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The increasing deployment of algorithmic management in the workplace poses significant occupational safety and health risks for workers. In this article, we argue that existing and proposed EU regulatory frameworks are inadequate to address these risks, especially psychosocial risks, created or exacerbated by algorithmic management. While existing and proposed regulatory frameworks have significant implications for employers’ obligations to mitigate these risks, we identify several psychosocial risks created or exacerbated by algorithmic management and show how the current and proposed regulatory frameworks fall short of adequately addressing these risks. We observe that these frameworks, based largely in the ‘safety by design’ tradition, focus on the design phase of the technology life cycle. This focus does not adequately address risks that arise in the use or deployment stage of algorithmic management. There is therefore a need for a stand-alone piece of legislation at the EU level on algorithmic management. To address these shortcomings, we outline suggestions for provisions necessary for safe and healthy digitally managed work.

Purpose: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Experimental Design: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. Results: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6–40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment.

Injury : international journal of the care of the injured 53(8), 2774-2782 (2022). doi:10.1016/j.injury.2022.05.009, Published by Elsevier Science, Amsterdam [u.a.]

Discovery mark tagging provided the first evidence of linkages between eastern Australian and Oceania Humpback whale breeding grounds and the Antarctic Area V feeding areas. Early investigation of movements of humpback whales in the Western Pacific led to the view that the Balleny Islands and the Ross Sea were the summer destinations for humpback whales from eastern Australia and the Oceania breeding grounds. Recent photo-identification (ID) studies provided further evidence of low levels of migratory interchange and complex linkages within Oceania and between eastern Australia and Oceania. We report here the migratory movement of three humpback whales (Megaptera novaeangliae) between Eastern Australia (E(i) breeding stock) and the Area V Antarctic feeding area in the vicinity of the Balleny Islands. Using photo-ID techniques, comparisons between a Balleny Island fluke catalogue (n = 11 individuals) and existing fluke catalogues from eastern Australia (n = 3,120 individuals) and Oceania (n = 725 individuals), yielded three matches to Hervey Bay, Byron Bay and Ballina in eastern Australia and no matches to Oceania. The eastern Australia catalogue (n = 3,120) was made up of Hervey Bay (n = 1,556), Byron Bay, (n = 916) and Ballina (n = 648). The Oceania catalogue (n = 725) is made up of Tonga (n = 282); New Caledonia (n = 160); French Polynesia (n = 159); New Zealand (n = 41); Cook Islands (n = 36); American Samoa (n = 31); Vanuatu, Niue, Samoa and Fiji (n = 11) and Norfolk Island (n = 5). Only three previous individual photo-ID matches have been reported between eastern Australia Breeding Stock E(i) and Antarctic Area V feeding areas in the vicinity of the Balleny Islands and the Ross Sea. Only one genotype match has been reported between Antarctic Area V feeding areas and Oceania breeding grounds. An analysis of the frequencies of whales seen and not seen in the Balleny Islands, Oceania and eastern Australia, relative to the expected frequencies, based on the estimated population sizes and the sizes of the catalogues, supports the hypothesis that Antarctic Area V waters, in the vicinity of the Balleny islands, is a summer feeding area for some eastern Australian humpback whales.

Background and ObjectivesBrain-computer interfaces (BCIs) are being developed to restore mobility, communication, and functional independence to people with paralysis. Though supported by decades of preclinical data, the safety of chronically implanted microelectrode array BCIs in humans is unknown. We report safety results from the prospective, open-label, nonrandomized BrainGate feasibility study (NCT00912041), the largest and longest-running clinical trial of an implanted BCI.MethodsAdults aged 18–75 years with quadriparesis from spinal cord injury, brainstem stroke, or motor neuron disease were enrolled through 7 clinical sites in the United States. Participants underwent surgical implantation of 1 or 2 microelectrode arrays in the motor cortex of the dominant cerebral hemisphere. The primary safety outcome was device-related serious adverse events (SAEs) requiring device explantation or resulting in death or permanently increased disability during the 1-year postimplant evaluation period. The secondary outcomes included the type and frequency of other adverse events and the feasibility of the BrainGate system for controlling a computer or other assistive technologies.ResultsFrom 2004 to 2021, 14 adults enrolled in the BrainGate trial had devices surgically implanted. The average duration of device implantation was 872 days, yielding 12,203 days of safety experience. There were 68 device-related adverse events, including 6 device-related SAEs. The most common device-related adverse event was skin irritation around the percutaneous pedestal. There were no safety events that required device explantation, no unanticipated adverse device events, no intracranial infections, and no participant deaths or adverse events resulting in permanently increased disability related to the investigational device.DiscussionThe BrainGate Neural Interface system has a safety record comparable with other chronically implanted medical devices. Given rapid recent advances in this technology and continued performance gains, these data suggest a favorable risk/benefit ratio in appropriately selected individuals to support ongoing research and development.Trial Registration InformationClinicalTrials.gov Identifier:NCT00912041.Classification of EvidenceThis study provides Class IV evidence that the neurosurgically placed BrainGate Neural Interface system is associated with a low rate of SAEs defined as those requiring device explantation, resulting in death, or resulting in permanently increased disability during the 1-year postimplant period.

This analysis highlights the potential value in reanalysing early national meteorological records from around the world. These were oftentimes measured via techniques that preceded standardisation of instrumentation and methods of observation and thus could be subject to considerable biases and uncertainties. This analysis uses the techniques pioneered by WMO record assessment teams. The highest currently recognised air temperature (33.3 ∘C) ever recorded in the Republic of Ireland was logged at Kilkenny Castle in 1887. The original observational record however no longer exists. Given that Ireland is now the only country in Europe to have a national heat record that was set in the 19th century, a reassessment of the verity of this record is both timely and valuable. The present analysis undertakes a fundamental reassessment of the plausibility of the 1887 temperature record using methods similar to those used to assess various weather extremes under WMO auspices over recent years. Specifically, we undertake an inter-station reassessment using sparse available records and make recourse to the new and improved 20CRv3 sparse-input reanalysis product. Neither surrounding available stations nor the reanalysis offer substantive support for the Kilkenny record of 33.3 ∘C being correct. Moreover, recent data rescue efforts have uncovered several earlier extreme values, one of which exceeds the Kilkenny value (33.5 ∘C on 16 July 1876 recorded at the Phoenix Park). However, the sparsity of early observational networks, a distinct lack of synoptic support from 20CRv3 for many of the extreme heat values, and the fact that these measurements were obtained using non-standard exposures lead us to conclude that there is grossly insufficient evidence to support any of these 19th century extremes as robust national heat record candidates. Data from the early 20th century onwards benefit from a denser network of stations undertaking measurements in a more standardised manner, many under the direct auspices of Met Éireann and its predecessors, adhering to WMO guidance and protocols. This enables more robust cross-checking of records. We argue that the Met Éireann-recognised 20th century heat record from Boora in 1976 is verified as the most plausible robust national temperature record based upon the synoptic situation and comparisons with nearby neighbouring stations. This measurement of 32.5 ∘C thus likely constitutes the highest reliably recorded temperature measurement in the Republic of Ireland. Ultimately, the formal decision on any reassessment and reassignment of the national record rests with the national meteorological service, Met Éireann.

Structural color is poorly known in plants relative to animals. In fruits, only a handful of cases have been described, including in Viburnum tinus where the blue color results from a disordered multilayered reflector made of lipid droplets. Here, we examine the broader evolutionary context of fruit structural color across the genus Viburnum. We obtained fresh and herbarium fruit material from 30 Viburnum species spanning the phylogeny and used transmission electron microscopy, optical simulations, and ancestral state reconstruction to identify the presence/absence of photonic structures in each species, understand the mechanism producing structural color in newly identified species, relate the development of cell wall structure to reflectance in Viburnum dentatum, and describe the evolution of cell wall architecture across Viburnum. We identify at least two (possibly three) origins of blue fruit color in Viburnum in species which produce large photonic structures made of lipid droplets embedded in the cell wall and which reflect blue light. Examining the full spectrum of mechanisms producing color in pl, including structural color as well as pigments, will yield further insights into the diversity, ecology, and evolution of fruit color.

Neurotrophic Tyrosine Receptor Kinase (NTRK) genes undergo chromosomal translocations to create novel open reading frames coding for oncogenic fusion proteins; the N-terminal portion, donated by various partner genes, becomes fused to the tyrosine kinase domain of either NTRK1, NTRK2, or NTRK3. NTRK fusion proteins have been identified as driver oncogenes in a wide variety of tumors over the past three decades, including Pediatric Gliomas, Papillary Thyroid Carcinoma, Spitzoid Neoplasms, Glioblastoma, and additional tumors. Importantly, NTRK fusions function as drivers of pediatric sarcomas, accounting for approximately 15% of childhood cancers including Infantile Fibrosarcoma (IFS), a subset of pediatric soft tissue sarcoma (STS). While tyrosine kinase inhibitors (TKIs), such as larotrectinib and entrectinib, have demonstrated profound results against NTRK fusion-positive cancers, acquired resistance to these TKIs has resulted in the formation of gatekeeper, solvent-front, and compound mutations. We present a comprehensive compilation of oncogenic fusions involving NTRKs focusing specifically on pediatric STS, examining their biological signaling pathways and mechanisms of activation. The importance of an obligatory dimerization or multimerization domain, invariably donated by the N-terminal fusion partner, is discussed using characteristic fusions that occur in pediatric sarcomas. In addition, examples are presented of oncogenic fusion proteins in which the N-terminal partners may contribute additional biological activities beyond an oligomerization domain. Lastly, therapeutic approaches to the treatment of pediatric sarcoma will be presented, using first generation and second-generation agents such as selitrectinib and repotrectinib.

Scientific reports 12, 16571 (2022). doi:10.1038/s41598-022-20170-2, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Background Esports players, like traditional athletes, practice for long hours and, thus, are vulnerable to the negative health effects of prolonged sitting. There is a lack of research on the physical activity and the health ramifications of prolonged sitting by competitive players. The purpose of this study was to investigate activity levels, body mass index (BMI), and body composition in collegiate esports players as compared to age-matched controls. Methods Twenty-four male collegiate esports players and non-esports players between 18 and 25 years of age signed a written consent to participate. Physical activity was examined using daily activity (step count) with a wrist-worn activity tracker. A questionnaire assessing physical activity was also administered. Secondary outcomes included body-fat percentage, lean-body mass, BMI, and bone mineral content measured using dual X-ray absorptiometry. Results The step count in the esports players was significantly lower than the age-matched controls (p = 0.004; 6040.2 ± 3028.6 vs. 12843.8 ± 5661.1). Esports players exhibited greater body-fat percentage (p = 0.05), less lean body mass (p = 0.003), and less bone mineral content (p = 0.03), despite no difference in BMI between the esports and non-esports players. Conclusion As compared to non-esports players, collegiate esports players were significantly less active and had a higher body-fat percentage, with lower lean body mass and bone mineral content. The BMIs showed no difference between the 2 groups. Esports athletes displayed significantly less activity and poor body composition, which are all correlated with potential health issues and risk of injury. BMI did not capture this difference and should not be considered an accurate measure of health in competitive esports players.

Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD) are associated with hypermobility, musculoskeletal pain, a decreased bone mineral density (BMD) and gastrointestinal (GI) complications. The role of GI symptoms and diet in BMD has not been established in this population. The GI complications can lead to an energy deficit due to lack of essential macronutrients. The primary objective of this study was to determine the severity of GI symptoms compared to body composition and BMD in individuals with hEDS/HSD. The secondary objective is to examine GI symptoms on energy balance, body composition and strength.This study was IRB approved. Eighteen female participants (aged 28.2 ± 4.9; BMI 22.5 ± 4.9) with a diagnosis of hEDS or HSD and 18 female healthy control participants (aged 28.1 ± 3.8; BMI 22.8 ±3.9) signed consent to participate. Participants were matched by sex, age, and BMI. The Gastrointestinal Symptom Rating Scale (GSRS) was used to investigate severity of GI symptoms. Dual X-ray absorptiometry was used to determine body composition (body fat%, lean body mass (LBM). BMD was measured by Z- scores of both femurs and lumbar spine. Resting metabolic rate (RMR) was measured using indirect calorimetry and strength was determined using a hand grip dynamometer.All hEDS/HSD participants reported GI symptoms. There was no difference in body composition between hEDS/HSD and controls. Participants with hEDS/HSD had lower BMD both femoral z scores (p=0.02,0.004) and spine z scores (p= 0.04). There was no difference in caloric intake between groups; yet both groups demonstrated caloric deficits. Additionally, hEDS/HSD consumed less protein and more carbohydrates (p=0.03, p=0.03). There were no differences in grip strength.This study identified that pre-menopausal women with hEDS/HSD presented with significant GI complications and lower BMD than age matched controls. The GI complications and the reduced protein intake long-term may have a lasting impact on bone health. This study found that the GSRS identified and quantified GI symptoms in persons with hEDS/HSD. Future studies are needed for the longitudinal effects of a caloric/protein deficit in this population and to help guide future preventive and nutritional treatment approaches in individuals with hEDS/HSD.

Paired fins are a major innovation that evolved within the jawed vertebrate lineage after divergence from the living jawless vertebrates. Extinct jawless armored stem-gnathostomes exhibit a diversity of paired bodywall extensions, from skeletal processes to simple flaps. However, osteostracans (sister to jawed vertebrates) are interpreted to manifest the first true paired appendages in a pectoral position, with pelvic appendages evolving later in association with jaws. Here we show, based on articulated remains of Tujiaaspis vividus from the Silurian of China, that galeaspids (sister to osteostracans and jawed vertebrates) possessed three unpaired dorsal fins, an approximately symmetrical hypochordal tail and a pair of continuous, branchial to caudal ventro-lateral fins. The ventro-lateral fins compare to paired fin flaps in other stem-gnathostomes but specifically to the ventro-lateral ridges of cephalaspid osteostracans which also possess differentiated pectoral fins. The ventro-lateral fins as compatible with aspects of the fin-fold hypothesis for the origin of vertebrate paired appendages. Galeaspids manifest a precursor condition to osteostracans and jawed vertebrates where paired fins arose initially as continuous pectoral-pelvic lateral fins that our Computed Fluid Dynamic experiments demonstrate passively generate lift. Only later in the stem-lineage to osteostracans and jawed vertebrates did pectoral fins differentiate anteriorly. This was followed by restriction of the remaining field of fin competence to a pelvic position, facilitating active propulsion and steering.

Context Cattle and sheep emit methane, a potent greenhouse gas, as part of the fermentation process of feed digestion in their gut; however, the mechanisms explaining differences among animals in enteric methane production are not fully understood. Aim To investigate whether variation among animals in their ability to digest their test ration was associated with phenotypic and genetic variation in methane production. Methods The experiment used 135 Angus beef cattle measured for their phenotypic and genetic merit for methane production. The extent of digestion of the dry matter (DMD) in the test ration by individual cattle was determined using silica as a naturally present indigestible marker. Its concentration in feed consumed and faeces was determined using rapid portable X-ray fluorescence spectroscopy, from which DMD was calculated. Key results Higher daily methane-production rate (MPR), higher methane produced per unit of feed consumed (methane yield; MY) and higher methane produced than the predicted daily production (residual MPR; RMP) by animals was accompanied by higher DMD. Higher genetic merit for MPR was also accompanied by higher DMD, but DMD had no detectable association with genetic variation in the other two methane emission traits. The regression coefficients for change in MPR (g/day), MY (g/kg DMI), RMP (g/day) with change in DMD (%) were 2.6 ± 1.1 (s.e.; P

Structural color is poorly known in plants relative to animals. In fruits, only a handful of cases have been described, including in Viburnum tinus where the blue color results from a disordered multilayered reflector made of lipid droplets. Here, we examine the broader evolutionary context of fruit structural color across the genus Viburnum. We obtained fresh and herbarium fruit material from 30 Viburnum species spanning the phylogeny and used transmission electron microscopy, optical simulations, and ancestral state reconstruction to identify the presence/absence of photonic structures in each species, understand the mechanism producing structural color in newly identified species, relate the development of cell wall structure to reflectance in Viburnum dentatum, and describe the evolution of cell wall architecture across Viburnum. We identify at least two (possibly three) origins of blue fruit color in Viburnum in species which produce large photonic structures made of lipid droplets embedded in the cell wall and which reflect blue light. Examining the full spectrum of mechanisms producing color in pl, including structural color as well as pigments, will yield further insights into the diversity, ecology, and evolution of fruit color.

Objectives Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria (GNE variants) and infantile sialic acid storage disease/Salla disease (SLC17A5 variants). Traditionally, UFSA has been measured using specific single-plex methodology in relatively small cohorts of patients with clinical symptoms suggestive of these disorders. The use of multiplex tandem mass spectrometry urine screening (UMSMS) has meant that UFSA can be measured semi-quantitatively in a much larger cohort of patients being investigated for suspected metabolic disorders. We hypothesised that the neuraminidase of Streptococcus pneumoniae may release free sialic acid from endogenous sialylated glycoconjugates and result in increased UFSA levels. Methods We conducted a retrospective review of clinical records of patients who were identified as having S. pneumoniae infection and who also had UMSMS at the time of their acute infection. Results We identified three cases of increased UFSA detected by UMSMS screening that were secondary to S. pneumoniae sepsis. Additional testing ruled out genetic causes of increased UFSA in the first patient. All three patients had overwhelming sepsis with multiorgan dysfunction which was fatal. Glycosylation abnormalities consistent with the removal of sialic acid were demonstrated in serum transferrin patterns in one patient. Conclusions We have demonstrated in a retrospective cohort that elevation of UFSA levels have been observed in cases of S. pneumoniae sepsis. This expands our knowledge of UFSA as a biomarker in human disease. This research demonstrates that infection with organisms with neuraminidase activity should be considered in patients with unexplained increases in UFSA.

Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases—Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications—each associated with specific histological stages across the premalignant and malignant spectrum. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53—the ‘guardian of the genome’—is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours.

The early history of deuterostomes, the group composed of the chordates, echinoderms and hemichordates, is still controversial, not least because of a paucity of stem-representatives to these clades. The early Cambrian microscopic animal Saccorhytus coronarius was interpreted as an early deuterostome on the basis of purported pharyngeal openings, providing evidence for a meiofaunal ancestry and an explanation for the temporal mismatch between palaeontological and molecular clock timescales of animal evolution. Here we report new material of Saccorhytus coronarius, which is reconstructed as a millimetric and ellipsoidal meiobenthic animal with spinose armor and a terminal mouth but no anus. Purported pharyngeal openings in support of the deuterostome hypothesis are shown to be taphonomic artifacts. Phylogenetic analyses indicate that Saccorhytus coronarius belongs to total-group Ecdysozoa, expanding the morphological disparity and ecological diversity of early Cambrian ecdysozoans.

Organismal grade multicellularity has been achieved only in animals, plants, and fungi. All three kingdoms manifest phenotypically disparate body plans, but their evolution has only been considered in detail for animals. Here we test the general relevance of hypotheses on the evolutionary assembly of animal body plans by characterising the evolution of fungal phenotypic variety (disparity). The distribution of living fungal form is defined by four distinct morphotypes: flagellated, zygomycetous, sac-bearing, and club-bearing. The discontinuity between morphotypes is a consequence of extinction, indicating that a complete record of fungal disparity would present a more homogeneous distribution of form. Fungal disparity expands episodically through time, punctuated by a sharp increase associated with the emergence of multicellular body plans. Simulations show these temporal trends to be non-random and at least partially shaped by hierarchical contingency. These trends are decoupled from changes in gene number, genome size, and taxonomic diversity. Only differences in organismal complexity, characterised as the number of traits that constitute an organism, exhibit a meaningful relationship with fungal disparity. Both animals and fungi exhibit episodic increases in disparity through time, resulting in distributions of form made discontinuous by extinction. These congruences suggest a common mode of multicellular body plan evolution.

Background The extent to which gait and mobility measures predict falls relative to other risk factors is unclear. This study examined the predictive accuracy of over 70 baseline risk factors, including gait and mobility, for future falls and syncope using conditional inference forest models. Methods Data from 3 waves of The Irish Longitudinal Study on Ageing (TILDA), a population-based study of community-dwelling adults aged ≥50 years were used (n = 4 706). Outcome variables were recurrent falls, injurious falls, unexplained falls, and syncope occurring over 4-year follow-up. The predictive accuracy was calculated using 5-fold cross-validation; as there was a class imbalance, the algorithm was trained using undersampling of the larger class. Classification rate, the area under the receiver operating characteristic curve (AUROC), and area under the precision recall curve (PRAUC) assessed predictive accuracy. Results Highest overall accuracy was 69.7% for recurrent falls in 50–64-year olds. AUROC and PRAUC were ≤0.69 and ≤0.39, respectively, for all outcomes indicating low predictive accuracy. History of falls, unsteadiness while walking, fear of falling, mobility, medications, mental health, and cardiovascular health and function were the most important predictors for most outcomes. Conclusions Conditional inference forest models using over 70 risk factors resulted in low predictive accuracy for future recurrent, injurious and unexplained falls, and syncope in community-dwelling adults. Gait and mobility impairments were important predictors of most outcomes but did not discriminate well between fallers and non-fallers. Results highlight the importance of multifactorial risk assessment and intervention and validate key modifiable risk factors for future falls and syncope.

The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

Telemedicine has long been considered as an attractive alternative methodology in clinical genetics to improve patient access and convenience. Given the importance of the dysmorphology physical examination and anthropometric measurement in clinical genetics, many have wondered if lost information would hamper diagnosis. We previously addressed this question by analyzing thousands of diagnostic encounters in a single practice involving multiple practitioners and found no evidence for a difference in new molecular diagnosis rates. However, our previous study design resulted in variability in providers between in-person and telemedicine evaluation groups. To address this in our present study, we expanded our analysis to 1104 new patient evaluations seen by one highly experienced clinical geneticist across two 10-month periods before and after the start of the COVID-19 pandemic. Comparing patients seen in-person to those seen by telemedicine, we found significant differences in race and ethnicity, preferred language, and home zip code median income. The clinical geneticist intended to send more genetic testing for those patients seen by telemedicine, but due to issues with test authorization and sample collection, there was no difference in ultimate completion rate between groups. We found no significant difference in new molecular diagnosis rate. Overall, we find telemedicine to be an acceptable alternative to in-person evaluation for routine pediatric clinical genetics care.

To determine whether Empathy, Emotional Intelligence, and Burnout scores differ by specialty in incoming residents.This is a single-site, prospective, cross-sectional study. Three validated survey instruments, the Jefferson Scale of Physician Empathy, Maslach Burnout Inventory, and Emotional and Social Competency Inventory, were written into a survey platform as a single 125-question Qualtrics survey. Over three academic years, 2015-2017, 229 incoming residents across all specialties were emailed the survey link during orientation. Residents were grouped by incoming specialty with anonymity assured. A total of 229 responses were included, with 121 (52.8%) identifying as female. Statistical analysis was performed using the Analysis of Variance or Kruskal-Wallis test, Chi-Square or Fisher's Exact test, and Independent Samples t-test or Mann Whitney U test. A Bonferroni correction was applied for pairwise comparisons.Family Medicine had a higher median Jefferson Scale of Physician Empathy score (127) compared to Emergency Medicine (115), (U=767.7, p=0.0330). Maslach Burnout Inventory depersonalization and personal accomplishment subcategory scores showed a significant difference between specialties when omnibus tests were performed, but pairwise comparisons with emergency medicine residents showed no differences. Differences were found in the Maslach Burnout Inventory categories of Depersonalization (χDifferences in measures of well-being exist across specialties, even prior to the start of residency training. The implication for educators of residency training is that some incoming residents, regardless of specialty, already exhibit troublesome features of burnout, and resources to effectively deal with these residents should be developed and utilized.

On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease–associated RCC, ORR was 49% [95% confidence interval (CI), 36–62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41–81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52–98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.

To investigate the relationship between self-reported triggers and the occurrence of migraine attacks using a smartphone application.One of several issues around the study of migraine attack triggers is that limited available evidence supports whether self-reported triggers can induce a headache on a particular subject.This is an observational longitudinal cohort study of individuals with migraine registered to track their headaches prospectively using a smartphone application. For 90 days, participants entered daily data about triggers (potential triggers and premonitory symptoms) that may be associated with attack risk, as well as migraine symptoms. The statistical significance of univariate associations between each trigger and migraine recurrent events was determined for each individual. Statistically identified triggers were then compared to self-reported triggers.In 328 individuals (290/328 [88.4%] female; mean [standard deviation] 4.2 [1.5] migraine attacks/month) the mean (standard deviation) number of triggers moderately or highly endorsed per individual was 28.0 (7.7) in individuals presented with up to 38 possible triggers. Of these, an average (standard deviation) of 2.2 (2.1) triggers per individual were statistically associated with increased risk of attacks. Even the most commonly endorsed triggers (sleep quality, stress, tiredness/fatigue, sleep duration, dehydration, neck pain, missed meals, eyestrain, mean barometric pressure, and anxiety) were statistically associated in fewer than one third of individuals suspecting each, with the exception of neck pain (117/302 [38.7%]).Individuals with episodic migraine believe that many triggers contribute to their attacks; however, few of these withstand statistical testing at the individual level. Improved personal knowledge of potential triggers and premonitory symptoms may help individuals adopt behavioral changes to mitigate attack risk.

To describe and compare the systemic and ocular findings in two siblings with mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome), one treated with recombinant galsulfase, and one who was untreated.One female patient aged 33 years (case 1) who had received galsulfase enzyme replacement therapy for 11 years, and her younger male sibling by 3 years (case 2), who had declined systemic treatment, underwent clinical ophthalmic examination and retinal ocular coherence tomography. The female sibling underwent electrophysiology testing of visual function.Case 1 had best corrected visual acuity right 6/4.8 and left 6/6. Case 2 had best corrected visual acuity of 6/6 in each eye. Case 1 had bilateral mild corneal haze and a clinically unremarkable posterior segment examination. Case 2 had bilateral very mild corneal haze and retinal striae on examination. Ocular coherence tomography showed choroidal folds at the maculae in both patients, more pronounced in Case 2, who also had retinal folds and epiretinal membrane. Electroretinography showed very mild involvement of the rods only in Case 1.These two siblings with mucopolysaccharidosis type VI, one treated and one untreated, displayed variable levels of systemic, corneal, and chorioretinal involvement in their disease Further studies of choroidal changes in MPS VI may prove useful as a biomarker of ocular response to treatment outside the blood-retina barrier. Both patients have provided written consent to publish case details.

Sustained multisensory integration over long inter-stimulus time delays is typically found in older adults, particularly those with a history of falls. However, the extent to which the temporal precision of audio-visual integration is associated with longitudinal fall or fall risk trajectories is unknown. A large sample of older adults (N = 2319) were grouped into longitudinal trajectories of self-reported fall incidents (i.e., decrease, stable, or increase in number) and, separately, their performance on a standard, objective measure of fall risk, Timed Up and Go (TUG; stable, moderate decline, severe decline). Multisensory integration was measured once as susceptibility to the Sound-Induced Flash Illusion (SIFI) across three stimulus onset asynchronies (SOAs): 70 ms, 150 ms and 230 ms. Older adults with an increasing fall number showed a significantly different pattern of performance on the SIFI than non-fallers, depending on age: For adults with increasing incidents of falls, those aged 53–59 years showed a much smaller difference in illusion susceptibility at 70 ms versus 150 ms than those aged 70 + years. In contrast, non-fallers showed a more comparable difference between these SOA conditions across age groups. There was no association between TUG performance trajectories and SIFI susceptibility. These findings suggests that a fall event is associated with distinct temporal patterns of multisensory integration in ageing and have implications for our understanding of the mechanisms underpinning brain health in older age.

Background: The onset of COVID-19 coincided with the peak growth of video game usage with 2.7 billion gamers in 2020. During the pandemic, gaming and streaming platforms offered an entertaining, social, and safe alternative to recreation during severe lockdowns and social isolations. This study aimed to examine the impact of the COVID-19 pandemic on health-related outcomes in self-proclaimed video gamers based on the type of lockdown experienced, and to discuss the potential role of video games during times of preventive lockdown measures. Methods: This was a cross-sectional international survey constructed by two academic institutions NYIT (NY; USA); McGill University, (Montreal, Canada) and Adamas Esports (BC, Canada). The survey consisted of questions including demographics, multiple-choice, rating, and Likert scales relating to prior and during the COVID-19 lockdowns. Respondents included 897 replies from North America (72.7%), Europe (10.9%), Asia (4.9%) and other countries (11.5%) mean age 22 years. Results: Significant increases in game time were reported in casual and competitive gamers during the first months of the pandemic. Level of gaming, type of lockdown, and physical activity level prior to the pandemic were examined as potential moderating factors. Significant increases in sedentary behaviors (video game time and sitting time) were observed, while physical activity levels remained unchanged in most participants regardless of the type of lockdown. Sleep time, but not sleep quality, increased, while mental health exhibited opposing effects, influenced by the type of lockdown and gaming competition levels. Conclusions:Video games, when played moderately, could offer a cost-effective, safe strategy to promote socialization, mental health, and improve the overall well-being of the non-gaming and gaming population during pandemic times when strict lockdowns are in place.

The timing of early cellular evolution from the divergence of Archaea and Bacteria to the origin of eukaryotes remains poorly constrained. The ATP synthase complex is thought to have originated prior to the Last Universal Common Ancestor (LUCA) and analyses of ATP synthase genes, together with ribosomes, have played a key role in inferring and rooting the tree of life. Here we reconstruct the evolutionary history of ATP synthases using an expanded sampling of Archaea, Bacteria, and eukaryotes. We developed a phylogenetic cross-bracing approach making use of endosymbioses and ancient gene duplications of the major ATP synthase subunits to infer a highly resolved, dated species tree and establish an absolute timeline for ATP synthase evolution. Our analyses show that the divergence of the ATP synthase into F- and A/V-type lineages, was a very early event in cellular evolution dating back to more than 4Ga potentially predating the diversification of Archaea and Bacteria. Our cross-braced, dated tree of life also provides insight into more recent evolutionary transitions including eukaryogenesis, showing that the eukaryotic nuclear and mitochondrial lineages diverged from their closest archaeal (2.67-2.19Ga) and bacterial (2.58-2.12Ga) relatives at roughly the same time, with the nuclear stem being moderately longer.

Whole genome duplications (WGDs) are major events that drastically reshape genome architecture and are causally associated with organismal innovations and radiations1. The 2R Hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution2,3. However, the veracity and timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved4-6 and whether these WGD events underlie vertebrate phenotypic diversification remains elusive7. Here we present the genome of the inshore hagfish, Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and the 2R event occurred in the gnathostome stem-lineage in the late Cambrian after its divergence from cyclostomes. We find that the genome of stem-cyclostomes experienced two additional, independent genome duplications (herein CR1 and CR2). Functional genomic and morphospace analyses demonstrate that WGD events generally contribute to developmental evolution with similar changes in the regulatory genome of both vertebrate groups. However, appreciable morphological diversification occurred only after the 2R event, questioning the general expectation that WGDs lead to leaps of morphological complexity7.

Investigations of hippocampal functions have revealed a dizzying array of findings, from lesion-based behavioral deficits, to a diverse range of characterized neural activations, to computational models of putative functionality. Across these findings, there remains an ongoing debate about the core function of the hippocampus and the generality of its representation. Researchers have debated whether the hippocampus’s primary role relates to the representation of space, the neural basis of (episodic) memory, or some more-general computation that generalizes across various cognitive domains. Within these different perspectives, there is much debate about the nature of feature encodings. Here, we suggest that in order to evaluate hippocampal responses – investigating, for example, whether neuronal representations are narrowly targeted to particular tasks or if they subserve domain-general purposes – a promising research strategy may be the use of multi-task experiments, or more generally switching between multiple task contexts while recording from the same neurons in a given session. We argue that this strategy – when combined with explicitly defined theoretical motivations that guide experiment design – could be a fruitful approach to better understand how hippocampal representations support different behaviors. In doing so, we briefly review key open questions in the field, as exemplified by articles in this special issue, as well as previous work using multi-task experiments, and extrapolate to consider how this strategy could be further applied to probe fundamental questions about hippocampal function.

Supplementary Figures 1-7

Supplementary Figures S1 - S5

Supplementary Figure Legends 1-5 and Supplementary Table 1. Primer Sequences

Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre/posttransformation samples, supports that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm. We observed enhanced expression of genes involved in the PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacologic inhibition of the PI3K/AKT pathway delayed tumor growth and NE transformation in an EGFR-mutant patient-derived xenograft model. Our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.Significance:The difficulty in collection of transformation samples has precluded the performance of molecular analyses, and thus little is known about the lineage plasticity mechanisms leading to LUAD-to-SCLC transformation. Here, we describe biological pathways dysregulated upon transformation and identify potential predictors and potential therapeutic vulnerabilities of NE transformation in the lung.See related commentary by Meador and Lovly, p. 2962.This article is highlighted in the In This Issue feature, p. 2945

Supplemental figures and figure legends.

Supplementary Tables 1-4

Supplemental tables S1-S15