Hybrid immunity and SARS-CoV-2 antibodies: results of the HEROES-RECOVER prospective cohort study.

BACKGROUND: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. METHODS: Exposures included event-count (sum of infections and vaccine doses) and event-order, categorized into seven permutations of vaccination and/or infection. Outcome was level of serum binding antibodies against receptor binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding Ig), measured by enzyme-linked immunosorbent assay. Mean antibody levels were examined up to 365 days after each of the 1st-7th events. RESULTS: Analysis included 5,793 participants measured from August 7, 2020 to April 15, 2023. Hybrid immunity from infection before one or two vaccine doses elicited modestly superior antibody responses after the 2nd and 3rd events (compared to infections or vaccine-doses alone). This superiority was not evident after the 4th and 5th events (additional doses). Among adults infected before vaccination, adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (0.81-0.94), and 0.99 (0.85-1.15) after the 2nd-5th events, respectively. Post-vaccination infections elicited superior responses: adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were: 0.93 (0.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the 2nd-5th events, respectively. CONCLUSIONS AND RELEVANCE: Findings reflecting heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines.

BACKGROUND: Information is limited regarding the effectiveness of the two-dose messenger RNA (mRNA) vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in attenuating coronavirus disease 2019 (Covid-19) when administered in real-world conditions. METHODS: We conducted a prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers. From December 14, 2020, to April 10, 2021, the participants completed weekly SARS-CoV-2 testing by providing mid-turbinate nasal swabs for qualitative and quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) analysis. The formula for calculating vaccine effectiveness was 100% × (1 - hazard ratio for SARS-CoV-2 infection in vaccinated vs. unvaccinated participants), with adjustments for the propensity to be vaccinated, study site, occupation, and local viral circulation. RESULTS: SARS-CoV-2 was detected in 204 participants (5%), of whom 5 were fully vaccinated (≥14 days after dose 2), 11 partially vaccinated (≥14 days after dose 1 and <14 days after dose 2), and 156 unvaccinated; the 32 participants with indeterminate vaccination status (<14 days after dose 1) were excluded. Adjusted vaccine effectiveness was 91% (95% confidence interval [CI], 76 to 97) with full vaccination and 81% (95% CI, 64 to 90) with partial vaccination. Among participants with SARS-CoV-2 infection, the mean viral RNA load was 40% lower (95% CI, 16 to 57) in partially or fully vaccinated participants than in unvaccinated participants. In addition, the risk of febrile symptoms was 58% lower (relative risk, 0.42; 95% CI, 0.18 to 0.98) and the duration of illness was shorter, with 2.3 fewer days spent sick in bed (95% CI, 0.8 to 3.7). CONCLUSIONS: Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infection when administered in real-world conditions, and the vaccines attenuated the viral RNA load, risk of febrile symptoms, and duration of illness among those who had breakthrough infection despite vaccination. (Funded by the National Center for Immunization and Respiratory Diseases and the Centers for Disease Control and Prevention.).

Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study.

BACKGROUND: Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset. METHODS: Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls. Correlations and subgroup analyses within the SCA cohorts were undertaken based on disease duration and ataxia severity. RESULTS: Individuals in the ataxic stage of SCA1, SCA2 and SCA3, relative to non-ataxic controls, had significantly reduced CSA and increased eccentricity at all examined levels. CSA showed large effect sizes (d>2.0) and correlated with ataxia severity (r<-0.43) and disease duration (r<-0.21). Eccentricity correlated only with ataxia severity in SCA2 (r=0.28). No significant spinal cord differences were evident in SCA6. In preataxic individuals, CSA was significantly reduced in SCA2 (d=1.6) and SCA3 (d=1.7), and the SCA2 group also showed increased eccentricity (d=1.1) relative to nonataxic controls. Subgroup analyses confirmed that CSA and eccentricity are abnormal in early disease stages in SCA1, SCA2 and SCA3. CSA declined with disease progression in all, whereas eccentricity progressed only in SCA2. CONCLUSIONS: Spinal cord abnormalities are an early and progressive feature of SCA1, SCA2 and SCA3, but not SCA6, which can be captured using quantitative MRI.

Prevalence and Diagnostic Journey of Friedreich's Ataxia in the State of São Paulo, Brazil.

Friedreich's Ataxia (FRDA) is the leading cause of ataxia worldwide, but data on epidemiology and diagnostic journey are scarce, particularly in Latin America. Herein we estimated the prevalence of FRDA in the most populous Brazilian state and characterized the diagnostic odyssey of the disease. We received anonymized data of patients with FRDA from advocacy groups and physicians. Prevalence was estimated dividing the number of patients by the population of the state as reported in the last census. Patients were invited to answer an online survey to describe clinical data and diagnostic journey of the disease. FRDA estimated prevalence was 0.367:100,000, with a slight predominance of women (58.2% vs 41.7%). One hundred and four patients answered the survey (mean age of 37.3 ± 13.8 years; 75.9% classical and 24.0% late onset). On average, 6.2 ± 4.1 physicians were visited before reaching the diagnosis. Mean diagnostic delay was 7.8 ± 6.7 years; no difference between classical and LOFA groups was found. Most of the patients reported unsteadiness and gait abnormalities as the first symptom. Neurologists and orthopedical surgeons were the main specialties first sought by patients. We found a prevalence of 0.36:100,000 for FRDA in the state of São Paulo, Brazil. The disease is characterized by remarkable diagnostic delay, with no relevant differences between classical and LOFA patients.

Factors influencing the health-related quality of life of older men and women living with HIV in Spain.

The number of older people living with HIV (OPLHIV) is increasing worldwide. However, little is known about the factors that better predict their health-related quality of life (HRQoL). We administered the validated WHOQoL-HIV BREF questionnaire to 247 Spanish OPLHIV (192 men and 55 women). In addition to the six domains of the questionnaire, we constructed a seventh domain as theaverage of punctuations of all domains. Multivariable Poisson regression models with robust estimates by sex were constructed for the seven domains (14 in total). The best-subset selection method together with Mallow's Cp metric was used to select the model factors. The percentage of variability explained by Poisson models ranged from15-38% for men and 29-70% for women. The analysis showed that women were most affected by ageing (four domains), mobility impairments (five domains), and mental disorders (five domains). The factors with the greatest negative influence on men were heterosexuality (six domains), mental disorders (six domains), being single (five domains), and poverty risk (three domains). Physical activity was found to improve HRQoL in both men (six domains) and women (four domains). Future OPLHIV programmes would benefit from considering sex specific HRQoL factors. This could also improve the cost-effectiveness of interventions.

Mandibular advancement devices decrease systolic pressure during the day and night in patients with obstructive sleep apnea: A systematic review and meta-analysis.

The aim of this systematic review and meta-analysis was to analyze whether or not mandibular advancement devices (MADs) produce changes in blood pressure in patients with obstructive sleep apnea (OSA) in relation to use time and if the device is used at night or day. MATERIALS AND METHOD: A systematic review of the literature and meta-analysis was carried out in accordance with PRISMA guidelines. In the bibliographic search, a total of four databases were consulted: PubMed-Medline, Scopus, Web of Science, and Cochrane. Of the 622 articles initially revealed, 160 duplicates were eliminated. After applying the selection criteria, 17 articles were included for the qualitative analysis and 4 for the meta-analysis. The studies were combined using a random effects model with the inverse method of variance, determining the mean differences in systolic and diastolic pressure before and after treatment using the MAD splint as the effect size. Day/night circadian effect and treatment time were analyzed using meta-regression with a mixed-effects model. RESULTS: MAD treatment was not found to affect diastolic pressure. By combining the four studies with the control group in a meta-analysis (I2 = 75%; z = - 0.15; p-value = 0.882), the mean difference in diastolic pressure between the MAD group and the control group was estimated at - 0.06 (- 0.86; 0.74). The meta-regression also showed no significant effect of day/night (p = 0.560) or treatment time (p = 0.854) on diastolic pressure. When combining the four studies with the control group (I2 = 84%%; z = - 1.47; p-value = 0.142), a non-significant mean difference in systolic pressure between the MAD group and the control group of - 0.99 (- 2.31; 0.33) was estimated in the meta-analysis. However, when assessing the effect of day/night or treatment time on systolic blood pressure using a meta-regression, the latter showed significant covariates that reduce systolic blood pressure values in the model at night (p < 0.001) and in relation to treatment time (p < 0.001). CONCLUSIONS: Only systolic pressure appears to be affected by the use of the MAD in patients with OSA, and this decrease in systolic pressure is greater at night and when treatment time is longer.

Epidural angioleiomyoma: an extraordinary cause of compressive myelopathy-MRI findings with histopathological correlation.

BACKGROUND: Angioleiomyomas are benign mesenchymal tumors usually located in the limbs, with anecdotal reports in the spine. We present an atypical case of an epidural spine angioleiomyoma presenting with compressive myelopathy symptoms. The diagnosis was suggested based on MRI findings, and subsequently confirmed histopathologically. RESULTS: This is the first known occurrence of pure spinal epidural angioleiomyoma as a source of compressive myelopathy. The imaging presentation, especially the 'dark reticular sign' on MRI, was crucial in suggesting the diagnosis despite the atypical location CONCLUSION: This report serves to raise awareness among clinicians and radiologists about including angioleiomyoma in differential diagnoses for spinal epidural lesions with indicative MRI features. The favorable outcome after surgical intervention underscores the necessity of swift and accurate diagnosis followed by appropriate treatment for such uncommon spinal tumors.

Prevalence and predictors of colon and prostate cancer screening among volunteer firefighters: The United States Firefighter Cancer Assessment and Prevention Study.

BACKGROUND: Although firefighters have increased risk for colon and prostate cancer, limited information exists on screening practices for these cancers in volunteer firefighters who compose two-thirds of the US fire service. We estimated the prevalence of colon and prostate cancer screening among volunteer firefighters using eligibility criteria from 4 evidence-based screening recommendations and evaluated factors influencing screening. METHODS: We evaluated colon (n = 569) and prostate (n = 498) cancer screening prevalence in a sample of US volunteer firefighters using eligibility criteria from the US Preventive Services Taskforce (USPSTF), National Fire Protection Association, American Cancer Society, and National Comprehensive Cancer Network. We assessed associations with fire service experience, demographics, and cancer risk perception based on USPSTF guidelines. RESULTS: For those eligible based on USPSTF guidelines, colon and prostate cancer screening prevalence was 51.7% (95% CI: 45.7, 57.8) and 48.8% (95% CI: 40.0, 57.6), respectively. Higher odds of colon and prostate cancer screening were observed with older age and with some college education compared to those with less education. Fire service experience and cancer risk perception were not associated with screening practices. CONCLUSION: This is the first large study to assess colon and prostate cancer screening among US volunteer firefighters based on different screening guidelines. Our findings suggest gaps in cancer prevention efforts in the US volunteer fire service. Promoting cancer screening education and opportunities for volunteer firefighters by their fire departments, healthcare professionals, and public health practitioners, may help to address the gaps.

Characterization of fire investigators' polyaromatic hydrocarbon exposures using silicone wristbands.

BACKGROUND: Exposures to polyaromatic hydrocarbons (PAHs) contribute to cancer in the fire service. Fire investigators are involved in evaluations of post-fire scenes. In the US, it is estimated that there are up to 9000 fire investigators, compared to approximately 1.1 million total firefighting personnel. This exploratory study contributes initial evidence of PAH exposures sustained by this understudied group using worn silicone passive samplers. OBJECTIVES: Evaluate PAH exposures sustained by fire investigators at post-fire scenes using worn silicone passive samplers. Assess explanatory factors and health risks of PAH exposure at post-fire scenes. METHODS: As part of a cross-sectional study design, silicone wristbands were distributed to 16 North Carolina fire investigators, including eight public, seven private, and one public and private. Wristbands were worn during 46 post-fire scene investigations. Fire investigators completed pre- and post-surveys providing sociodemographic, occupational, and post-fire scene characteristics. Solvent extracts from wristbands were analyzed via gas chromatography-mass spectrometry (GC-MS). Results were used to estimate vapor-phase PAH concentration in the air at post-fire scenes. RESULTS: Fire investigations lasted an average of 148 minutes, standard deviation ± 93 minutes. A significant positive correlation (r=0.455, p<.001) was found between investigation duration and PAH concentrations on wristbands. Significantly greater time-normalized PAH exposures (p=0.039) were observed for investigations of newer post-fire scenes compared to older post-fire scenes. Regulatory airborne PAH exposure limits were exceeded in six investigations, based on exposure to estimated vapor-phase PAH concentrations in the air at post-fire scenes. DISCUSSION: Higher levels of off-gassing and suspended particulates at younger post-fire scenes may explain greater PAH exposure. Weaker correlations are found between wristband PAH concentration and investigation duration at older post-fire scenes, suggesting reduction of off-gassing PAHs over time. Exceedances of regulatory PAH limits indicate a need for protection against vapor-phase contaminants, especially at more recent post-fire scenes.

Collaborative online international learning in physiology: a case study.

Internationalization in higher education is essential, and although active learning methodologies are increasing and allow students to develop transversal skills, most still have a very local scope. In this context, the Collaborative Online International Learning (COIL) methodology is an interesting approach to benefit the students' development. It consists of an online program that involves creating multicultural teams to develop a specific learning project. Although this methodology is expanding, its use in physiology is still scarce. This paper aims to show an example of applying COIL methodology in physiology topics to enhance higher-education students' innovation and business skills. Our example project developed a sports-assessment service concept focused on physiology and biomechanics assessments. The program involved teams from Brazil, Germany, and Spain, comprising undergraduate and master students. Over 7 weeks, these teams, mentored by professors and researchers, engaged in workshops covering COIL methodology, business model design, executive summary planning, economic analyses, and communication techniques. Key outcomes included learning new concepts, developing soft skills, building confidence in innovative solution proposals, and experiencing diverse cultures. Challenges faced were language barriers, scheduling, task complexity, and logistical issues. This experience confirms the effectiveness of incorporating programs using COIL methodology into educational curriculums. Doing so exposes physiology students to innovation, entrepreneurship, and business creation while strengthening their professional connections and opening up postgraduation opportunities.NEW & NOTEWORTHY Although the Collaborative Online International Learning (COIL) methodology is expanding, its use in physiology is still scarce. Our example COIL project of 7 weeks developed a sports-assessment service concept focused on physiology and biomechanics assessments. The program involved teams from Brazil, Germany, and Spain, comprising undergraduate and master's students. Students perceived extracurricular activities in this format as beneficial. Coaches also expressed positive views about such initiatives, noting benefits for students and their development.

Effectiveness of Bivalent mRNA COVID-19 Vaccines in Preventing SARS-CoV-2 Infection in Children and Adolescents Aged 5 to 17 Years.

Importance: Bivalent mRNA COVID-19 vaccines were recommended in the US for children and adolescents aged 12 years or older on September 1, 2022, and for children aged 5 to 11 years on October 12, 2022; however, data demonstrating the effectiveness of bivalent COVID-19 vaccines are limited. Objective: To assess the effectiveness of bivalent COVID-19 vaccines against SARS-CoV-2 infection and symptomatic COVID-19 among children and adolescents. Design, Setting, and Participants: Data for the period September 4, 2022, to January 31, 2023, were combined from 3 prospective US cohort studies (6 sites total) and used to estimate COVID-19 vaccine effectiveness among children and adolescents aged 5 to 17 years. A total of 2959 participants completed periodic surveys (demographics, household characteristics, chronic medical conditions, and COVID-19 symptoms) and submitted weekly self-collected nasal swabs (irrespective of symptoms); participants submitted additional nasal swabs at the onset of any symptoms. Exposure: Vaccination status was captured from the periodic surveys and supplemented with data from state immunization information systems and electronic medical records. Main Outcome and Measures: Respiratory swabs were tested for the presence of the SARS-CoV-2 virus using reverse transcriptase-polymerase chain reaction. SARS-CoV-2 infection was defined as a positive test regardless of symptoms. Symptomatic COVID-19 was defined as a positive test and 2 or more COVID-19 symptoms within 7 days of specimen collection. Cox proportional hazards models were used to estimate hazard ratios for SARS-CoV-2 infection and symptomatic COVID-19 among participants who received a bivalent COVID-19 vaccine dose vs participants who received no vaccine or monovalent vaccine doses only. Models were adjusted for age, sex, race, ethnicity, underlying health conditions, prior SARS-CoV-2 infection status, geographic site, proportion of circulating variants by site, and local virus prevalence. Results: Of the 2959 participants (47.8% were female; median age, 10.6 years [IQR, 8.0-13.2 years]; 64.6% were non-Hispanic White) included in this analysis, 25.4% received a bivalent COVID-19 vaccine dose. During the study period, 426 participants (14.4%) had laboratory-confirmed SARS-CoV-2 infection. Among these 426 participants, 184 (43.2%) had symptomatic COVID-19, 383 (89.9%) were not vaccinated or had received only monovalent COVID-19 vaccine doses (1.38 SARS-CoV-2 infections per 1000 person-days), and 43 (10.1%) had received a bivalent COVID-19 vaccine dose (0.84 SARS-CoV-2 infections per 1000 person-days). Bivalent vaccine effectiveness against SARS-CoV-2 infection was 54.0% (95% CI, 36.6%-69.1%) and vaccine effectiveness against symptomatic COVID-19 was 49.4% (95% CI, 22.2%-70.7%). The median observation time after vaccination was 276 days (IQR, 142-350 days) for participants who received only monovalent COVID-19 vaccine doses vs 50 days (IQR, 27-74 days) for those who received a bivalent COVID-19 vaccine dose. Conclusion and Relevance: The bivalent COVID-19 vaccines protected children and adolescents against SARS-CoV-2 infection and symptomatic COVID-19. These data demonstrate the benefit of COVID-19 vaccine in children and adolescents. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations.

Impact of graft reperfusion on cardiac function assessed by transesophageal echocardiography during liver transplantation: an observational retrospective study.

Cardiovascular instability is common during the reperfusion phase of orthotopic liver transplantation (OLT), and some patients experience a postreperfusion syndrome (PRS). However, there are no reports comparing the cardiac dysfunction between patients with PRS and those without. Thus, the aim of this study was to evaluate cardiac dysfunction in patients exhibiting PRS. This observational retrospective study included 34 patients who underwent OLT and were monitored with transesophageal echocardiography (TEE). The right ventricular/left ventricular (RV/LV) end diastolic area, tricuspid annular plane systolic excursion (TAPSE), left ventricular ejection fraction (LVEF) by Simpson method, pulsed Doppler of the mitral valve, and tissue Doppler motion of the mitral annulus were determined. Echocardiographic measurements were registered at the beginning of surgery and at 1 and 30 min after vascular unclamping. Patients with PRS (PRS group) were identified, and their echocardiographic parameters of ventricular function were compared with those in patients without PRS (non-PRS group). To check the evolution of diastolic-systolic dysfunction, general linear model-repeated measures were estimated. No patient presented systolic/diastolic dysfunction on the basal echocardiogram. One minute after vascular unclamping, the incidence of RV dilation was 4.5 times greater in patients with PRS (Cramer´s V > 0.6), and the incidence of RV systolic dysfunction was 62.5% in patients with PRS compared to 15.40% in patients without PRS (Cramer´s V = 0.45). The incidence of LV systolic dysfunction was 25% in patients with PRS compared to 0% in those without (Cramer´s V = 0.45), and left ventricular diastolic dysfunction was 4.8 times greater in patients with PRS (Cramer´s V = 0.45). No patient presented diastolic dysfunction type III. There were significant differences between groups in the evolutionary pattern at 1 and 30 min after unclamping for RV dilation (p = 0.008) and for TAPSE (p = 0.014). Liver graft reperfusion may alter cardiac function. Cardiac dysfunction was more frequent in patients with PRS. These patients exhibited temporary dysfunction of the RV associated with a varying degree of LV diastolic-systolic dysfunction. Trial registration: clinicaltrials.gov (NCT05175534). January 03, 2022; "retrospectively registered".

Derived neutrophil-to-lymphocyte ratio (dNLR) as a diagnostic biomarker of pediatric acute appendicitis.

Appendicitis stands as the most common surgical emergency in pediatric populations. Despite the existence of numerous diagnostic biomarkers, their utility is constrained by limitations in cost-effectiveness, potentially leading to therapeutic delays. This research aims to determine the diagnostic accuracy of the derived neutrophil-to-lymphocyte ratio (dNLR) in appendicitis. Although its role in this context has been recently described, this is the first study to compare its performance against acute-phase reactants routinely employed in clinical practice. Following approval from the Research Committee (2023/390894), a diagnostic study was conducted including patients under 15 years old undergoing surgery for acute appendicitis (AA) and those presenting with non-surgical abdominal pain (AP).

Alternative Models for Pelvic Marker Occlusion in Cycling.

Bike fitting aims to optimize riders' positions to improve their performance and reduce the risk of injury. To calculate joint angles, the location of the joint centers of the lower limbs needs to be identified. However, one of the greatest difficulties is the location of the hip joint center due to the frequent occlusion of the anterior superior iliac spine markers. Therefore, the objective of this study was to validate a biomechanical model adapted to cycling (modified pelvic model, MPM), based on the traditional pelvic model (TPM) with an additional lateral technical marker placed on the iliac crests. MPM was also compared with a widely used model in cycling, trochanter model (TM). Thirty-one recreational cyclists pedaled on a roller bike while the movement was captured with a 7-camera VICON system. The position of the hip joint center and knee angle were calculated and compared with the TPM continuously (along 10 pedaling cycles) and discreetly at 90° and 180° crank positions. No significant differences were found in the position of the hip joint center or in the knee flexion/extension angle between the TPM and the MPM. However, there are differences between TPM and TM (variations between 4.1° and 6.9° in favor of the TM at 90° and 180°; P < .001). Bland-Altman graphs comparing the models show an average difference or bias close to 0° (limits of agreement [0.2 to -8.5]) between TPM and MPM in both lower limbs and a mean difference of between -4° and -7° (limits of agreement [-0.6 to -13.2]) when comparing TPM and TM. Given the results, the new cycling pelvic model has proven to be valid compared with the TPM when performing bike fitting studies, with the advantage that the occluded markers are avoided. Despite its simplicity, the TM presents measurement errors that may be relevant when making diagnoses, which makes its usefulness questionable.

Muscle glycogen unavailability and fat oxidation rate during exercise: Insights from McArdle disease.

Carbohydrate availability affects fat metabolism during exercise; however, the effects of complete muscle glycogen unavailability on maximal fat oxidation (MFO) rate remain unknown. Our purpose was to examine the MFO rate in patients with McArdle disease, comprising an inherited condition caused by complete blockade of muscle glycogen metabolism, compared to healthy controls. Nine patients (three women, aged 36 ± 12 years) and 12 healthy controls (four women, aged 40 ± 13 years) were studied. Several molecular markers of lipid transport/metabolism were also determined in skeletal muscle (gastrocnemius) and white adipose tissue of McArdle (Pygm p.50R*/p.50R*) and wild-type male mice. Peak oxygen uptake ( V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ ), MFO rate, the exercise intensity eliciting MFO rate (FATmax) and the MFO rate-associated workload were determined by indirect calorimetry during an incremental cycle-ergometer test. Despite having a much lower V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ (24.7 ± 4 vs. 42.5 ± 11.4 mL kg-1  min-1 , respectively; P < 0.0001), patients showed considerably higher values for the MFO rate (0.53 ± 0.12 vs. 0.33 ± 0.10 g min-1 , P = 0.001), and for the FATmax (94.4 ± 7.2 vs. 41.3 ± 9.1 % of V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ , P < 0.0001) and MFO rate-associated workload (1.33 ± 0.35 vs. 0.81 ± 0.54 W kg-1 , P = 0.020) than controls. No between-group differences were found overall in molecular markers of lipid transport/metabolism in mice. In summary, patients with McArdle disease show an exceptionally high MFO rate, which they attained at near-maximal exercise capacity. Pending more mechanistic explanations, these findings support the influence of glycogen availability on MFO rate and suggest that these patients develop a unique fat oxidation capacity, possibly as an adaptation to compensate for the inherited blockade in glycogen metabolism, and point to MFO rate as a potential limiting factor of exercise tolerance in this disease. KEY POINTS: Physically active McArdle patients show an exceptional fat oxidation capacity. Maximal fat oxidation rate occurs near-maximal exercise capacity in these patients. McArdle patients' exercise tolerance might rely on maximal fat oxidation rate capacity. Hyperpnoea might cloud substrate oxidation measurements in some patients. An animal model revealed overall no higher molecular markers of lipid transport/metabolism.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection History and Antibody Response to 3 Coronavirus Disease 2019 Messenger RNA Vaccine Doses.

BACKGROUND: Data on antibody kinetics are limited among individuals previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From a cohort of healthcare personnel and other frontline workers in 6 US states, we assessed antibody waning after messenger RNA (mRNA) dose 2 and response to dose 3 according to SARS-CoV-2 infection history. METHODS: Participants submitted sera every 3 months, after SARS-CoV-2 infection, and after each mRNA vaccine dose. Sera were tested for antibodies and reported as area under the serial dilution curve (AUC). Changes in AUC values over time were compared using a linear mixed model. RESULTS: Analysis included 388 participants who received dose 3 by November 2021. There were 3 comparison groups: vaccine only with no known prior SARS-CoV-2 infection (n = 224); infection prior to dose 1 (n = 123); and infection after dose 2 and before dose 3 (n = 41). The interval from dose 2 and dose 3 was approximately 8 months. After dose 3, antibody levels rose 2.5-fold (95% confidence interval [CI] = 2.2-3.0) in group 2 and 2.9-fold (95% CI = 2.6-3.3) in group 1. Those infected within 90 days before dose 3 (and median 233 days [interquartile range, 213-246] after dose 2) did not increase significantly after dose 3. CONCLUSIONS: A third dose of mRNA vaccine typically elicited a robust humoral immune response among those with primary vaccination regardless of SARS-CoV-2 infection >3 months prior to boosting. Those with infection <3 months prior to boosting did not have a significant increase in antibody concentrations in response to a booster.

Risk Factors for Reinfection with SARS-CoV-2 Omicron Variant among Previously Infected Frontline Workers.

In a cohort of essential workers in the United States previously infected with SARS-CoV-2, risk factors for reinfection included being unvaccinated, infrequent mask use, time since first infection, and being non-Hispanic Black. Protecting workers from reinfection requires a multipronged approach including up-to-date vaccination, mask use as recommended, and reduction in underlying health disparities.

A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide.

BACKGROUND: There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). METHODS: We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. RESULTS: Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. CONCLUSIONS: TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia.

BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. CONCLUSIONS: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A qualitative analysis of female patient perspectives on physician communication regarding sexual dysfunction associated with pelvic radiotherapy.

BACKGROUND: Sexual dysfunction is a known side effect of pelvic radiotherapy, resulting from a complex intersection of physiologic and psychosocial factors. Maintaining sexual function is relevant to long-term quality of life and is an important aspect of survivorship. Many female patients report being insufficiently informed before treatment about the potential sexual side effects of radiation therapy. AIM: To elucidate how radiation oncologists communicate sexual function side effects with their female patients and how discussing sexual side effects of cancer treatment can positively affect patient-physician rapport. METHODS: Semistructured interviews in English and Spanish were conducted with 20 female participants who received pelvic radiation as part of their cancer treatment. Patients responded to advertisements or were referred by physicians. All interviews were conducted virtually between June and October 2021. Thematic analysis was conducted with NVivo. Patients also completed an online demographics survey in REDCap. OUTCOMES: We found 4 primary themes addressing patient perspectives on patient-physician communication of sexual dysfunction and how it affected the cancer care experience. RESULTS: Theme 1: This may be expected, but I didn't expect it! The participants who were not properly informed about sexual side effects felt blindsided and embarrassed about their symptoms. Theme 2: I do not feel like a woman anymore . . . The psychological impact included lower self-esteem and no longer feeling sexy nor like a woman. Theme 3: Fine, I'll deal with this myself! Patients turned to the internet rather than their doctors for answers once they began experiencing symptoms, and they found information, normalization, and community online. Theme 4: Ask me about my sex life and find out if sex is a priority for me. Participants emphasized that their radiation oncologist should take a sexual history early to monitor sexual dysfunction and to identify individual patient priorities surrounding sex posttreatment. CLINICAL IMPLICATIONS: This evidence provides a guide to patient-physician communication that may help to mitigate the impacts of radiotherapy on female sexual function as well as the negative impact that the absence of communication about sexual dysfunction may have on patient-physician trust. STRENGTHS AND LIMITATIONS: While this project did have a small sample size, there is considerable diversity in race, education level, and age, with interviews conducted in Spanish and English. CONCLUSION: Overall these findings provide physicians with important information about the unmet information needs of patients and their preferences for how to help them feel more prepared and less distressed when sexual dysfunction occurs.