Neighborhood deprivation in relation to ovarian reserve and outcomes of ovarian stimulation among oocyte donors.

OBJECTIVE: To study the relationship between neighborhood deprivation index (NDI) and markers of ovarian reserve and outcomes of controlled ovarian stimulation among young, healthy oocyte donors. DESIGN: Retrospective cohort study. PATIENTS: A total of 547 oocyte donors who underwent 905 oocyte retrieval cycles (2008-2020) at a private fertility center in Sandy Springs, Georgia, United States. INTERVENTIONS: Neighborhood deprivation index was calculated using principal component analysis applied to census-level measures of poverty, employment, household composition, and public assistance, which was then standardized and linked to donor information on the basis of donor residence. MAIN OUTCOME MEASURES: Markers of ovarian reserve, including antral follicle count (AFC) and antimüllerian hormone (AMH) levels, and outcomes of controlled ovarian stimulation including number of total and mature oocytes retrieved and ovarian sensitivity index (OSI) (defined as the number of oocytes retrieved/total gonadotropin dose × 1,000). Multivariable generalized estimating equations with Poisson and normal distribution were used to model the relationship between NDI and outcome measures adjusting for age, body mass index, and year of retrieval. RESULTS: The mean (SD) age of donors was 25.0 (2.8) years and 29% of the donors were racial or ethnic minorities. There were no associations between donor NDI and ovarian reserve markers. For every interquartile range increase in NDI, there was a reduction of -1.5% (95% confidence interval: -5.3% to 2.4%) in total oocytes retrieved although the effect estimate was imprecise. Associations of NDI with a number of mature oocytes retrieved and OSI were in a similar direction. We observed evidence for effect modification of the NDI and OSI association by donor race. There was a suggestive positive association between NDI and OSI in Black donors but no association in White donors. CONCLUSION: In this cohort of young, healthy, racially diverse oocyte donors, we found little evidence of associations between NDI and markers of ovarian reserve or outcomes of ovarian stimulation.

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

Impact of cash transfers on the association between prenatal exposures to high temperatures and low birthweight: Retrospective analysis from the LEAP 1000 study.

OBJECTIVE: To explore the associations between prenatal temperature exposures and low birthweight (LBW) and modification by cash transfer (CT) receipt. DESIGN: Retrospective cohort study. SETTING: Five rural districts in Northern Ghana. POPULATION OR SAMPLE: A total of 3016 infants born to women interviewed as part of the Livelihood Empowerment Against Poverty (LEAP 1000) impact evaluation between 2015 and 2017. METHODS: Birthweight was collected using household surveys administered to LEAP 1000 eligible women. We used a UNICEF-developed multiple imputation approach to address missingness of birthweight and applied an empirical heaping correction to the multiply imputed birthweight data. Survey data were linked to the European Centre for Medium-Range Weather Forecasts Reanalysis 5-hourly temperature averaged to weeks for 2011-2017 using community centroids. Using distributed-lag nonlinear models, we explored the lag-specific associations between weekly average temperatures greater than 30°C and LBW, and stratified by LEAP 1000 treatment. MAIN OUTCOME MEASURES: Low birthweight (<2.5 kg). RESULTS: Twelve percent (n = 365) of infants were LBW; the mean ± SD birthweight was 3.02 ± 0.37 kg. Overall, increasing temperatures were associated with increased odds of LBW, with the greatest odds observed in the 3 weeks before birth (odds ratio 1.005-1.025). These positive associations were even larger among comparison infants and null among treatment infants. CONCLUSIONS: Our study found increased odds of LBW with high weekly average temperatures throughout pregnancy and the preconception period and demonstrate mitigated effects by the LEAP 1000 CT program. More evidence on the potential of CTs to serve as adaptation interventions in low- and middle-income countries is needed to protect pregnant persons and their infants from the impacts of climate change.

Ambient traffic related air pollution in relation to ovarian reserve and oocyte quality in young, healthy oocyte donors.

Studies in mice and older, subfertile women have found that air pollution exposure may compromise female reproduction. Our objective was to evaluate the effects of air pollution on ovarian reserve and outcomes of ovarian stimulation among young, healthy females. We included 472 oocyte donors who underwent 781 ovarian stimulation cycles at a fertility clinic in Atlanta, Georgia, USA (2008-2019). Antral follicle count (AFC) was assessed with transvaginal ultrasonography and total and mature oocyte count was assessed following oocyte retrieval. Ovarian sensitivity index (OSI) was calculated as the total number of oocytes divided by total gonadotrophin dose × 1000. Daily ambient exposure to nitric oxide (NOx), carbon monoxide (CO), and particulate matter ≤ 2.5 (PM2.5) was estimated using a fused regional + line-source model for near-surface releases at a 250 m resolution based on residential address. Generalized estimating equations were used to evaluate the associations of an interquartile range (IQR) increase in pollutant exposure with outcomes adjusted for donor characteristics, census-level poverty, and meteorological factors. The median (IQR) age among oocyte donors was 25.0 (5.0) years, and 31% of the donors were racial/ethnic minorities. The median (IQR) exposure to NOx, CO, and PM2.5 in the 3 months prior to stimulation was 37.7 (32.0) ppb, 612 (317) ppb, and 9.8 (2.9) µg/m3, respectively. Ambient air pollution exposure in the 3 months before AFC was not associated with AFC. An IQR increase in PM2.5 in the 3 months before AFC and during stimulation was associated with -7.5% (95% CI -14.1, -0.4) and -6.4% (95% CI -11.0, -1.6) fewer mature oocytes, and a -1.9 (95% CI -3.2, -0.5) and -1.0 (95% CI -1.8, -0.2) lower OSI, respectively. Our results suggest that lowering the current 24-h PM2.5 standard in the US to 25 µg/m3 may still not adequately protect against the reprotoxic effects of short-term PM2.5 exposure.

Weight loss and lifestyle change among high-risk individuals enrolled in a digital diabetes prevention program: A longitudinal study of private and public health insurance members in Western New York.

Weight loss is critical to reduce diabetes risk. Diabetes Prevention Programs (DPPs) are effective for weight loss, although less is known about digital DPPs. This study explores the association between Brook+, a 52-week digital DPP, and weight loss. This longitudinal observational study uses a sample of 5,516 private, Medicare, and Medicaid health insurance members from Western New York enrolled into Brook+ between December 2020 and December 2022. We used multivariable generalized linear regression models to estimate the association between completion of the Brook+ program, overall and stratified by health insurance type, and 5% weight loss using odds ratios (OR) and 95% confidence intervals (CI), adjusted for age and gender. We also estimated average weight loss from baseline associated with high engagement with the program using adjusted linear regression models. In the pooled sample, those who completed the Brook + program had 21% increased odds of 5% weight loss (OR = 1.21 95% CI: (1.02 - 1.44)). Among users enrolled in private, Medicare, and Medicaid health insurance, program completion was associated with 21%, 33%, and 13% increased odds of 5% weight loss, compared to those who did not complete Brook+. Interacting with health coaches, increased physical activity, and meal logging were all significant predictors of weight loss. Our results suggest that digital DPPs are promising for large-scale diabetes prevention via weight loss and lifestyle change.

Diet and recreational drug use in relation to male reproductive health.

Diet and lifestyle interventions present promising avenues for the improvement of male fertility. Our objective was to review and synthesize the existing observational and experimental studies among humans on the associations of diet and recreational drug use with semen quality and fertility outcomes. The available data on this topic are limited and, at times, conflicting. Nevertheless, on the basis of this review, dietary patterns that are composed of higher intakes of fruits, vegetables, whole grains, nuts, low-fat dairy, and seafood, as well as lower intakes of red and processed meats, sweets, and sugar-sweetened beverages were identified as having the strongest evidence for associations with better sperm quality. However, whether these dietary patterns translate into positive associations with clinical fertility endpoints such as assisted reproductive technology success rates or time-to-pregnancy among couples trying to conceive without medical assistance remains unclear. Male caffeine and alcohol intake, within low-to-moderate ranges of intake, do not appear to be detrimental to semen quality. Yet high-quality research on this topic, focused on clinical fertility endpoints, should continue given the conflicting evidence, particularly in populations undergoing infertility treatment with assisted reproductive technology. Recreational drug use, including marijuana, electronic cigarettes, and other illicit drugs, does not appear to be beneficial for male reproductive health and should be avoided or ceased. In conclusion, men should be encouraged to consume a healthy diet rich in fruits, vegetables, whole grains, nuts, low-fat dairy, and seafood, as well as lacking in red and processed meats, sweets, and sugar-sweetened beverages, and to avoid recreational drug use for improved male reproductive health.

Molecular testing for adolescent and young adult central nervous system tumors: A Canadian guideline.

The 2021 World Health Organization (WHO) classification of CNS tumors incorporates molecular signatures with histology and has highlighted differences across pediatric vs adult-type CNS tumors. However, adolescent and young adults (AYA; aged 15-39), can suffer from tumors across this spectrum and is a recognized orphan population that requires multidisciplinary, specialized care, and often through a transition phase. To advocate for a uniform testing strategy in AYAs, pediatric and adult specialists from neuro-oncology, radiation oncology, neuropathology, and neurosurgery helped develop this review and testing framework through the Canadian AYA Neuro-Oncology Consortium. We propose a comprehensive approach to molecular testing in this unique population, based on the recent tumor classification and within the clinical framework of the provincial health care systems in Canada. Contributions to the field: While there are guidelines for testing in adult and pediatric CNS tumor populations, there is no consensus testing for AYA patients whose care occur in both pediatric and adult hospitals. Our review of the literature and guideline adopts a resource-effective and clinically-oriented approach to improve diagnosis and prognostication of brain tumors in the AYA population, as part of a nation-wide initiative to improve care for AYA patients.

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults.

BACKGROUND: "Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. METHODS: Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis. RESULTS: Median patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus (n = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the H3F3A gene and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric DMGs. Accompanying mutations in TP53, PPM1D, FGFR1, NF1, and ATRX were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults. CONCLUSIONS: Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.

Central neurogenic hyperventilation in conscious patients due to CNS neoplasm: a case report and review of the literature on treatment.

BACKGROUND: Central neurogenic hyperventilation (CNH) is increasingly reported in conscious patients with a CNS neoplasm. We aimed to synthesize the available data on the treatment of this condition to guide clinicians in their approach. METHODS: We describe the case of a 39-year-old conscious woman with CNH secondary to glioma brainstem infiltration for whom hyperventilation was aborted with hydromorphone, dexamethasone, and brainstem radiotherapy. We then performed a review of the literature on the treatment of CNH in conscious patients due to a CNS neoplasm. RESULTS: A total of 31 studies reporting 33 cases fulfilled the selection criteria. The underlying neoplasm was lymphoma in 15 (45%) and glioma in 13 (39%) patients. Overall, CNH was aborted in 70% of cases. Opioids and sedatives overall seemed useful for symptom relief, but the benefit was often of short duration when the medication was administered orally or subcutaneously. Methadone and fentanyl were successful but rarely used. Chemotherapy was most effective in patients with lymphoma (89%), but not glioma (0%) or other neoplasms (0%). Patients with lymphoma (80%) and other tumors (100%) responded to radiotherapy more frequently than patients with glioma (43%). Corticosteroids were moderately effective. Subtotal surgical resection was successful in the 3 cases for which it was attempted. CONCLUSION: Definitive treatment of the underlying neoplasm may be more successful in aborting hyperventilation. Variable rates of palliation have been observed with opioids and sedatives. Treatment of CNH is challenging but successful in a majority of cases.

Searching for autoimmune encephalitis: Beware of normal CSF.

OBJECTIVE: To determine the prevalence of cerebrospinal fluid (CSF) markers associated with inflammation (i.e., elevated white blood cell count, protein concentration, and CSF-specific oligoclonal bands) in patients with early active autoimmune encephalitis (AE). METHODS: CSF characteristics, including WBC count, protein concentration, and oligoclonal banding, were analyzed in patients diagnosed with AE at two tertiary care centers. RESULTS: Ninety-five patients were included in the study. CSF white blood cell counts and protein levels were within normal limits for 27% (CI95%: 19-37) of patients with AE. When results of oligoclonal banding were added, 14% (CI95%: 6-16) of patients with AE had "normal" CSF. The median CSF white blood cell count was 8 cells/mm3 (range: 0-544) and the median CSF protein concentration was 0.42 g/L (range: 0.15-3.92). CONCLUSIONS: White blood cell counts and protein levels were within normal limits in the CSF of a substantial proportion of patients with early active AE. Inclusion of CSF oligoclonal banding identified a higher proportion of patients with an inflammatory CSF profile, especially when CSF was sampled early in the disease process.

A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study.

The PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was administered at a starting dose of 100 mg bid 2 days on/5 days off weekly with TMZ 150 mg/m2 daily for 5 days/28-days cycle. Dose escalation was according to a 3 + 3 design. Secondary objectives included assessment of vistusertib safety and toxicity profile, and preliminary efficacy. 15 patients were enrolled in the study (median age 66 (range 51-77), females 8). Vistusertib 125 mg BID in combination with TMZ 150 mg/m2 daily for 5 days was well tolerated. Vistusertib treatment-related adverse events were generally grade 1-2, with the most frequently reported being fatigue, gastrointestinal symptoms, and rash. Of 13 response evaluable patients, 1 patient (8%) had a partial response ongoing at 7.6 months of follow-up, and 5 patients had stable disease (38%) as best response (median duration 9.6 months, range 3.7-not yet reached). Six-month progression-free survival (PFS) rate was 26.6%. Combination of vistusertib with TMZ in GBM patients at first recurrence demonstrated a favorable safety profile at the tested dose levels.

Primary brain tumours in adults.

Primary CNS tumours refer to a heterogeneous group of tumours arising from cells within the CNS, and can be benign or malignant. Malignant primary brain tumours remain among the most difficult cancers to treat, with a 5 year overall survival no greater than 35%. The most common malignant primary brain tumours in adults are gliomas. Recent advances in molecular biology have improved understanding of glioma pathogenesis, and several clinically significant genetic alterations have been described. A number of these (IDH, 1p/19q codeletion, H3 Lys27Met, and RELA-fusion) are now combined with histology in the revised 2016 WHO classification of CNS tumours. It is likely that understanding such molecular alterations will contribute to the diagnosis, grading, and treatment of brain tumours. This progress in genomics, along with significant advances in cancer and CNS immunology, has defined a new era in neuro-oncology and holds promise for diagntic and therapeutic improvement. The challenge at present is to translate these advances into effective treatments. Current efforts are focused on developing molecular targeted therapies, immunotherapies, gene therapies, and novel drug-delivery technologies. Results with single-agent therapies have been disappointing so far, and combination therapies seem to be required to achieve a broad and durable antitumour response. Biomarker-targeted clinical trials could improve efficiencies of therapeutic development.

Impact of standard care on elderly glioblastoma patients.

BACKGROUND: Uncertainty persists about the survival advantage of concomitant and adjuvant temozolomide (TMZ) plus radiotherapy (RT) in elderly patients with newly diagnosed glioblastoma (GBM). We compared the clinical outcome of unselected elderly GBM patients treated with 4 adjuvant treatment modalities, including the Stupp protocol. METHODS: From 2010 to 2014, retrospective chart review was performed on 171 GBM patients aged ≥55 who received either concurrent chemoradiation therapy (CCRT) with standard 60 Gy/30 (SRT); CCRT with hypofractionated 40 Gy/15 (HRT); HRT alone; or TMZ alone. Stratification is by age (55-69, ≥70), KPS (<70, ≥70), and resection status (biopsy, resection). RESULTS: Out of 171 patients identified, 128(75%) had surgical resection, median age was 66(55-83), and median overall survival (mOS) 11.4mo. Majority (109/171) were treated according to the Stupp protocol (CCRT-SRT), and 106/171 received post-CCRT adjuvant TMZ (median of 3 cycles). In our population, age <70yo was a significant prognostic factor (mOS of patients aged 55-69 vs ≥70 yo = 13.3 vs 6.6 mo; P = .001). However, among the population receiving the Stupp regimen, there was no difference in survival between patients aged 55-69 and those ≥70 (respectively, 14.4 vs 13.2 mo; P = .798). Patients ≥70 yo had similar survival when treated with CCRT-HRT and CCRT-SRT (P = .248), although numbers were small. CONCLUSIONS: Our data suggests that, despite having a worse global prognostic than their younger counterparts, GBM patients ≥70yo with a good performance status could be treated according to the Stupp protocol with similar survival. Theses results need prospective confirmation.

Prophylactic anticonvulsants for gliomas: a seven-year retrospective analysis.

BACKGROUND: The American Academy of Neurology (AAN) does not recommend routine use of prophylactic antiepileptic drugs (pAEDs) in patients with newly diagnosed brain tumors. If used in the perioperative setting, discontinuation is suggested after the first postoperative week. It is unclear whether such recommendations are followed. Our objective was to compare our perioperative and long-term pAED use in glioma patients with AAN practice parameters. METHODS: Retrospective chart review was performed on 578 glioma patients from 2006 to 2013. Seizures and AED use were assessed at surgery, 3 months postoperatively and death, last visit or 16 months postoperatively. Patients were divided into three groups at surgery: seizure-free with pAED, seizure-free without pAED, and seizure patients. Long-term pAED use was defined as continued use at 3 months postsurgery without seizures. pAEDs efficacy, factors influencing its use, and survival were examined. RESULTS: Out of 578 patients identified, 330 (57.1%) were seizure-naïve preoperatively. There were no significant differences in age, histology, tumor location or resection status between seizure-free populations with and without prophylaxis. Of 330 seizure-naïve patients, 205 (62.1%) received pAEDs at surgery. Ninety-six (46.9%) of those patients were still on pAEDs 3 months postsurgery (median use = 58 days). Rate of long-term prophylaxis use decreased by 13.5% over 6 years (70.3% in 2006; 56.8% in 2012). Phenytoin was preferred in 2006 (98.2%) with increasing use of levetiracetam over 6 years (44.6% in 2012). The only predictive factor for pAED use was complete resection (P = .0069). First seizure prevalence was similar in both seizure-free populations (P = .91). The seizure population had more men (P = .007), younger patients (P < .0001), lower-grade gliomas (P = .0003) and survived longer (P = .001) compared with seizure-free populations. CONCLUSIONS: In our center, long-term prophylactic AED use is high, deviating from current AAN Guidelines. Corrective measures are warranted.