Keypoint-MoSeq: parsing behavior by linking point tracking to pose dynamics.

Keypoint tracking algorithms can flexibly quantify animal movement from videos obtained in a wide variety of settings. However, it remains unclear how to parse continuous keypoint data into discrete actions. This challenge is particularly acute because keypoint data are susceptible to high-frequency jitter that clustering algorithms can mistake for transitions between actions. Here we present keypoint-MoSeq, a machine learning-based platform for identifying behavioral modules ('syllables') from keypoint data without human supervision. Keypoint-MoSeq uses a generative model to distinguish keypoint noise from behavior, enabling it to identify syllables whose boundaries correspond to natural sub-second discontinuities in pose dynamics. Keypoint-MoSeq outperforms commonly used alternative clustering methods at identifying these transitions, at capturing correlations between neural activity and behavior and at classifying either solitary or social behaviors in accordance with human annotations. Keypoint-MoSeq also works in multiple species and generalizes beyond the syllable timescale, identifying fast sniff-aligned movements in mice and a spectrum of oscillatory behaviors in fruit flies. Keypoint-MoSeq, therefore, renders accessible the modular structure of behavior through standard video recordings.

Folate receptor alpha expression in low-grade serous ovarian cancer: Exploring new therapeutic possibilities.

OBJECTIVE: Mirvetuximab soravtansine may be a potentially effective therapeutic option for ovarian low-grade serous carcinoma (LGSC), but the prevalence of folate receptor alpha (FRα) overexpression in this tumor type is unknown. We sought to characterize FRα expression in LGSC and its association with clinical and molecular features. METHODS: FRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined. RESULTS: Of 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n = 23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p < 0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p = 0.008). CONCLUSIONS: Future studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup.

Ethological computational psychiatry: Challenges and opportunities.

Studying the intricacies of individual subjects' moods and cognitive processing over extended periods of time presents a formidable challenge in medicine. While much of systems neuroscience appropriately focuses on the link between neural circuit functions and well-constrained behaviors over short timescales (e.g., trials, hours), many mental health conditions involve complex interactions of mood and cognition that are non-stationary across behavioral contexts and evolve over extended timescales. Here, we discuss opportunities, challenges, and possible future directions in computational psychiatry to quantify non-stationary continuously monitored behaviors. We suggest that this exploratory effort may contribute to a more precision-based approach to treating mental disorders and facilitate a more robust reverse translation across animal species. We conclude with ethical considerations for any field that aims to bridge artificial intelligence and patient monitoring.

Walking status and spinopelvic parameters in young children with achondroplasia: 10-year follow-up.

PURPOSE: Thoracolumbar kyphosis (TLK) is common in children with achondroplasia and resolves in 90% by 10 years of age. Our purpose was to describe the natural progression of TLK in a cohort of pre-walking children with achondroplasia. METHODS: A single-center, retrospective review identified 62 children (32 male, 30 female) with achondroplasia. Clinical information and sagittal spinopelvic parameters were collected. The children were divided into positive pelvic tilt (PT) and negative PT. All parents were routinely counseled about unsupported sitting. RESULTS: Spontaneous resolution rate was 64.5% at 1-year post-walking, 74.2% at 5 years of age, and 88.7% at 10 years of age. None of the children required posterior spinal decompression and fusion for progressive deformity or symptomatic spinal stenosis. At 1-year post-walking, the negative PT group had a higher sacral slope (p = 0.006), higher lumbar lordosis (p < 0.001), and lower pelvic incidence (p < 0.001). This relationship remained constant up to 10 years of age, and there was no association with TLK. CONCLUSION: In this largest series to date, spontaneous resolution of TLK in children with achondroplasia was 64.5% at 1-year post-walking, 74.2% at 5 years of age, and 88.7% in children followed to 10 years of age. With early identification and regular follow-up with patient education, no patient in this series required treatment or developed symptomatic spinal stenosis. While not predictive of resolution of TLK, the dichotomous presentation of PT in young children with achondroplasia persists at 5 and 10 years of age and reliably predicts the spinopelvic parameters. LEVEL OF EVIDENCE: III-retrospective comparative study.

Achondroplasia natural history study (CLARITY): 60-year experience in orthopedic surgery from four skeletal dysplasia centers.

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database. RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. 12.7% (n = 175) of patients underwent spine surgery at a mean age at first surgery of 22.4 ± 15.3 years old. The median age was 16.7 years old (0.1-67.4). 21.2% (n = 291) of patients underwent lower extremity surgery at a mean age at first surgery of 9.9 ± 8.3 years old with a median age of 8.2 years (0.2-57.8). The most common spinal procedure was decompression (152 patients underwent 271 laminectomy procedures), while the most common lower extremity procedure was osteotomy (200 patients underwent 434 procedures). Fifty-eight (4.2%) patients had both a spine and lower extremity surgery. Specific risk factors increasing the likelihood of orthopedic surgery included: patients with hydrocephalus requiring shunt placement having higher odds of undergoing spine surgery (OR 1.97, 95% CI 1.14-3.26); patients having a cervicomedullary decompression also had higher odds of undergoing spine surgery (OR 1.85, 95% CI 1.30-2.63); and having lower extremity surgery increased the odds of spine surgery (OR 2.05, 95% CI 1.45-2.90). CONCLUSIONS: Orthopedic surgery was a common occurrence in achondroplasia with 29.7% of patients undergoing at least one orthopedic procedure. Spine surgery (12.7%) was less common and occurred at a later age than lower extremity surgery (21.2%). Cervicomedullary decompression and hydrocephalus with shunt placement were associated with an increased risk for spine surgery. The results from CLARITY, the largest natural history study of achondroplasia, should aid clinicians in counseling patients and families about orthopedic surgery.

NeuroAI: If grid cells are the answer, is path integration the question?

Spatially modulated neurons known as grid cells are thought to play an important role in spatial cognition. A new study has found that units with grid-cell-like properties can emerge within artificial neural networks trained to path integrate, and developed a unifying theory explaining the formation of these cells which shows what circuit constraints are necessary and how learned systems carry out path integration.

Maturational patterns of the infant gut mycobiome are associated with early-life body mass index.

Unlike the bacterial microbiome, the role of early-life gut fungi in host metabolism and childhood obesity development remains poorly characterized. To address this, we investigate the relationship between the gut mycobiome of 100 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study and body mass index Z scores (BMIz) in the first 5 years of life. An increase in fungal richness during the first year of life is linked to parental and infant BMI. The relationship between richness pattern and early-life BMIz is modified by maternal BMI, maternal diet, infant antibiotic exposure, and bacterial beta diversity. Further, the abundances of Saccharomyces, Rhodotorula, and Malassezia are differentially associated with early-life BMIz. Using structural equation modeling, we determine that the mycobiome's contribution to BMIz is likely mediated by the bacterial microbiome. This demonstrates that mycobiome maturation and infant growth trajectories are distinctly linked, advocating for inclusion of fungi in larger pediatric microbiome studies.

Cervical Cancer Screening and Follow-Up Practices in U.S. Prisons.

INTRODUCTION: The objective of this study is to better understand cervical cancer screening and follow-up practices in U.S. prisons. METHODS: A 29-question survey examining cervical cancer screening practices, education, and facility/patient characteristics was disseminated to state-prison medical directors. RESULTS: A total of 70% (35/50) of state medical directors completed the survey between August 2021 and January 2022. All prison systems provided cervical cancer screening both at intake and specified intervals. A total of 36% provided colposcopy on site, and 9% performed excisional procedures on site. A total of 11 states identified 1‒5 cases of cervical cancer within the last year. Frequently cited challenges included a perceived lack of patient interest, delays in community referral, and lack of follow-up of abnormal results after release. CONCLUSIONS: This study found relatively high rates of screening with a perceived lack of patient interest as the most reported barrier. Follow-up care was also often affected by reported lack of patient interest, delays in community referral for diagnostic procedures, and patient release before follow-up. There is room for further optimization of screening and surveillance among incarcerated women by understanding and addressing systems-based challenges. By understanding patient barriers to primary screening, expanding access to onsite testing and community referral for abnormal results, and streamlining post-release follow-up, disparities in care among incarcerated women can be reduced.

Growth Modulation by Tension Band Plate in Achondroplasia With Varus Knee Deformity: Comparison of Gait Analysis Measurements.

BACKGROUND: Limited evidence exists concerning growth modulation by tension band plate (TBP) to correct varus deformity in patients with achondroplasia with limited growth due to FGFR3 gene mutation. We evaluated the efficacy of TBP in children with achondroplasia with genu varum and reported the static radiographic and dynamic motion data to determine parameters that impact the rate of deformity correction. METHODS: Patients with achondroplasia with genu varum who underwent TBP surgery for growth modulation were studied. Those with at least 1 year of follow-up with TBP were included. Radiographic parameters were measured. Growth velocity of femoral/tibial length was calculated separately. Patients were deemed successful or unsuccessful. Spearman correlation analysis and Student t test were used to describe statistical results. RESULTS: Twenty-two patients (41 limbs; 12 girls) fulfilled our criteria. Mean age at TBP surgery was 7.6±2.4 years. Thirty-six femoral TBP and 41 tibial TBP were in place for 24.5±9.7 months. Mean mechanical axis deviation, mechanical lateral distal femoral angle, and medial proximal tibial angle preoperatively were 30.1±7.6 mm, 97.2±6.4, and 80.3±4.3 degrees, and 11±15.6 mm, 87.4±5.9, and 84.7±5.3 degrees at last follow-up ( P <0.001). Fifteen limbs were successfully straightened; 4 limbs were in more varus than the initial deformity. Twenty-four limbs with TBP were still undergoing correction. In successful limbs, mean age at surgery was 6.5±1.7 years and duration of TBP was 29.9±7.8 months. In 4 unsuccessful limbs, mean age at surgery was 11.7±1.2 years. Analysis in the gait laboratory included physical examination with the measurement of knee varus and kinematic varus based on a posterior view static standing photograph. Photographic measurement of varus was higher than the radiographic measurement. CONCLUSIONS: Growth modulation by TBP surgery is a reliable and simple technique to correct genu varum in achondroplasia. An early age at TBP implementation (mean: 6.5 y) is crucial to successfully correct the varus knee deformity. Furthermore, we recommend early and regular surveillance of achondroplasia for progressive varus knee deformity. LEVEL OF EVIDENCE: Level IV-cohort study.

Fentanyl in the labor epidural impacts the results of intrapartum and postpartum maternal and neonatal toxicology tests.

BACKGROUND: A positive urine fentanyl toxicology test may have considerable consequences for peripartum individuals, yet the extent to which fentanyl administration in a labor epidural may lead to such a positive test is poorly characterized. OBJECTIVE: This study aimed to quantify the extent to which neuraxial fentanyl in labor neuraxial analgesia can lead to a positive peripartum maternal or neonatal urine toxicology test. STUDY DESIGN: We performed a prospective cohort study of pregnant participants planning a vaginal delivery with neuraxial analgesia. Participants with a history of substance use disorder, hypertension, or renal or liver disease were excluded. A urine sample was collected before initiation of neuraxial analgesia, each time the bladder was emptied during labor, and up to 4 times postpartum. Neonatal urine was collected once. Urine fentanyl testing was performed using 2 common toxicology testing methods, namely immunoassay and liquid chromatography with tandem mass spectrometric detection. RESULTS: A total of 33 maternal-infant dyads yielded a total of 178 urine specimens. All maternal specimens were negative for fentanyl using liquid chromatography with tandem mass spectrometric analysis and immunoassay before initiation of neuraxial analgesia. Intrapartum, 26 of 30 (76.7%) participants had positive liquid chromatography with tandem mass spectrometry results for fentanyl or its metabolites, and 12 of 30 (40%) participants had positive immunoassay results. Postpartum, 19 of 21 (90.5%) participants had positive liquid chromatograph with tandem mass spectrometric results, and 13 of 21 (61.9%) had a positive immunoassay result. Of the 13 neonatal specimens collected, 10 (76.9%) were positive on liquid chromatography with tandem mass spectrometry analysis, the last of which remained positive 29 hours and 50 minutes after delivery. CONCLUSION: Neuraxial fentanyl for labor analgesia may lead to positive maternal and neonatal toxicology tests at various times after epidural initiation and cessation and at different rates depending on the testing method used. Caution should be used in interpreting toxicology test results of individuals who received neuraxial analgesia to avoid false assumptions about nonprescribed use.

What Happened and Why: Responding to Racism, Discrimination, and Microaggressions in the Clinical Learning Environment.

Introduction: Within clinical learning environments, medical students are uniquely faced with power differentials that make acts of racism, discrimination, and microaggressions (RDM) challenging to address. Experiences of microaggressions and mistreatment are correlated with higher rates of positive depression screening and lower satisfaction with medical training. We developed a curriculum for medical students beginning clerkship rotations to promote the recognition of and response to RDM. Methods: Guided by generalized and targeted needs assessments, we created a case-based curriculum to practice communication responses to address RDM. The communication framework, a 6Ds approach, was developed through adaptation and expansion of established and previously learned communication upstander frameworks. Cases were collected through volunteer submission and revised to maintain anonymity. Faculty and senior medical students cofacilitated the small-group sessions. During the sessions, students reviewed the communication framework, explored their natural response strategies, and practiced all response strategies. Results: Of 196 workshop participants, 152 (78%) completed the evaluation surveys. Pre- and postsession survey cohort comparison demonstrated a significant increase in students' awareness of instances of RDM (from 34% to 46%), knowledge of communication strategies to mitigate RDM (presession M = 3.4, postsession M = 4.6, p < .01), and confidence to address RDM (presession M = 3.0, postsession M = 4.4, p < .01). Discussion: Students gained valuable communication skills from interactive sessions addressing RDM using empathy, reflection, and relatability. The workshop empowered students to feel prepared to enter professional teams and effectively mitigate harmful discourse.

Next-generation brain observatories.

We propose centralized brain observatories for large-scale recordings of neural activity in mice and non-human primates coupled with cloud-based data analysis and sharing. Such observatories will advance reproducible systems neuroscience and democratize access to the most advanced tools and data.

The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC.

The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders.

Current and Possible Future Therapeutic Options for Huntington's Disease.

Huntington's disease (HD) is an autosomal neurodegenerative disease that is characterized by an excessive number of CAG trinucleotide repeats within the huntingtin gene (HTT). HD patients can present with a variety of symptoms including chorea, behavioural and psychiatric abnormalities and cognitive decline. Each patient has a unique combination of symptoms, and although these can be managed using a range of medications and non-drug treatments there is currently no cure for the disease. Current therapies prescribed for HD can be categorized by the symptom they treat. These categories include chorea medication, antipsychotic medication, antidepressants, mood stabilizing medication as well as non-drug therapies. Fortunately, there are also many new HD therapeutics currently undergoing clinical trials that target the disease at its origin; lowering the levels of mutant huntingtin protein (mHTT). Currently, much attention is being directed to antisense oligonucleotide (ASO) therapies, which bind to pre-RNA or mRNA and can alter protein expression via RNA degradation, blocking translation or splice modulation. Other potential therapies in clinical development include RNA interference (RNAi) therapies, RNA targeting small molecule therapies, stem cell therapies, antibody therapies, non-RNA targeting small molecule therapies and neuroinflammation targeted therapies. Potential therapies in pre-clinical development include Zinc-Finger Protein (ZFP) therapies, transcription activator-like effector nuclease (TALEN) therapies and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas) therapies. This comprehensive review aims to discuss the efficacy of current HD treatments and explore the clinical trial progress of emerging potential HD therapeutics.

"Molding" immunity-modulation of mucosal and systemic immunity by the intestinal mycobiome in health and disease.

Fungi are important yet understudied contributors to the microbial communities of the gastrointestinal tract. Starting at birth, the intestinal mycobiome undergoes a period of dynamic maturation under the influence of microbial, host, and extrinsic influences, with profound functional implications for immune development in early life, and regulation of immune homeostasis throughout life. Candida albicans serves as a model organism for understanding the cross-talk between fungal colonization dynamics and immunity, and exemplifies unique mechanisms of fungal-immune interactions, including fungal dimorphism, though our understanding of other intestinal fungi is growing. Given the prominent role of the gut mycobiome in promoting immune homeostasis, emerging evidence points to fungal dysbiosis as an influential contributor to immune dysregulation in a variety of inflammatory and infectious diseases. Here we review current knowledge on the factors that govern host-fungi interactions in the intestinal tract and immunological outcomes in both mucosal and systemic compartments.

Single-molecule Taq DNA polymerase dynamics.

Taq DNA polymerase functions at elevated temperatures with fast conformational dynamics-regimes previously inaccessible to mechanistic, single-molecule studies. Here, single-walled carbon nanotube transistors recorded the motions of Taq molecules processing matched or mismatched template-deoxynucleotide triphosphate pairs from 22° to 85°C. By using four enzyme orientations, the whole-enzyme closures of nucleotide incorporations were distinguished from more rapid, 20-µs closures of Taq's fingers domain testing complementarity and orientation. On average, one transient closure was observed for every nucleotide binding event; even complementary substrate pairs averaged five transient closures between each catalytic incorporation at 72°C. The rate and duration of the transient closures and the catalytic events had almost no temperature dependence, leaving all of Taq's temperature sensitivity to its rate-determining open state.

Perspectives in machine learning for wildlife conservation.

Inexpensive and accessible sensors are accelerating data acquisition in animal ecology. These technologies hold great potential for large-scale ecological understanding, but are limited by current processing approaches which inefficiently distill data into relevant information. We argue that animal ecologists can capitalize on large datasets generated by modern sensors by combining machine learning approaches with domain knowledge. Incorporating machine learning into ecological workflows could improve inputs for ecological models and lead to integrated hybrid modeling tools. This approach will require close interdisciplinary collaboration to ensure the quality of novel approaches and train a new generation of data scientists in ecology and conservation.

Patient-reported outcomes and chemotherapy-related cognitive impairment in gynecologic malignancy.

OBJECTIVE: Chemotherapy has multiple adverse effects, including chemotherapy-related cognitive impairment, the phenomenon colloquially referred to as 'chemobrain'. The objective of this study was to understand patient-reported experiences of this phenomenon in relation to chemotherapy administration among gynecologic oncology patients. METHODS: A prospective patient-reported outcomes program was implemented in the Gynecologic Oncology clinic of a tertiary academic institution in January 2018. Patients with endometrial or ovarian cancer who received chemotherapy were included through September 2019 in this cohort study. Patients completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire. Serial responses were compared before, during, and after chemotherapy using a mixed effects linear regression with random effects for repeated measures within patients and a fixed effect for endometrial versus ovarian cancer. RESULTS: Fifty patients were included who completed a total of 152 patient-reported outcome measures. Thirty-five questionnaires were administered before chemotherapy, 59 during treatment, and 58 at a median of 161 days after the final cycle of chemotherapy. Seventy-one percent of patients reported no difficulties with concentration before chemotherapy, which remained stable after chemotherapy (72%). Sixty-six percent reported no difficulty with memory before chemotherapy versus 52% after chemotherapy. There were significant differences in feeling tension (p<0.001), worry (p<0.001), and depression (p=0.02) before and after chemotherapy on mixed effects linear regression, with higher levels of adverse emotional symptoms before chemotherapy administration compared with after. Women reported more interference with their social lives during chemotherapy (mean 1.08) compared with before (mean 0.85) and after chemotherapy (0.75, p=0.04). CONCLUSIONS: While no overt memory issues were discovered with serial administration of patient-reported outcome measures, rates of adverse emotional symptoms such as depression, tension, and worry diminished after chemotherapy administration. Further study is needed about the phenomenon of chemotherapy-related cognitive impairment using a larger cohort.