The gut is a major source of bacteria and antigens that contribute to neuroinflammation after brain injury. Colonic epithelial cells (ECs) are responsible for secreting major cellular components of the innate defense system, including antimicrobial proteins (AMP) and mucins. These cells serve as a critical regulator of gut barrier function and maintain host-microbe homeostasis. In this study, we determined post-stroke host defense responses at the colonic epithelial surface in mice. We then tested if the enhancement of these epithelial protective mechanisms is beneficial in young and aged mice after stroke. AMPs were significantly increased in the colonic ECs of young males, but not in young females after experimental stroke. In contrast, mucin-related genes were enhanced in young females and contributed to mucus formation that maintains the distance between the host and gut bacteria. Bacterial community profiling was done using universal amplification of 16S rRNA gene sequences. The sex-specific colonic epithelial defense responses after stroke in young females were reversed with ovariectomy and led to a shift from a predominately mucin response to the enhanced AMP expression seen in males after stroke. Estradiol (E2) replacement prior to stroke in aged females increased mucin gene expression in the colonic ECs. Interestingly, we found that E2 treatment reduced stroke-associated neuronal hyperactivity in the insular cortex, a brain region that interacts with visceral organs such as the gut, in parallel to an increase in the composition of Lactobacillus and Bifidobacterium in the gut microbiota. This is the first study demonstrating sex differences in host defense mechanisms in the gut after brain injury.
- Ana S Ferrigno Guajardo
- Bryan Vaca-Cartagena
- Erica L Mayer
- Hatem A Azim
Introduction The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy. Methods This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data. Results A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%). Conclusion Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated.
- Casey Crump
- Pär Stattin
- James D Brooks
- Weiva Sieh
Background A diagnosis of prostate cancer (PC) may cause psychosocial distress not only in a man but also his intimate partner. However, long-term risks of depression, anxiety, or suicide in partners of men with PC are largely unknown. Methods A national cohort study was conducted of 121,530 partners of men diagnosed with PC during 1998-2017 and 1,093,304 population-based controls in Sweden. Major depression, anxiety disorder, and suicide death were ascertained through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors. Results Partners of men with high-risk PC had increased risks of major depression (adjusted HR, 1.34; 95% CI, 1.30-1.39) and anxiety disorder (1.25; 1.20-1.30), which remained elevated ≥10 years later. Suicide death was increased in partners of men with distant metastases (adjusted HR, 2.38; 95% CI, 1.08-5.22) but not other high-risk PC (1.14; 0.70-1.88). Among partners of men with high-risk PC, risks of major depression and anxiety disorder were highest among those aged ≥80 years (adjusted HR, 1.73; 95% CI, 1.53-1.96; and 1.70; 1.47-1.96, respectively), whereas suicide death was highest among those aged <60 years (7.55; 2.20-25.89). In contrast, partners of men with low- or intermediate-risk PC had modestly or no increased risks of these outcomes. Conclusions In this large cohort, partners of men with high-risk PC had increased risks of major depression and anxiety disorder, which persisted for ≥10 years. Suicide death was increased 2-fold in partners of men with distant metastases. Partners as well as men with PC need psychosocial support and close follow-up for psychosocial distress.
Background: Colon and Rectal Surgery fellowships are training programs that aim to train surgeons in the management of small bowel, colon, rectal, and anal pathologies. Objective: We investigated trends in Colon and Rectal Surgery fellowship match to help applicants anticipate future fellowship application cycles. Design: This was a retrospective cohort study of applicants in the Colon and Rectal Surgery match from 2009 to 2023. Proportion of positions filled, match rates, and rank-order lists were collected. The impact of US-MD, non-US-MD, and DO status on match rate was assessed. We used the Mann Kendall trend test to obtain tau statistic and P-value for temporal trends over time, while associations between categorical variables were investigated by a chi-square test. Results: Fellowship programs increased from 43 to 67, positions increased from 78 to 110, and number of applicants rose from 113 to 135. Nearly all positions were filled from 2009 to 2023 (range: 96.3%-100%). The overall match rate fluctuated between 67.3% and 80.7%. The match rate over the past 5 years was 72.0%. The match rate for US-MDs was 80.0%, while non-US-MDs had a 56.2% match rate. The percentage matching at each rank were first choice 28.0%, second choice 10.4%, third choice 6.9%, and fourth choice or lower 23.5%. Conclusion: Despite an increase in Colon and Rectal Surgery fellowship positions, the overall match rate has not changed significantly over the years, mainly as a result of increased applicants.
Background In the United States, nearly 85,000 Veterans experienced homelessness during 2020, and thousands more are experiencing housing instability, representing a significant proportion of the population. ¹ Many Veterans experiencing homelessness are aging and have complex co‐occurring medical, psychiatric, and substance use disorders. Homelessness and older age put Veterans at greater risk for age‐related disorders, including Alzheimer's disease and related dementias (ADRD). Methods We examined the rate of ADRD diagnosis for Veterans experiencing homelessness and housing instability compared to a matched cohort of stably housed Veterans over a nine‐year period using cox proportional hazard models. Results In the matched cohort, 95% ( n = 88,811) of Veterans were men, and 67% ( n = 59,443) were White and were on average 63 years old (SD = 10.8). Veterans with housing instability had a higher hazard of 1.53 (95% confidence interval (CI) 1.50, 1.59) for ADRD compared to Veterans without housing instability. Conclusions Veterans experiencing housing instability have a substantially higher risk of receiving an ADRD diagnosis than a matched cohort of stably housed Veterans. Health systems and providers should consider cognitive screening among people experiencing housing insecurity. Existing permanent supportive housing programs should consider approaches to modify wraparound services to support Veterans experiencing ADRD.
Congenital hepatic arteriovenous malformations (HAVM) are rare and serious with a known high mortality rate. They are mostly described in the term population and, if symptomatic, present with early-onset congestive heart failure. To our knowledge, there have been no published cases of an affected very preterm infant. Prenatal diagnosis and preprocedural planning are paramount in these critically ill infants. Strategies for management of HAVM differ depending on the size of both the infant and HAVM as well as severity of symptoms. Management may include supportive pharmacologic therapy, transcatheter embolization, and surgical resection or ligation. In this report, we present the case of a 28-week gestation infant with high-output cardiac failure secondary to prenatally diagnosed hepatic arteriovenous malformation. On day of life 3, the infant underwent successful transcatheter occlusion. However, despite maximal medical management and partial embolization of his HAVM, he did not survive.
Background The relationship between obesity and non-Hodgkin’s lymphoma (NHL) was controversial, which may be due to the crudeness definition of obesity based on body mass index (BMI). As obesity and metabolic abnormalities often coexist, we aimed to explore whether the classification of obesity based on metabolic status can help to evaluate the real impact of obesity on the readmission of NHL. Methods In this retrospective cohort study, utilizing the 2018 Nationwide Readmissions Database, we identified NHL-related index hospitalizations and followed them for non-elective readmission. The patients with NHL were classified as metabolically healthy non-obese (MHNO) and obese (MHO) and metabolically unhealthy non-obese (MUNO) and obese (MUO). Readmission rates for each phenotype were calculated at 30-day intervals. Multiple COX regression was used to analyze the association of metabolic-defined obesity with 30-day, 90-day, and 180-day readmission rates in patients with NHL. Results There were 22,086 index hospitalizations with NHL included. In the multivariate COX regression, MUNO was associated with increased 30-day (HR = 1.113, 95% CI 1.036–1.195), 90-day (HR = 1.148, 95% CI 1.087–1.213), and 180-day readmission rates (HR = 1.132, 95% CI 1.077–1.189), and MUO was associated with increased 30-day (HR=1.219, 95% CI: 1.081-1.374), 90-day (HR = 1.228, 95% CI 1.118–1.348), and 180-day readmission rates (HR = 1.223, 95% CI 1.124–1.33), while MHO had no associations with readmission rates. Conclusions The presence of metabolic abnormalities with or without obesity increased the risk of non-selective readmission in patients with NHL. However, obesity alone had no associations with the risk of non-selective readmission, suggesting that interventions for metabolic abnormalities may be more important in reducing readmissions of NHL patients.
Background Millions of women give birth annually without the support of a trained birth attendant. Generally and globally, countries provide maternal health services for their citizens but there is a coverage gap for undocumented migrant women who often can’t access the same care due to their legal status. The objective of this investigation is to explore undocumented migrants’ experiences and perceptions of maternal healthcare accessibility. Methods We held focus groups discussions with 64 pregnant women at 3 migrant health clinics on the Thailand–Myanmar border and asked how they learned about the clinic, their health care options, travel and past experiences with birth services. In this context undocumented women could sign up for migrant health insurance at the clinic that would allow them to be referred for tertiary care at government hospitals if needed. Results Women learned about care options through a network approach often relying on information from community members and trusted care providers. For many, choice of alternate care was limited by lack of antenatal care services close to their homes, limited knowledge of other services and inability to pay fees associated with hospital care. Women travelled up to 4 h to get to the clinic by foot, bicycle, tractor, motorcycle or car, sometimes using multiple modes of transport. Journeys from the Myanmar side of the border were sometimes complicated by nighttime border crossing closures, limited transport and heavy rain. Conclusions Undocumented migrant women in our study experienced a type of conditional or variable accessibility where time of day, transport and weather needed to align with the onset of labour to ensure that they could get to the migrant clinic on time to give birth. We anticipate that undocumented migrants in other countries may also experience conditional accessibility to birth care, especially where travel is necessary due to limited local services. Care providers may improve opportunities for undocumented pregnant women to access maternal care by disseminating information on available services through informal networks and addressing travel barriers through mobile services and other travel supports. Trial registration The research project was approved by Research Ethics Committee at the Faculty of Medicine, Chiang Mai University (FAM-2560-05204), and the Department of Community Medicine and Global Health at the University of Oslo—Norwegian Centre for Research Data (58542).
Aneurysmal subarachnoid hemorrhage (aSAH) develops quickly once it occurs and threatens the life of patients. We aimed to use machine learning to predict mortality for SAH patients at an early stage which can help doctors make clinical decisions. In our study, we applied different machine learning methods to an aSAH cohort extracted from a national EHR database, the Cerner Health Facts EHR database (2000–2018). The outcome of interest was in-hospital mortality, as either passing away while still in the hospital or being discharged to hospice care. Machine learning-based models were primarily evaluated by the area under the receiver operating characteristic curve (AUC). The population size of the SAH cohort was 6728. The machine learning methods achieved an average of AUCs of 0.805 for predicting mortality with only the initial 24 hours’ EHR data. Without losing the prediction power, we used the logistic regression to identify 42 risk factors, —examples include age and serum glucose—that exhibit a significant correlation with the mortality of aSAH patients. Our study illustrates the potential of utilizing machine learning techniques as a practical prognostic tool for predicting aSAH mortality at the bedside.
Transcutaneous spinal stimulation (TSS) is emerging as a valuable tool for electrophysiological and clinical assessment. This study had the objective of examining the recruitment patterns of upper limb (UL) motor pools through the delivery of TSS above and below a spinal lesion. It also aimed to explore the connection between the recruitment pattern of UL motor pools and the neurological and functional status following spinal cord injury (SCI). In eight participants with tetraplegia due to cervical SCI, TSS was delivered to the cervical spinal cord between the spinous processes of C3–C4 and C7–T1 vertebrae, and spinally evoked motor potentials in UL muscles were characterized. We found that responses observed in UL muscles innervated by motor pools below the level of injury demonstrated relatively reduced sensitivity to TSS compared to those above the lesion, were asymmetrical in the majority of muscles, and were dependent on the level, extent, and side of SCI. Overall, our findings indicate that electrophysiological data acquired through TSS can offer insights into the extent of UL functional asymmetry, disruptions in neural pathways, and changes in motor control following SCI. This study suggests that such electrophysiological data can supplement clinical and functional assessment and provide further insight regarding residual motor function in individuals with SCI.
Previous research suggests that bilingual language control requires domain-general cognitive control. Recent research suggests that exploration of individual differences is key for understanding the relationship between bilingual language control and cognitive control. The current study used multi-voxel pattern analysis (MVPA) to examine within-subject patterns of fMRI activity in the dorsolateral prefrontal cortex (DLPFC) during bilingual language switching and non-linguistic task-switching. We hypothesized that bilinguals would have identifiable, within-subject patterns of DLPFC activity for both types of switching and that bilinguals and monolinguals would differ in patterns of DLPFC activity for task-switching. We were unable to identify patterns of DLPFC activity associated with bilingual language switching. Task-switching was related to patterns of left DLPFC activity for both bilinguals and monolinguals, and there were identifiable patterns of right DLPFC activity for the bilinguals only. These findings suggest that the DLPFC is not the key brain structure connecting bilingual language and task-switching.
The mandibular condylar cartilage (MCC) is an essential component of the temporomandibular joint, which orchestrates the vertical growth of the mandibular ramus through endochondral ossification with distinctive modes of cell differentiation. Parathyroid hormone–related protein (PTHrP) is a master regulator of chondrogenesis; in the long bone epiphyseal growth plate, PTHrP expressed by resting zone chondrocytes promotes chondrocyte proliferation in the adjacent layer. However, how PTHrP regulates chondrogenesis in the MCC remains largely unclear. In this study, we used a Pthrp-mCherry knock-in reporter strain to map the localization of PTHrP ⁺ cells in the MCC and define the function of PTHrP in the growing mandibular condyle. In the postnatal MCC of Pthrp mCherry/+ mice, PTHrP-mCherry was specifically expressed by cells in the superficial layer immediately adjacent to RUNX2-expressing cells in the polymorphic layer. PTHrP ligands diffused across the polymorphic and chondrocyte layers where its cognate receptor PTH1R was abundantly expressed. We further analyzed the mandibular condyle of Pthrp mCherry/mCherry mice lacking functional PTHrP protein (PTHrP-KO). At embryonic day (E) 18.5, the condylar process and MCC were significantly truncated in the PTHrP-KO mandible, which was associated with a significant reduction in cell proliferation across the polymorphic layer and a loss of SOX9 ⁺ cells in the chondrocyte layers. The PTHrP-KO MCC showed a transient increase in the number of Col10a1 ⁺ hypertrophic chondrocytes at E15.5, followed by a significant loss of these cells at E18.5, indicating that superficial layer–derived PTHrP prevents premature chondrocyte exhaustion in the MCC. The expression of Runx2, but not Sp7, was significantly reduced in the polymorphic layer of the PTHrP-KO MCC. Therefore, PTHrP released from cells in the superficial layer directly acts on cells in the polymorphic layer to promote proliferation of chondrocyte precursor cells and prevent their premature differentiation by maintaining Runx2 expression, revealing a unique PTHrP gradient-directed mechanism that regulates MCC chondrogenesis.
Importance Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. Objective To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia. Design, Setting, and Participants Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. Exposure Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks’ gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. Main Outcomes and Measures The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. Results The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks’ gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions ( P = .01), gestational age greater than 32 weeks ( P = .005), and higher birth weight ( P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). Conclusions and Relevance Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden. Trial Registration ClinicalTrials.gov Identifier: NCT03101891
Infantile fibrosarcoma (IF) is a rare malignant fibroblastic tumor that affects infants and young children, occurring most commonly in the extremities. Here, we present a 14-year-old patient with an abdominal mass incidentally detected after a blunt injury to the abdomen. The initial trauma protocol CT revealed a high attenuation mesenteric lesion in the left central abdomen suggestive of mesenteric hematoma. However, the possibility of a solid neoplastic mass lesion could not be excluded. Further evaluation with dynamic contrast-enhanced serial MRI showed a progressive enhancing mass and excluded a hyperacute hematoma with active bleeding. The mass was resected, and histopathological examination and molecular analysis of tumor cells were consistent with a high-grade fibrosarcoma with KMT2D : BCOR fusion.
Using a multidimensional, integrative approach this study examined the influence of social position factors (nativity, economic hardship, and language) and environmental contexts (community trauma, geographic location, and discrimination) on three domains of school engagement (cognitive, behavioral, and relational) among a community sample of first‐ and second‐generation Latino adolescents. Findings from this study reveal that both social position and environmental contexts significantly and differentially predicted each of the three domains of school engagement. Participants ( n = 306) included students from 11 high schools in two US cities. Fifty‐three percent were first‐generation immigrants and 80% were born, or had a parent from, Mexico or Central America. Results indicated that all three social position factors (nativity, economic hardship, and language) and two of the three environmental contexts (community trauma exposure and discrimination) significantly and differentially predicted each of the three domains of school engagement. Findings emphasize the direct effects of student's social positionality and environmental contexts on their engagement in school.
Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients’ parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.
Objective The early stages of chronic disease typically progress slowly, so symptoms are usually only noticed until the disease is advanced. Slow progression and heterogeneous manifestations make it challenging to model the transition from normal to disease status. As patient conditions are only observed at discrete timestamps with varying intervals, an incomplete understanding of disease progression and heterogeneity affects clinical practice and drug development. Materials and Methods We developed the Gaussian Process for Stage Inference (GPSI) approach to uncover chronic disease progression patterns and assess the dynamic contribution of clinical features. We tested the ability of the GPSI to reliably stratify synthetic and real-world data for osteoarthritis (OA) in the Osteoarthritis Initiative (OAI), bipolar disorder (BP) in the Adolescent Brain Cognitive Development Study (ABCD), and hepatocellular carcinoma (HCC) in the UTHealth and The Cancer Genome Atlas (TCGA). Results First, GPSI identified two subgroups of OA based on image features, where these subgroups corresponded to different genotypes, indicating the bone-remodeling and overweight-related pathways. Second, GPSI differentiated BP into two distinct developmental patterns and defined the contribution of specific brain region atrophy from early to advanced disease stages, demonstrating the ability of the GPSI to identify diagnostic subgroups. Third, HCC progression patterns were well reproduced in the two independent UTHealth and TCGA datasets. Conclusion Our study demonstrated that an unsupervised approach can disentangle temporal and phenotypic heterogeneity and identify population subgroups with common patterns of disease progression. Based on the differences in these features across stages, physicians can better tailor treatment plans and medications to individual patients.
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