exposure was a woman's number of recorded pregnancies (0, 1, 2, 3, or 4) and the number of those with complications (preterm delivery <35 gestational weeks, preeclampsia, placental abruption, perinatal death, and term or near-term birth weight <2700 g). Cox models provided estimates of hazard ratios across exposure categories. The group with the lowest ASCVD mortality was that with 3 pregnancies and no complications, which served as the reference group. Among women reaching 40 years of age, risk of ASCVD mortality through 69 years of age increased with the number of complicated pregnancies in a strong dose-response fashion, reaching 23-fold increased risk (95% CI, 10-51) for women with 4 complicated pregnancies. Based on pregnancy history alone, 19% of women at 40 years of age (including nulliparous women) had an increased ASCVD mortality risk in the range of 2.5- to 5-fold. CONCLUSIONS: Pregnancy history at 40 years of age is strongly associated with ASCVD mortality. Further research should explore how much pregnancy history at 40 years of age adds to established cardiovascular disease risk factors in predicting cardiovascular disease mortality.

Optic Neuropathy and Myelopathy in a Teenager With Biotinidase Deficiency.

ABSTRACT: A 19-year-old man presented with 3 years of gradually progressive, painless vision loss in both eyes. The ophthalmic examination showed bilateral diminished visual acuity, dyschromatopsia, and temporal optic nerve pallor. The neurological examination was consistent with a mild myelopathy with decreased pin-prick sensation starting at T6-T7 and descending through the lower extremities. Hyperreflexia was also present in the lower more than upper extremities. Infectious, inflammatory, and nutritional serum workup and cerebrospinal fluid analysis were both unrevealing. MRI of the brain and spinal cord showed abnormal T2 hyperintensity of the fornix, corpus callosum, optic nerves, and lateral columns of the cervical and thoracic spine, with diffusion restriction in the inferior-posterior corpus callosum and fornix. Biotinidase serum enzyme activity was tested and showed a decreased level of activity. Biotinidase gene testing showed a homozygous pathogenic variant, c.424C>A (p.P142T), confirming the diagnosis of biotinidase deficiency and prompting oral biotin supplementation. Three months after starting treatment, the patient's visual acuity, color vision, visual fields, and MRI spine abnormalities all improved significantly. Biotinidase deficiency is an important diagnostic consideration in patients with unexplained optic neuropathy and/or myelopathy.

Genome sequencing and molecular networking analysis of the wild fungus Anthostomella pinea reveal its ability to produce a diverse range of secondary metabolites.

BACKGROUND: Filamentous fungi are prolific producers of bioactive molecules and enzymes with important applications in industry. Yet, the vast majority of fungal species remain undiscovered or uncharacterized. Here we focus our attention to a wild fungal isolate that we identified as Anthostomella pinea. The fungus belongs to a complex polyphyletic genus in the family of Xylariaceae, which is known to comprise endophytic and pathogenic fungi that produce a plethora of interesting secondary metabolites. Despite that, Anthostomella is largely understudied and only two species have been fully sequenced and characterized at a genomic level. RESULTS: In this work, we used long-read sequencing to obtain the complete 53.7 Mb genome sequence including the full mitochondrial DNA. We performed extensive structural and functional annotation of coding sequences, including genes encoding enzymes with potential applications in biotechnology. Among others, we found that the genome of A. pinea encodes 91 biosynthetic gene clusters, more than 600 CAZymes, and 164 P450s. Furthermore, untargeted metabolomics and molecular networking analysis of the cultivation extracts revealed a rich secondary metabolism, and in particular an abundance of sesquiterpenoids and sesquiterpene lactones. We also identified the polyketide antibiotic xanthoepocin, to which we attribute the anti-Gram-positive effect of the extracts that we observed in antibacterial plate assays. CONCLUSIONS: Taken together, our results provide a first glimpse into the potential of Anthstomella pinea to provide new bioactive molecules and biocatalysts and will facilitate future research into these valuable metabolites.

Sexual selection: When crickets go quiet.

Mutations that change male cricket song should be at a disadvantage because the song is used by females to choose amongst males. A new study caught evolution in action and showed that females may have flexible preferences, and new songs may even be preferred so that the mutations spread.

Recommended Resting-State fMRI Acquisition and Preprocessing Steps for Preoperative Mapping of Language and Motor and Visual Areas in Adult and Pediatric Patients with Brain Tumors and Epilepsy.

Resting-state (rs) fMRI has been shown to be useful for preoperative mapping of functional areas in patients with brain tumors and epilepsy. However, its lack of standardization limits its widespread use and hinders multicenter collaboration. The American Society of Functional Neuroradiology, American Society of Pediatric Neuroradiology, and the American Society of Neuroradiology Functional and Diffusion MR Imaging Study Group recommend specific rs-fMRI acquisition approaches and preprocessing steps that will further support rs-fMRI for future clinical use. A task force with expertise in fMRI from multiple institutions provided recommendations on the rs-fMRI steps needed for mapping of language, motor, and visual areas in adult and pediatric patients with brain tumor and epilepsy. These were based on an extensive literature review and expert consensus.Following rs-fMRI acquisition parameters are recommended: minimum 6-minute acquisition time; scan with eyes open with fixation; obtain rs-fMRI before both task-based fMRI and contrast administration; temporal resolution of ≤2 seconds; scanner field strength of 3T or higher. The following rs-fMRI preprocessing steps and parameters are recommended: motion correction (seed-based correlation analysis [SBC], independent component analysis [ICA]); despiking (SBC); volume censoring (SBC, ICA); nuisance regression of CSF and white matter signals (SBC); head motion regression (SBC, ICA); bandpass filtering (SBC, ICA); and spatial smoothing with a kernel size that is twice the effective voxel size (SBC, ICA).The consensus recommendations put forth for rs-fMRI acquisition and preprocessing steps will aid in standardization of practice and guide rs-fMRI program development across institutions. Standardized rs-fMRI protocols and processing pipelines are essential for multicenter trials and to implement rs-fMRI as part of standard clinical practice.

Offspring overcome poor parenting by being better parents.

The evolutionary repercussions of parental effects-the impact of the developmental environment provided by parents on offspring-are often discussed as static effects that can have negative influences on offspring fitness that may even persist across generations. However, individuals are not passive recipients and may mitigate the persistence of parental effects through their behaviour. Here, we tested how the burying beetle, Nicrophorus orbicollis, a species with complex parental care, responded to poor parenting. We cross-fostered young and manipulated the duration of parental care received and measured the impact on traits of both F1 and F2 offspring to experimentally extricate the effect of poor parenting from other parental effects. As expected, reducing parental care negatively affected traits that are ecologically important for burying beetles, including F1 offspring development time and body size. However, F1 parents that received reduced care as larvae spent more time feeding F2 offspring than parents that received full care as larvae. As a result, both the number and mass of F2 offspring were unaffected by the developmental experience of their parents. Our results show that flexible parental care may be able to overcome poor developmental environments and limit negative parental effects to a single generation.