Monocyte NLRP3 inflammasome and interleukin-1ß activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

INTRODUCTION: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1ß secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. METHODS: Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1ß secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. RESULTS: C3d acting via CR3 induces NLRP3 and pro-IL-1ß production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1ß secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1ß (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. DISCUSSION: These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.

Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

The mobilization and transport of newly fixed carbon are driven by plant water use in an experimental rainforest under drought.

Non-structural carbohydrates (NSCs) are building blocks for biomass and fuel metabolic processes. However, it remains unclear how tropical forests mobilize, export, and transport NSCs to cope with extreme droughts. We combined drought manipulation and ecosystem 13CO2 pulse-labeling in an enclosed rainforest at Biosphere 2, assessed changes in NSCs, and traced newly assimilated carbohydrates in plant species with diverse hydraulic traits and canopy positions. We show that drought caused a depletion of leaf starch reserves and slowed export and transport of newly assimilated carbohydrates below ground. Drought effects were more pronounced in conservative canopy trees with limited supply of new photosynthates and relatively constant water status than in those with continual photosynthetic supply and deteriorated water status. We provide experimental evidence that local utilization, export, and transport of newly assimilated carbon are closely coupled with plant water use in canopy trees. We highlight that these processes are critical for understanding and predicting tree resistance and ecosystem fluxes in tropical forest under drought.

Bornean tropical forests recovering from logging at risk of regeneration failure.

Active restoration through silvicultural treatments (enrichment planting, cutting climbers and liberation thinning) is considered an important intervention in logged forests. However, its ability to enhance regeneration is key for long-term recovery of logged forests, which remains poorly understood, particularly for the production and survival of seedlings in subsequent generations. To understand the long-term impacts of logging and restoration we tracked the diversity, survival and traits of seedlings that germinated immediately after a mast fruiting in North Borneo in unlogged and logged forests 30-35 years after logging. We monitored 5119 seedlings from germination for ~1.5 years across a mixed landscape of unlogged forests (ULs), naturally regenerating logged forests (NR) and actively restored logged forests via rehabilitative silvicultural treatments (AR), 15-27 years after restoration. We measured 14 leaf, root and biomass allocation traits on 399 seedlings from 15 species. Soon after fruiting, UL and AR forests had higher seedling densities than NR forest, but survival was the lowest in AR forests in the first 6 months. Community composition differed among forest types; AR and NR forests had lower species richness and lower evenness than UL forests by 5-6 months post-mast but did not differ between them. Differences in community composition altered community-weighted mean trait values across forest types, with higher root biomass allocation in NR relative to UL forest. Traits influenced mortality ~3 months post-mast, with more acquisitive traits and relative aboveground investment favoured in AR forests relative to UL forests. Our findings of reduced seedling survival and diversity suggest long time lags in post-logging recruitment, particularly for some taxa. Active restoration of logged forests recovers initial seedling production, but elevated mortality in AR forests lowers the efficacy of active restoration to enhance recruitment or diversity of seedling communities. This suggests current active restoration practices may fail to overcome barriers to regeneration in logged forests, which may drive long-term changes in future forest plant communities.

A restauração ativa por meio de tratamentos silviculturais (plantio de enriquecimento, corte de trepadeiras e desbaste) é considerada uma intervenção importante em florestas com exploração de madeira. No entanto, sua capacidade de melhorar a regeneração, essencial para a recuperação de longo prazo das florestas exploradas, permanece pouco compreendida, especialmente no que diz respeito à produção e sobrevivência de mudas em gerações subsequentes. Para compreender os impactos de longo prazo da exploração madeireira e da restauração, acompanhamos a diversidade, sobrevivência e características de plântulas que germinaram imediatamente após uma frutificação em massa no norte de Bornéu, em florestas com e sem exploração de madeira, 30-35 anos após o fim da extração. Monitoramos 5119 mudas desde a germinação por aproximadamente 1,5 anos em uma paisagem mista de florestas não exploradas (UL), florestas exploradas em regeneração natural (NR) e florestas exploradas restauradas ativamente por meio de tratamentos silviculturais de reabilitação (AR), 15-27 anos após a restauração. Medimos 14 traços funcionais de folhas, raízes e alocação de biomassa em 399 mudas de 15 espécies. Logo após a frutificação, as florestas UL e AR apresentaram densidades de mudas mais altas do que as florestas NR, mas a sobrevivência foi mais baixa nas florestas AR nos primeiros seis meses. A composição da comunidade diferiu entre os tipos de floresta; as florestas AR e NR teviram menor riqueza de espécies e menor equidade do que as florestas UL 5-6 meses após a frutificação, mas não diferiram entre si. As diferenças na composição da comunidade alteraram os valores de média ponderada pela comunidade das características entre os tipos de floresta com maior alocação de biomassa radicular nas florestas NR em relação às florestas UL. As características influenciaram a mortalidade aproximadamente 3 meses após a frutificação, com traços mais aquisitivos maior investimento em biomassa relativa acima do solo nas florestas AR em relação às florestas UL. Nossas descobertas de redução na sobrevivência e diversidade de plântulas sugerem que há longos retardos no recrutamento após o fim da exploração de madeira, particularmente para alguns táxons. A restauração ativa de florestas exploradas recupera a produção inicial de plântulas, mas a mortalidade elevada nas florestas AR diminui a eficácia da restauração ativa no melhorio do recrutamento e da diversidade das comunidades de mudas. Isso sugere que as práticas atuais de restauração ativa podem não superar as barreiras à regeneração em florestas exploradas, o que pode levar a mudanças de longo prazo nas comunidades florestais no futuro.

Punctuated equilibrium at 50: Anything there for evolutionary anthropology? Yes; definitely.

The theory of punctuated equilibrium (PE) was developed a little over 50 years ago to explain long-term, large-scale appearance and disappearance of species in the fossil record. A theory designed specifically for that purpose cannot be expected, out of the box, to be directly applicable to biocultural evolution, but in revised form, PE offers a promising approach to incorporating not only a wealth of recent empirical research on genetic, linguistic, and technological evolution but also large databases that document human biological and cultural diversity across time and space. Here we isolate the fundamental components of PE and propose which pieces, when reassembled or renamed, can be highly useful in evolutionary anthropology, especially as humanity faces abrupt ecological challenges on an increasingly larger scale.

Global Run-On sequencing to measure nascent transcription in Saccharomyces cerevisiae.

Global Run-On sequencing is a reliable and widely used approach for monitoring nascent transcription on a genomewide scale. The assay has been successfully used for studying global transcription in humans, plants, worms, flies, and fission yeast. Here we describe a GRO-seq protocol for studying transcription in budding yeast, Saccharomyces cerevisiae. Briefly, the technique involves permeabilization of actively growing yeast cells, allowing transcription to proceed in permeabilized cells in the presence of brominated UTP, affinity purification of bromo-UMP incorporated nascent transcripts followed by cDNA library construction, deep sequencing, and mapping against the reference genome. The approach maps the position of transcriptionally active RNA polymerase on a genomewide basis. In addition to identifying the complete set of transcriptionally active genes in a cell under a given set of conditions, the method can be used to determine elongation rate, termination defect and promoter directionality at the genomewide level. The approach is especially useful in identifying short-lived unstable transcripts that are rapidly degraded even before they leave the nucleus.

Fixed dose ketamine for prehospital management of hyperactive delirium with severe agitation.

INTRODUCTION: Patients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA. METHODS: Emergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events. RESULTS: Review of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67-10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation. CONCLUSION: The 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors.

Vergence and accommodation deficits in paediatric and adolescent patients during sub-acute and chronic phases of concussion recovery.

INTRODUCTION: Visual function deficits have been reported in adolescents following concussion. We compared vergence and accommodation deficits in paediatric and adolescent patients at a tertiary medical centre in the sub-acute (15 days to 12 weeks) and chronic (12 weeks to 1 year) phases of concussion recovery. METHODS: The study included patients aged 7 to <18 years seen between 2014 and 2021, who had a binocular vision (BV) examination conducted within 15 days and 1 year of their concussion injury. Included patients had to have 0.10 logMAR monocular best-corrected vision or better in both eyes and be wearing a habitual refractive correction. BV examinations at near included measurements of near point of convergence, convergence and divergence amplitudes, vergence facility, monocular accommodative amplitude and monocular accommodative facility. Vergence and accommodation deficits were diagnosed using established clinical criteria. Group differences were assessed using nonparametric statistics and ANCOVA modelling. RESULTS: A total of 259 patients were included with 111 in the sub-acute phase and 148 in the chronic phase of concussion recovery. There was no significant difference in the rates of vergence deficits between the two phases of concussion recovery (sub-acute = 48.6%; chronic = 49.3%). There was also no significant difference in the rates of accommodation deficits between the two phases of concussion recovery (sub-acute = 82.0%; chronic = 77.0%). CONCLUSION: Patients in both the sub-acute and chronic phases of concussion recovery exhibited a high frequency of vergence and accommodation deficits, with no significant differences between groups. Results indicate that patients exhibiting vision deficits in the sub-acute phase may not resolve without intervention, though a prospective, longitudinal study is required to test the hypothesis.

An open repository of real-time COVID-19 indicators.

The COVID-19 pandemic presented enormous data challenges in the United States. Policy makers, epidemiological modelers, and health researchers all require up-to-date data on the pandemic and relevant public behavior, ideally at fine spatial and temporal resolution. The COVIDcast API is our attempt to fill this need: Operational since April 2020, it provides open access to both traditional public health surveillance signals (cases, deaths, and hospitalizations) and many auxiliary indicators of COVID-19 activity, such as signals extracted from deidentified medical claims data, massive online surveys, cell phone mobility data, and internet search trends. These are available at a fine geographic resolution (mostly at the county level) and are updated daily. The COVIDcast API also tracks all revisions to historical data, allowing modelers to account for the frequent revisions and backfill that are common for many public health data sources. All of the data are available in a common format through the API and accompanying R and Python software packages. This paper describes the data sources and signals, and provides examples demonstrating that the auxiliary signals in the COVIDcast API present information relevant to tracking COVID activity, augmenting traditional public health reporting and empowering research and decision-making.

Medial Ulnar Collateral Ligament Reconstruction With Allograft Provides Excellent Clinical Outcomes, High Rates of Return to Play, and a Low Incidence of Postoperative Complications: A Systematic Review.

PURPOSE: To perform a systematic review evaluating clinical outcomes in patients undergoing medial ulnar collateral ligament reconstruction (MUCLR) with soft-tissue allograft. METHODS: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcomes evaluated were patient-reported outcome scores, return to play (RTP) rates, incidence of postoperative complications, and rates of graft rupture or mechanical failure. RESULTS: The literature search identified 395 articles, and 5 studies met final inclusion criteria after full-text review. A total of 274 patients were analyzed in the included studies and follow-up ranged from 3.0 to 7.6 years. Two studies (number of patients = 141) reported outcomes exclusively of MUCLR with allograft, whereas 3 studies (number of patients = 133) reported outcomes in patients undergoing MUCLR with either allograft or autograft. Allograft sources included gracilis, semitendinosus, plantaris, peroneus longus, and palmaris longus. Level of patient athletic competition ranged from recreational athletes to the professional level; however, nonathletes in the setting of trauma were also included. The RTP rate after MUCLR with soft-tissue allograft was 95.3%, and 89.3% of patients returned to a similar or greater level of play postoperatively. The Timmerman-Andrews score was reported in 2 studies, and the means postoperatively ranged from 94.55 to 97. Postoperative complication rates were low (range, 0% to 20%), and there were no reported incidences of allograft rupture or mechanical failure. CONCLUSIONS: Based on the available data, soft-tissue allograft for MUCLR in athletic patient populations provides excellent clinical outcomes, high rates of RTP, and low rates of postoperative complications and graft failure at short-term follow-up. There remains a lack of high-quality evidence directly comparing autograft versus allograft outcomes in elite overhead-throwing athletes to support allograft as an acceptable alternative for MUCLR in this patient population. LEVEL OF EVIDENCE: Level IV, systematic review of Level III-IV studies.

Prevalence of thiamine deficiency in anorexia nervosa: a systematic review and narrative synthesis.

Thiamine is an essential vitamin that plays a crucial role in many biochemical processes in the body. Anorexia nervosa (AN) is one potential cause of a state of deficiency which can result in grave medical sequelae. There is limited available evidence of the prevalence of thiamine deficiency in patients who suffer from AN. The current study aimed to systematically review all available evidence on the prevalence of thiamine deficiency in cohorts with AN. Studies were included where thiamine status in a group of participants with AN was measured, either through self-reporting or objective measurement. Eight databases (Scopus, CINAHL complete, Medline complete, EMBASE, WEB OF SCIENCE, PROSPERO, COCHRANE DATABASE OF SYSTEMATIC REVIEWS and Cochrane Central Register of Controlled Trials (CENTRAL) were searched. PRISMA guidelines were followed. The study was registered on PROSPERO. A minimum of two researchers conducted each part of the review. The search identified 42 articles whose full texts were screened for eligibility, with 17 retained for qualitative synthesis. The prevalence rates of thiamine deficiency in AN varied from 5.9% to 100% when based on self-report dietary intake. When objective measurements were taken, rates ranged from 0% to 56.7%. The review suggested that age, body mass index (BMI), duration of illness and subtype of AN were not associated with thiamine status. The limited available evidence suggested that the use of supplements, prior treatment and higher energy intakes were associated with a reduced risk of developing a thiamine deficiency among individuals with AN. Poor study methodology including small sample size, inconsistent deficiency definition and study heterogeneity limits the conclusions that can be drawn. Ultimately, there is insufficient strength of evidence to draw definitive clinical recommendations. This review highlights the need for further studies with more robust methodology to help further inform clinical practice.

Impact of comorbidities on immediate post-operative complications in oral cavity free flap patients.

PURPOSE: To examine the relationship between comorbidities and the development of immediate post-operative complications in patients undergoing oral cavity composite resection (OCCR) with free flap (FF) reconstruction. MATERIALS AND METHODS: Retrospective analysis was completed on all consecutive OCCRs with FF reconstruction performed at a single quaternary care facility between 1999 and 2020. Comorbidities, immediate post-operative complications, patient demographics, and tumor characteristics were collected. Odds ratios (OR) with 95 % confidence intervals were calculated for associations between comorbidities and immediate post-operative complications. RESULTS: 320 patients who underwent OCCR with FF reconstruction were included. One hundred twenty-one (37.8 %) patients developed a post-operative complication during their initial hospital admission. The most common complications were non-pneumonia cardiopulmonary events (14.1 %), pneumonia (9.4 %), and wound infection (8.4 %). Other complications included flap compromise, bleeding, and fistula. On multivariate analysis, patients without comorbid conditions were less likely to develop a post-operative complication (OR 0.64; 0.41-0.98). Atrial fibrillation (OR 2.94; 1.17-7.39) and cerebrovascular disease (OR 2.28; 1.08-4.84) were associated with increased odds of developing any complications. Furthermore, cerebrovascular disease (OR: 2.33; 1.04-5.39) and peripheral vascular disease (OR: 2.7; 1.2-6.08) were independently associated with pneumonia. CONCLUSION: In this retrospective review of patients undergoing OCCR with FF reconstruction for oral cavity SCC, lack of identifiable comorbidities appeared to be protective for post-operative complications while atrial fibrillation and cerebrovascular disease were associated with increased odds of any complication. Pre-existing vascular disease was also associated with an increased risk of pneumonia.

Medial elbow injuries in the throwing athlete.

There has been an epidemic increase in injuries to the elbow in our youth sports over the past 15 years. Initially, career-ending elbow injuries occurred almost exclusively in the professional population. The landmark procedure developed by Dr. Frank Jobe, colloquially termed "Tommy John surgery" after the initial player in whom he performed the surgical procedure, allowed roughly two-thirds of professional athletes to return to play at or near the same level. As the surgical procedure became more widespread, modifications of the technique by Jobe and many other contributors raised the return-to-play level to 85%-94% of players regaining the ability to return to sport at the preinjury level. Almost simultaneously, the emphasis on velocity in the professional ranks led to an unintentional increase in stress on the throwing elbow. This was magnified in our athletes by the advent of year-round sports, as well as the formation of "showcase" events to demonstrate skills and measure velocity. This, unfortunately, has resulted in an increase in both repetitive stress injuries and acute traumatic injuries in our young athletes. The purpose of this article is to discuss age-related injuries from both a preventative standpoint and a treatment standpoint.

TFIIB-Termination Factor Interaction Affects Termination of Transcription on Genome-Wide Scale.

Apart from its well-established role in the initiation of transcription, the general transcription factor TFIIB has been implicated in the termination step as well. The ubiquity of TFIIB involvement in termination as well as mechanistic details of its termination function, however, remain largely unexplored. Using GRO-seq analyses, we compared the terminator readthrough phenotype in the sua7-1 mutant (TFIIBsua7-1) and the isogenic wild type (TFIIBWT) strains. Approximately 74% of genes analyzed exhibited a 2-3-fold increase in readthrough of the poly(A)-termination signal in the TFIIBsua7-1 mutant compared to TFIIBWT cells. To understand the mechanistic basis of TFIIB's role in termination, we performed the mass spectrometry of TFIIB-affinity purified from chromatin and soluble cellular fractions-from TFIIBsua7-1 and TFIIBWT cells. TFIIB purified from the chromatin fraction of TFIIBWT cells exhibited significant enrichment of CF1A and Rat1 termination complexes. There was, however, a drastic decrease in TFIIB interaction with CF1A and Rat1 complexes in the TFIIBsua7-1 mutant. ChIP assays revealed about a 90% decline in the recruitment of termination factors in the TFIIBsua7-1 mutant compared to wild type cells. The overall conclusion of these results is that TFIIB affects the termination of transcription on a genome-wide scale, and the TFIIB-termination factor interaction plays a crucial role in the process.

Rebound Phenomenon After Nirmatrelvir/Ritonavir Treatment of Coronavirus Disease 2019 (COVID-19) in High-Risk Persons.

In a cohort of 483 high-risk patients treated with nirmatrelvir/ritonavir for COVID-19, 2 patients (0.4%) required hospitalization by day 30. Four patients (0.8%) experienced rebound of symptoms, which were generally mild, at a median of 9 days after treatment, and all resolved without additional COVID-19-directed therapy.

CT pectoralis muscle area is associated with DXA lean mass and correlates with emphysema progression in a tobacco-exposed cohort.

INTRODUCTION: Muscle loss is an important extrapulmonary manifestation of COPD. Dual energy X-ray absorptiometry (DXA) is the method of choice for body composition measurement but is not widely used for muscle mass evaluation. The pectoralis muscle area (PMA) is quantifiable by CT and predicts cross-sectional COPD-related morbidity. There are no studies that compare PMA with DXA measures or that evaluate longitudinal relationships between PMA and lung disease progression. METHODS: Participants from our longitudinal tobacco-exposed cohort had baseline and 6-year chest CT (n=259) and DXA (n=164) data. Emphysema was quantified by CT density histogram parenchymal scoring using the 15th percentile technique. Fat-free mass index (FFMI) and appendicular skeletal mass index (ASMI) were calculated from DXA measurements. Linear regression model relationships were reported using standardised coefficient (ß) with 95% CI. RESULTS: PMA was more strongly associated with DXA measures than with body mass index (BMI) in both cross-sectional (FFMI: ß=0.76 (95% CI 0.65 to 0.86), p<0.001; ASMI: ß=0.76 (95% CI 0.66 to 0.86), p<0.001; BMI: ß=0.36 (95% CI 0.25 to 0.47), p<0.001) and longitudinal (ΔFFMI: ß=0.43 (95% CI 0.28 to 0.57), p<0.001; ΔASMI: ß=0.42 (95% CI 0.27 to 0.57), p<0.001; ΔBMI: ß=0.34 (95% CI 0.22 to 0.46), p<0.001) models. Six-year change in PMA was associated with 6-year change in emphysema (ß=0.39 (95% CI 0.23 to 0.56), p<0.001) but not with 6-year change in airflow obstruction. CONCLUSIONS: PMA is an accessible measure of muscle mass and may serve as a useful clinical surrogate for assessing skeletal muscle loss in smokers. Decreased PMA correlated with emphysema progression but not lung function decline, suggesting a difference in the pathophysiology driving emphysema, airflow obstruction and comorbidity risk.

Gender-Sexuality Alliance meeting experiences predict weekly variation in hope among LGBTQ+ youth.

Hope is considered a marker of resilience among youth facing oppression, including LGBTQ+ youth. This 8-week weekly diary study among 94 LGBTQ+ youth (ages 14-19; Mage  = 15.91, 46% youth of color, 44% transgender or nonbinary) in 2021 considered whether a youth's meeting-to-meeting experiences in Gender-Sexuality Alliances (GSAs; LGBTQ+ affirming school clubs) predicted subsequent hope from week to week. Youth reported greater hope on days following meetings where they felt more group support, greater advisor responsiveness, and had taken on more leadership responsibilities. Group support and advisor responsiveness were stronger predictors of a youth's hope on days closer to GSA meetings; leadership's effect was stronger when more days had elapsed. Findings suggest how GSAs may cultivate hope among LGBTQ+ youth.

Gymnastics and concussions: A retrospective chart review.

OBJECTIVE: The purpose of this study was to investigate the clinical presentation (using PCSS), mechanism of injury, and recovery time of concussions sustained by gymnasts. METHODS: A retrospective chart review was performed at Boston Children's Hospital: Sports Medicine Clinic. Patients were identified with the words 'gymnastics' and 'concussion.' Male and female gymnasts were included if they sustained a concussion during gymnastics training or competition and were between the ages of 6-22 years old. Sex, age, injury site, diagnosis, mechanism of injury, and time to presentation are described. Patients were compared during different types of gymnastics events for overall symptom burden, and individual symptom severities. RESULTS: A total of 201 charts were assessed over a 6-year period and 62 patients met inclusion criteria. Floor exercise was the most common event at the time of injury. Loss of consciousness occurred in 20% of injuries. There was no significant association between the type of event and PCSS upon initial clinical visit (p = 0.82). A total of 13 gymnasts returned to the clinic for a subsequent injury after their concussion (Table 3). CONCLUSIONS: Gymnasts are at risk for sport-related concussions. Most gymnasts reporting to a tertiary care center with the diagnosis of concussion sustain their injuries during floor exercise.

How do the top 10 known offending drug classes associated with decreased bone mineral density affect total shoulder arthroplasty outcomes?

BACKGROUND: Many regularly prescribed classes of drugs are known to negatively impact bone health. However, it is unclear if perioperative use of these drugs impacts total shoulder arthroplasty (TSA) outcomes. The purpose of this study was to analyze the impact of perioperative use of 10 drug classes with known negative effects on bone health on prosthesis-related outcomes of TSA. METHODS: Patients who underwent primary TSA were retrospectively identified in the PearlDiver database. Within this population, patients prescribed proton pump inhibitors (PPIs), thiazolidinediones (TZDs), loop diuretics, glucocorticoids, aromatase inhibitors, calcineurin inhibitors, selective serotonin reuptake inhibitors (SSRIs), antiepileptic drugs (AEDs), first-generation antipsychotics (FGAs), and second-generation antipsychotics (SGAs) within 6 months before or 6 months after primary TSA were identified (n = 23,748). These patients were propensity score matched 1:1 with controls (n = 23,748) on age, sex, and several comorbidities. After matching, patients with perioperative drug exposure were divided into 10 subgroups (ie, 1 for each drug class). Rates of prosthesis-related complications among patients taking each medication class vs. controls were compared with multivariable logistic regression. RESULTS: Relative to controls, SGA exposure was associated with significantly higher rates of all-cause revision (odds ratio [OR] 1.68) and aseptic revision (OR 1.57). Loop diuretic exposure was associated with significantly higher rates of all-cause revision (OR 1.44) and aseptic revision (OR 1.43). Glucocorticoid exposure was associated with significantly higher rates of all-cause revision (OR 1.32) and aseptic revision (OR 1.30). SSRI exposure was associated with significantly higher rates of all-cause revision (OR 1.27) and aseptic revision (OR 1.24). Periprosthetic fracture, aseptic loosening, and septic revision was comparable for all drug cohorts compared to matched controls (all P > .05). Patients with perioperative exposure to PPIs, TZDs, FGAs, AEDs, aromatase inhibitors, and calcineurin inhibitors displayed comparable rates of all queried complications compared with controls (all P > .05). CONCLUSION: Compared with matched controls, patients with perioperative exposure to SGAs, loop diuretics, glucocorticoids and SSRIs exhibited significantly higher rates of all-cause and aseptic revisions following primary TSA. Several other medications that are risk factors for osteoporosis and fragility fractures did not demonstrate significant associations with any complications, including periprosthetic fracture. These results highlight the need for a thorough review of patients' medical history and current medication usage prior to preoperative risk counseling for patients seeking TSA.