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The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention.

Kinesins are motor proteins involved in microtubule (MT)-mediated intracellular transport. They contribute to key cellular processes, including intracellular trafficking, organelle dynamics and cell division. Pathogenic variants in kinesin-encoding genes underlie several human diseases characterized by an extremely variable clinical phenotype, ranging from isolated neurodevelopmental/neurodegenerative disorders to syndromic phenotypes belonging to a family of conditions collectively termed as ‘ciliopathies.’ Among kinesins, kinesin-1 is the most abundant MT motor for transport of cargoes towards the plus end of MTs. Three kinesin-1 heavy chain isoforms exist in mammals. Different from KIF5A and KIF5C, which are specifically expressed in neurons and established to cause neurological diseases when mutated, KIF5B is an ubiquitous protein. Three de novo missense KIF5B variants were recently described in four subjects with a syndromic skeletal disorder characterized by kyphomelic dysplasia, hypotonia and DD/ID. Here, we report three dominantly acting KIF5B variants (p.Asn255del, p.Leu498Pro and p.Leu537Pro) resulting in a clinically wide phenotypic spectrum, ranging from dilated cardiomyopathy with adult-onset ophthalmoplegia and progressive skeletal myopathy to a neurodevelopmental condition characterized by severe hypotonia with or without seizures. In vitro and in vivo analyses provide evidence that the identified disease-associated KIF5B variants disrupt lysosomal, autophagosome and mitochondrial organization, and impact cilium biogenesis. All variants, and one of the previously reported missense changes, were shown to affect multiple developmental processes in zebrafish. These findings document pleiotropic consequences of aberrant KIF5B function on development and cell homeostasis, and expand the phenotypic spectrum resulting from altered kinesin-mediated processes.

Recent advancements in 3D deep learning have led to significant progress in improving accuracy and reducing processing time, with applications spanning various domains such as medical imaging, robotics, and autonomous vehicle navigation for identifying and segmenting different structures. In this study, we employ the latest developments in 3D semi-supervised learning to create cutting-edge models for the 3D object detection and segmentation of buried structures in high-resolution X-ray semiconductors scans. We illustrate our approach to locating the region of interest of the structures, their individual components, and their void defects. We showcase how semi-supervised learning is utilized to capitalize on the vast amounts of available unlabeled data to enhance both detection and segmentation performance. Additionally, we explore the benefit of contrastive learning in the data pre-selection step for our detection model and multi-scale Mean Teacher training paradigm in 3D semantic segmentation to achieve better performance compared with the state of the art. Our extensive experiments have shown that our method achieves competitive performance and is able to outperform by up to 16% on object detection and 7.8% on semantic segmentation. Additionally, our automated metrology package shows a mean error of less than 2 μm for key features such as Bond Line Thickness and pad misalignment.

Context: Two-thirds of an individual’s gut microbiota is unique and influenced by dietary and exercise habits, age, sex, genetics, ethnicity, antibiotics, health, and disease. It plays important roles in nutrient and vitamin metabolism, inflammatory modulation, immune system function, and overall health of an individual. Specifically, in sports it may help decrease recovery time and improve athletic performance. Evidence Acquisition: PubMed and Medline databases were used for the literature search. Bibliographies based on the original search were utilized to pursue further literature search. Study Design: Clinical review. Level of Evidence: Level 4. Results: Diet and exercise play very important roles in the composition of the gut microbiota in the athletic and nonathletic individual. Ingestion of carbohydrates during and after exercise seems to have an anti-inflammatory effect postexercise. Supplementation with probiotic seems to aid in recovery after exercise, too, especially restoring the “normal” gut microbiota. Physically active individuals of all levels have more alpha diversity and “health-promoting gut species” in their microbiome than nonactive individuals, along with higher concentrations of short-chain fatty acids (SCFA) and SCFA-producing organisms. However, exercise interventions should be longer than 8 weeks to see these positive characteristics. Immune function is highly influenced by the gut microbiota’s response to exercise. A transient immune dysfunction occurs after prolonged high-intensity exercise, which correlates with microbiota dysregulation. Nevertheless, long-term exposure to exercise will enhance the immune response and lead to positive changes in the gut microbiota. Conclusion: Although the exact mechanisms of the effects that diet, exercise, and genetics have on the gut microbiota remain largely unknown, there is evidence that suggests overall health benefits. In the athletic population, these benefits can ultimately lead to performance improvement.

Background The identification of parathyroid tumor(s) in patients with persistent/recurrent primary hyperparathyroidism (PHPT) is critical for a successful re-operative surgery. We describe our experience with invasive studies for parathyroid tumor localization and provide follow-up data regarding our experience with selective arterial hypocalcemic stimulation with central venous sampling (SAHSCVS). Methods We identified patients who underwent pre-operative invasive testing for localization of parathyroid tumor at our center. At our center, only PHPT patients with history of prior neck surgery without definitive findings on non-invasive testing (sestamibi, ultrasound, CT, MRI) proceed to invasive studies. The result of each invasive localization study (arteriogram, SAHSCVS and selective venous sampling (SVS)) was categorized as true-positive (TP), false-positive (FP) and false-negative (FN) based on biochemical outcome. Results Ninety-five patients with 98 tumors underwent invasive testing for parathyroid tumor localization. All but one had recurrent disease. Sixty-two patients (65%) had "apparently sporadic" PHPT, 19/95 (20%) had MEN1, three had parathyroid cancer (PC) and the remaining had other heritable forms of PHPT. Median age of index PHPT presentation was 47 [34-58] years. Of 87 tumors with available operative details, 66 (76%) were in the neck, 20 in the mediastinum (23%), and one in the forearm at site of prior autograft. Seventy-two (83%) showed hyperplasia or hypercellularity on histology. Median tumor size was 5 mm. Arteriogram, SAHSCVS and SVS accurately localized the tumor in 47/90 (52%), 54/90 (60%) and 49/61 (80%) tumors respectively. Positive Predictive Value of arteriogram, SAHSCVS and SVS was 47/50 (94%), 55/64 (86%) and 49/59 (83%) respectively. Both sensitivity and PPV showed no significant difference between patients with MEN1+PC vs. others. Among the 54 tumors accurately localized by SAHSCVS, SVS was performed in 29/54 with complete concordance. Twenty-seven tumors (30%) were missed (FN) on SAHSCVS, of these 14/25 (56%) were also missed on arteriogram. Nevertheless, 16/20 (80%) localized accurately on subsequent SVS. SAHSCVS was FP in localizing nine tumors - seven (78%) of these did not show a blush on arteriogram. All pre-operative localizing studies were unrevealing in 9/98 presentations (10%). Conclusion Patients with difficult to localize parathyroid tumors have clinical features suspicious for germline-predisposition forms of PHPT indicated by recurrent disease, hyperplastic glands, and age of index presentation. SAHSCVS can be a useful adjunct in patients who require invasive localization. 90% of these tumors are localized with combination of current non-invasive and invasive testing. AcknowledgementThis research is supported by the Intramural Research Program of NIDDK, NCI and NIH Clinical Center. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.