Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are ...limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.
Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease ...biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10−14). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.
In a cluster-randomized trial involving resident physicians working in pediatric ICUs, resident physicians were randomly assigned to schedules that included shifts of 24 hours or more or to schedules ...with shifts of 16 hours or less. Contrary to the authors’ hypothesis, resident physicians made fewer serious medical errors when they followed the extended schedule.
Neutralizing antibody responses gradually wane against several variants of concern (VOCs) after vaccination with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine messenger ...RNA-1273 (mRNA-1273). We evaluated the immune responses in nonhuman primates that received a primary vaccination series of mRNA-1273 and were boosted about 6 months later with either homologous mRNA-1273 or heterologous mRNA-1273.β, which encompasses the spike sequence of the B.1.351 Beta variant. After boost, animals had increased neutralizing antibody responses across all VOCs, which was sustained for at least 8 weeks after boost. Nine weeks after boost, animals were challenged with the SARS-CoV-2 Beta variant. Viral replication was low to undetectable in bronchoalveolar lavage and significantly reduced in nasal swabs in all boosted animals, suggesting that booster vaccinations may be required to sustain immunity and protection.
Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 μg of the mRNA-1273 ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs after SARS-CoV-2 challenge in vaccinated animals and most strongly correlated with levels of anti–S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway. Passive transfer of mRNA-1273–induced immunoglobulin G to naïve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine–induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs.
Athletes are increasingly required to travel domestically and internationally, often resulting in travel fatigue and jet lag. Despite considerable agreement that travel fatigue and jet lag can be a ...real and impactful issue for athletes regarding performance and risk of illness and injury, evidence on optimal assessment and management is lacking. Therefore 26 researchers and/or clinicians with knowledge in travel fatigue, jet lag and sleep in the sports setting, formed an expert panel to formalise a review and consensus document. This manuscript includes definitions of terminology commonly used in the field of circadian physiology, outlines basic information on the human circadian system and how it is affected by time-givers, discusses the causes and consequences of travel fatigue and jet lag, and provides consensus on recommendations for managing travel fatigue and jet lag in athletes. The lack of evidence restricts the strength of recommendations that are possible but the consensus group identified the fundamental principles and interventions to consider for both the assessment and management of travel fatigue and jet lag. These are summarised in travel toolboxes including strategies for pre-flight, during flight and post-flight. The consensus group also outlined specific steps to advance theory and practice in these areas.
We compared resident physician work hours and sleep in a multicenter clustered-randomized crossover clinical trial that randomized resident physicians to an Extended Duration Work Roster (EDWR) with ...extended-duration (≥24 hr) shifts or a Rapidly Cycling Work Roster (RCWR), in which scheduled shift lengths were limited to 16 or fewer consecutive hours.
Three hundred two resident physicians were enrolled and completed 370 1 month pediatric intensive care unit rotations in six US academic medical centers. Sleep was objectively estimated with wrist-worn actigraphs. Work hours and subjective sleep data were collected via daily electronic diary.
Resident physicians worked fewer total hours per week during the RCWR compared with the EDWR (61.9 ± 4.8 versus 68.4 ± 7.4, respectively; p < 0.0001). During the RCWR, 73% of work hours occurred within shifts of ≤16 consecutive hours. In contrast, during the EDWR, 38% of work hours occurred on shifts of ≤16 consecutive hours. Resident physicians obtained significantly more sleep per week on the RCWR (52.9 ± 6.0 hr) compared with the EDWR (49.1 ± 5.8 hr, p < 0.0001). The percentage of 24 hr intervals with less than 4 hr of actigraphically measured sleep was 9% on the RCWR and 25% on the EDWR (p < 0.0001).
RCWRs were effective in reducing weekly work hours and the occurrence of >16 consecutive hour shifts, and improving sleep duration of resident physicians. Although inclusion of the six operational healthcare sites increases the generalizability of these findings, there was heterogeneity in schedule implementation. Additional research is needed to optimize scheduling practices allowing for sufficient sleep prior to all work shifts.Clinical Trial: Multicenter Clinical Trial of Limiting Resident Work Hours on ICU Patient Safety (ROSTERS), https://clinicaltrials.gov/ct2/show/NCT02134847.
Extended-duration work rosters (EDWRs) with shifts of 24+ hours impair performance compared with rapid cycling work rosters (RCWRs) that limit shifts to 16 hours in postgraduate year (PGY) 1 ...resident-physicians. We examined the impact of a RCWR on PGY 2 and PGY 3 resident-physicians.
Data from 294 resident-physicians were analyzed from a multicenter clinical trial of 6 US PICUs. Resident-physicians worked 4-week EDWRs with shifts of 24+ hours every third or fourth shift, or an RCWR in which most shifts were ≤16 consecutive hours. Participants completed a daily sleep and work log and the 10-minute Psychomotor Vigilance Task and Karolinska Sleepiness Scale 2 to 5 times per shift approximately once per week as operational demands allowed.
Overall, the mean (± SE) number of attentional failures was significantly higher (
=.01) on the EDWR (6.8 ± 1.0) compared with RCWR (2.9 ± 0.7). Reaction time and subjective alertness were also significantly higher, by ∼18% and ∼9%, respectively (both
<.0001). These differences were sustained across the 4-week rotation. Moreover, attentional failures were associated with resident-physician-related serious medical errors (SMEs) (
=.04). Although a higher rate of SMEs was observed under the RCWR, after adjusting for workload, RCWR had a protective effect on the rate of SMEs (rate ratio 0.48 95% confidence interval: 0.30-0.77).
Performance impairment due to EDWR is improved by limiting shift duration. These data and their correlation with SME rates highlight the impairment of neurobehavioral performance due to extended-duration shifts and have important implications for patient safety.
B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence ...protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log
reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log
reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.
BACKGROUND
Blunt traumatic abdominal wall hernias (TAWH) occur in approximately 15,000 patients per year. Limited data are available to guide the timing of surgical intervention or the feasibility of ...nonoperative management.
METHODS
A retrospective study of patients presenting with blunt TAWH from January 2012 through December 2018 was conducted. Patient demographic, surgical, and outcomes data were collected from 20 institutions through the Western Trauma Association Multicenter Trials Committee.
RESULTS
Two hundred and eighty-one patients with TAWH were identified. One hundred and seventy-six (62.6%) patients underwent operative hernia repair, and 105 (37.4%) patients underwent nonoperative management. Of those undergoing surgical intervention, 157 (89.3%) were repaired during the index hospitalization, and 19 (10.7%) underwent delayed repair. Bowel injury was identified in 95 (33.8%) patients with the majority occurring with rectus and flank hernias (82.1%) as compared with lumbar hernias (15.8%). Overall hernia recurrence rate was 12.0% (n = 21). Nonoperative patients had a higher Injury Severity Score (24.4 vs. 19.4,
p
= 0.010), head Abbreviated Injury Scale score (1.1 vs. 0.6,
p
= 0.006), and mortality rate (11.4% vs. 4.0%,
p
= 0.031). Patients who underwent late repair had lower rates of primary fascial repair (46.4% vs. 77.1%,
p
= 0.012) and higher rates of mesh use (78.9% vs. 32.5%,
p
< 0.001). Recurrence rate was not statistically different between the late and early repair groups (15.8% vs. 11.5%,
p
= 0.869).
CONCLUSION
This report is the largest series and first multicenter study to investigate TAWHs. Bowel injury was identified in over 30% of TAWH cases indicating a significant need for immediate laparotomy. In other cases, operative management may be deferred in specific patients with other life-threatening injuries, or in stable patients with concern for bowel injury. Hernia recurrence was not different between the late and early repair groups.
LEVEL OF EVIDENCE
Therapeutic/care management, Level IV.
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