Discrimination of cell-intrinsic and environment-dependent effects of natural genetic variation on Kupffer cell epigenomes and transcriptomes.

Noncoding genetic variation drives phenotypic diversity, but underlying mechanisms and affected cell types are incompletely understood. Here, investigation of effects of natural genetic variation on the epigenomes and transcriptomes of Kupffer cells derived from inbred mouse strains identified strain-specific environmental factors influencing Kupffer cell phenotypes, including leptin signaling in Kupffer cells from a steatohepatitis-resistant strain. Cell-autonomous and non-cell-autonomous effects of genetic variation were resolved by analysis of F1 hybrid mice and cells engrafted into an immunodeficient host. During homeostasis, non-cell-autonomous trans effects of genetic variation dominated control of Kupffer cells, while strain-specific responses to acute lipopolysaccharide injection were dominated by actions of cis-acting effects modifying response elements for lineage-determining and signal-dependent transcription factors. These findings demonstrate that epigenetic landscapes report on trans effects of genetic variation and serve as a resource for deeper analyses into genetic control of transcription in Kupffer cells and macrophages in vitro.

Human microglia maturation is underpinned by specific gene regulatory networks.

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes.

Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis.

Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.

Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity.

Tissue environment plays a powerful role in establishing and maintaining the distinct phenotypes of resident macrophages, but the underlying molecular mechanisms remain poorly understood. Here, we characterized transcriptomic and epigenetic changes in repopulating liver macrophages following acute Kupffer cell depletion as a means to infer signaling pathways and transcription factors that promote Kupffer cell differentiation. We obtained evidence that combinatorial interactions of the Notch ligand DLL4 and transforming growth factor-b (TGF-ß) family ligands produced by sinusoidal endothelial cells and endogenous LXR ligands were required for the induction and maintenance of Kupffer cell identity. DLL4 regulation of the Notch transcriptional effector RBPJ activated poised enhancers to rapidly induce LXRα and other Kupffer cell lineage-determining factors. These factors in turn reprogrammed the repopulating liver macrophage enhancer landscape to converge on that of the original resident Kupffer cells. Collectively, these findings provide a framework for understanding how macrophage progenitor cells acquire tissue-specific phenotypes.

Predicting Knee Joint Contact Forces During Normal Walking Using Kinematic Inputs With a Long-Short Term Neural Network.

Knee joint contact forces are commonly estimated via surrogate measures (i.e., external knee adduction moments or musculoskeletal modeling). Despite its capabilities, modeling is not optimal for clinicians or persons with limited experience. The purpose of this study was to design a novel prediction method for knee joint contact forces that is simplistic in terms of required inputs. This study included marker trajectories and instrumented knee forces during normal walking from the "Grand Challenge" (n = 6) and "CAMS" (n = 2) datasets. Inverse kinematics were used to derive stance phase hip (sagittal, frontal, transverse), knee (sagittal, frontal), ankle (sagittal), and trunk (frontal) kinematics. A long-short term memory network (LSTM) was created using matlab to predict medial and lateral knee force waveforms using combinations of the kinematics. The Grand Challenge and CAMS datasets trained and tested the network, respectively. Musculoskeletal modeling forces were derived using static optimization and joint reaction tools in OpenSim. Waveform accuracy was determined as the proportion of variance and root-mean-square error between network predictions and in vivo data. The LSTM network was highly accurate for medial forces (R2 = 0.77, RMSE = 0.27 BW) and required only frontal hip and knee and sagittal hip and ankle kinematics. Modeled medial force predictions were excellent (R2 = 0.77, RMSE = 0.33 BW). Lateral force predictions were poor for both methods (LSTM R2 = 0.18, RMSE = 0.08 BW; modeling R2 = 0.21, RMSE = 0.54 BW). The designed LSTM network outperformed most reports of musculoskeletal modeling, including those reached in this study, revealing knee joint forces can accurately be predicted by using only kinematic input variables.

Dose-Response Effect of an Inertia Flywheel Postactivation Performance Enhancement Protocol on Countermovement Jump Performance.

The purpose of this study was to investigate the dose-response effect of a high-load, 6-repetition, maximum effort inertial flywheel (IFw) squat postactivation performance enhancement (PAPE) protocol on countermovement jump (CMJ) performance metrics. Thirteen subjects completed 5 squat testing sessions: 1 session to determine back-squat 6-repetition maximum, 1 session to determine 6-repetition maximum IFw load, and 3 sessions to investigate the dose-response effect of an IFw PAPE protocol set at the load determined in the second session. In the IFw PAPE sessions, subjects completed either 1, 2, or 3 sets of IFw squats, then performed 5 CMJs over 12 minutes (1, 3, 6, 9, and 12 min post-IFw). All CMJ tests were conducted on a force platform where CMJ performance outcomes and impulse variables were calculated. There was no main time or volume effect for jump height, contact time, reactive strength index, peak force, or any of the impulse variables. A main time effect was identified for flight time (P = .006, effect size = 0.24) and peak power (P = .001, effect size = 0.28). The lack of change in jump height may indicate that too much fatigue was generated following this near-maximal IFw squat protocol, thereby reducing the PAPE effect.

Evaluation of the Value of the Y-Balance Test to Predict Lower Limb Injuries in Professional Male Footballers.

CONTEXT: The aim of this prospective cohort study was to identify whether Y-Balance Test (YBT) performance and asymmetry are associated with lower limb injury in elite adult football athletes. DESIGN: A prospective cohort study. METHODS: Preseason YBT measures were obtained from 121 male footballers participating in National League One across the 2021-2022 season. Lower limb injuries were tracked across the season to determine the relationship between YBT variables and injury incidence using logistic regression analysis. The statistical significance level was .05. RESULTS: The average YBT score was 111.0 (5.8) cm on the left limb and 112.0 (5.5) cm on the right limb, with an average asymmetry of 2.3 (1.4) cm. Athletes with lower YBT scores on both the left (odds ratio = 2.9; 95% confidence interval, 1.7 to 4.8: P ≤ .001) and right (odds ratio = 2.3; 95% confidence interval, 1.6 to 3.2: P ≤ .001) limbs were at a greater risk of injury. Similarly, athletes with greater amounts of asymmetry were also more likely to get injured (odds ratio = 2.1; 95% confidence interval, 1.3 to 3.3: P = .002). CONCLUSIONS: Results indicate that lower and asymmetrical YBT scores have a significant relationship with future lower limb injuries in professional male footballers. The YBT offers a simple, reliable, and effective screening tool that can be used by practitioners in football to help identify players at a greater risk of injury before the season commences.

Oxygen uptake and heart rate responses to 4 weeks of RPE-guided handcycle training.

PURPOSE: To investigate the efficacy of using Ratings of Perceived Exertion (RPE) to prescribe and regulate a 4-week handcycle training intervention. METHODS: Thirty active adults, untrained in upper body endurance exercise, were divided into three groups to complete a 4-week intervention: (i) RPE-guided training (n = 10; 2 female), (ii) power output (PO)-guided (n = 10; 2 female) training, or (iii) non-training control (n = 10; 4 female). Training groups performed three sessions of handcycling each week. Oxygen uptake ([Formula: see text]), heart rate (HR), and Feeling Scale (FS) rating were collected during training sessions. RPE-guided training was performed at RPE 13. PO-guided training was matched for percentage of peak PO per session, based upon that achieved by the RPE-guided training group. RESULTS: There were no differences in percentage of peak [Formula: see text] (66 ± 13% vs 61 ± 9%, p = 0.22), peak HR (75 ± 8% vs 71 ± 6%, p = 0.11) or FS rating (1.2 ± 1.9 vs 0.8 ± 1.6, p = 0.48) between RPE- and PO-guided training, respectively. The average coefficient of variation in percentage of peak HR between consecutive training sessions was 2.8% during RPE-guided training, and 3.4% during PO-guided training. CONCLUSION: Moderate-vigorous intensity handcycling exercise can be prescribed effectively using RPE across a chronic training intervention, suggesting utility for practitioners in a variety of rehabilitation settings.

A Comparison of Squat Depth and Sex on Knee Kinematics and Muscle Activation.

The squat is an essential exercise for strengthening lower body musculature. Although squats are frequently employed to improve lower extremity strength and neuromuscular control, differences between sexes and slight modifications, such as squat depth, can dramatically alter muscle recruitment and thus the foci of the exercise. The purpose of this study was to assess the effect of sex and squat depth on lower extremity coactivation and kinematics. Twenty recreationally active (female = 10) participants were recruited. The first visit consisted of one repetition maximum testing. For the second visit, muscle activation was recorded of the gluteus maximus (GM), semitendinosus, biceps femoris (BF), vastus medialis, vastus lateralis, rectus femoris, and gastrocnemius. Reflective markers were placed on the lower body for three-dimensional motion capture. Participants performed a series of squats to 90 deg knee flexion and 120 deg knee flexion. Benjamin-Hochberg procedure was employed and the alpha level was set at 0.05. Knee flexion (p < 0.001), adduction (p < 0.001), and external rotation (p = 0.008) were reduced during 90 deg compared to deep squats. Hip flexion, abduction, and external rotation were greater in deep squats (p < 0.001). Males had greater hip extensor to quad (HE:Q) cocontraction in 90 deg compared to deep squats (p = 0.007); females produced greater posterior chain activation in deep squats (p = 0.001) on ascent. When comparing sexes, males displayed greater HE:Q in the 90 deg squat during ascent (p = 0.013). The addition of deep squats into a preventative training program could be beneficial in reducing deficits prevalent in females and decrease injury incidence.

Effect of Aging on Movement Quality in Australian Urban Firefighters.

ABSTRACT: Redshaw, AS, Carrick-Ranson, G, Bennett, H, Norton, KI, and Walker, A. Effect of aging on movement quality in Australian urban firefighters. J Strength Cond Res 37(11): e601-e608, 2023-Adequate levels of movement quality (MQ) are required to safely perform occupational tasks in physically demanding and hazardous professions such as firefighting. Although it is well established that MQ deteriorates with age in population studies, there is conflicting evidence in older tactical populations. This study sought to examine the relationship between age and MQ in Australian urban firefighters. The impact of physical activity, injury history, and body mass index on MQ were also explored. The MQ of 324 professional Australian urban firefighters was assessed using MovementSCREEN MQ assessment tool. Scores of whole-body MQ ranged from 35.3 to 82.6 (0-100 scale), with a mean score of 59.2 ± 10.0. There was a moderate, negative association between MQ and age (r = -0.500; p ≤ 0.001), with those older than 50 years of age having significantly lower scores of MQ than their younger counterparts (p ≤ 0.001). Secondary analysis found that higher body mass index (r = -0.285; p ≤ 0.001), lower habitual physical activity levels (r = 0.165; p ≤ 0.003), and the presence of any musculoskeletal injury in the previous 12 months (p = 0.016) had significant negative effects on composite MQ. Firefighters older than 50, obese, and engaging in low levels of physical activity should be considered a high priority for functional strength training interventions to maintain adequate MQ throughout their careers.

The effect of exercise on left ventricular global longitudinal strain.

Exercise improves measures of cardiovascular (CV) health and function. But as traditional measures improve gradually, it can be difficult to identify the effectiveness of an exercise intervention in the short-term. Left ventricular global longitudinal strain (LVGLS) is a highly sensitive CV imaging measure that detects signs of myocardial dysfunction prior to more traditional measures, with reductions in LVGLS a strong prognostic indicator of future CV dysfunction and mortality. Due to its sensitivity, LVGLS may offer useful method of tracking the effectiveness of an exercise intervention on CV function in the short-term, providing practitioners useful information to improve patient care in exercise settings. However, the effect of exercise on LVGLS is unclear. This systematic review and meta-analysis aimed to determine the effect exercise has on LVGLS across a range of populations. Included studies assessed LVGLS pre-post an exercise intervention (minimum 2 weeks) in adults 18 years and over, and were published in English from 2000 onwards. Study-level random-effects meta-analyses were performed using Stata (v16.1) to calculate summary standardized mean differences (SMD) and 95% confidence intervals (CI). 39 studies met selection criteria, with 35 included in meta-analyses (1765 participants). In primary analyses, a significant improvement in LVGLS was observed in populations with CV disease (SMD = 0.59; 95% CI 0.16-1.02; p = 0.01), however, no significant effect of exercise was observed in CV risk factor and healthy populations. In populations with CV disease, LVGLS could be used as an early biomarker to determine the effectiveness of an exercise regime before changes in other clinical measures are observed.

Relationship Between Movement Quality and Physical Performance in Elite Adolescent Australian Football Players.

ABSTRACT: Bennett, H, Fuller, J, Milanese, S, Jones, S, Moore, E, and Chalmers, S. The relationship between movement quality and physical performance in elite adolescent Australian football players. J Strength Cond Res 36(10): 2824-2829, 2022-The assessment of movement quality is commonplace in competitive sport to profile injury risk and guide exercise prescription. However, the relationship between movement quality scores and physical performance measures is unclear. Moreover, whether improvements in these measures are associated remain unknown. Over a 4-year period, 918 individual elite adolescent Australian Rules Footballers completed the Functional Movement Screen (FMS) and physical performance testing (5- and 20-m sprint, vertical jump, planned agility, and 20-m shuttle run test), allowing the analysis of relationships between FMS parameters and performance measures. In addition, 235 athletes completed testing over 2 consecutive years, allowing the analysis of relationships between changes in these outcomes. Small associations were observed between FMS composite score, hurdle step performance, in-line lunge performance, trunk stability push-up performance, rotary stability, and measures of speed, power, agility, and aerobic fitness (ρ = 0.071-0.238). Across consecutive seasons, significant improvements were observed in the deep squat subtest ( d = 0.21), FMS composite score ( d = 0.17), and 5- ( d = 0.16) and 20-m sprint times ( d = 0.39). A negative association between change in rotary stability and change in jump height (ρ = -0.236) from one season to the next was detected. Results suggest FMS scores have limited relationships with measures of performance in footballers. To optimize athletic performance, once acceptable movement capabilities have been established, training should not prioritize improving movement quality over improvements in strength, power, and change of direction ability.

Effects of External Load on Sagittal and Frontal Plane Lower Extremity Biomechanics During Back Squats.

Previous literature suggests the sticking region, the transition period between an early peak concentric velocity to a local minimum, in barbell movements may be the reason for failing repeated submaximal and maximal squats. This study determined the effects of load on lower extremity biomechanics during back squats. Twenty participants performed the NSCA's one-repetition-maximum (1RM) testing protocol, testing to supramaximum loads (failure). After completing the protocol and a 10-min rest, 80% 1RM squats were performed. Statistical parametric mapping (SPM) was used to determine vertical velocity, acceleration, ankle, knee, and hip sagittal and frontal plane biomechanics differences between 1RM, submaximum, and supramaximum squats (105% 1RM). Vertical acceleration was a better discriminative measure than velocity, exhibiting differences across all conditions. Supramaximum squats emphasized knee moments, whereas 1RM emphasized hip moments during acceleration. Submaximum squats had reduced hip and knee moments compared to supramaximum squats, but similar knee moments to 1RM squats. Across all conditions, knee loads mirrored accelerations and a prominent knee (acceleration) to hip (sticking) transition existed. These results indicate that (1) submaximum squats performed at increased velocities can provide similar moments at the ankle and knee, but not hip, as maximal loads and (2) significant emphasis on hip strength is necessary for heavy back squats.

Running Biomechanics of Adolescents With Autism Spectrum Disorder.

Research examining gait biomechanics of persons with autism spectrum disorder (ASD) has grown significantly in recent years and has demonstrated that persons with ASD walk at slower self-selected speeds and with shorter strides, wider step widths, and reduced lower extremity range of motion and moments compared to neurotypical controls. In contrast to walking, running has yet to be examined in persons with ASD. The purpose of this study was to examine lower extremity running biomechanics in adolescents (13-18-year-olds) with ASD and matched (age, sex, and body mass index (BMI)) neurotypical controls. Three-dimensional kinematics and ground reaction forces (GRFs) were recorded while participants ran at two matched speeds: self-selected speed of adolescents with ASD and at 3.0 m/s. Sagittal and frontal plane lower extremity biomechanics and vertical GRF waveforms were compared using two-way analyses of variances (ANOVAs) via statistical parametric mapping (SPM). Adolescents with ASD ran with reduced stride length at self-selected speed (0.29 m) and reduced vertical displacement (2.1 cm), loading-propulsion GRFs (by 14.5%), propulsion plantarflexion moments (18.5%), loading-propulsion hip abduction moments (44.4%), and loading knee abduction moments (69.4%) at both speeds. Running at 3.0 m/s increased sagittal plane hip and knee moments surrounding initial contact (both 10.4%) and frontal plane knee angles during midstance (2.9 deg) and propulsion (2.8 deg) compared to self-selected speeds. Reduced contributions from primarily the ankle plantarflexion but also knee abduction and hip abduction moments likely reduced the vertical GRF and displacement. As differences favored reduced loading, youth with ASD can safely be encouraged to engage in running as a physical activity.

Foot Rotation Gait Modifications Affect Hip and Ankle, But Not Knee, Stance Phase Joint Reaction Forces During Running.

Alterations of foot rotation angles have successfully reduced external knee adduction moments during walking and running. However, reductions in knee adduction moments may not result in reductions in knee joint reaction forces. The purpose of this study was to examine the effects of internal and external foot rotation on knee, hip, and ankle joint reaction forces during running. Motion capture and force data were recorded of 19 healthy adults running at 3.35 m/s during three conditions: (1) preferred (normal) and with (2) internal and (3) external foot rotation. Musculoskeletal simulations were performed using opensim and the Rajagopal 2015 model, modified to a two degree-of-freedom knee joint. Muscle excitations were derived using static optimization, including muscle physiology parameters. Joint reaction forces (i.e., the total force acting on the joints) were computed and compared between conditions using one-way analyses of variance (ANOVAs) via statistical parametric mapping (SPM). Internal foot rotation reduced resultant hip forces (from 18% to 23% stride), while external rotation reduced resultant ankle forces (peak force at 20% stride) during the stance phase. Three-dimensional and resultant knee joint reaction forces only differed at very early and very late stance phase. The results of this study indicate, similar to previous findings, that reductions in external knee adduction moments do not mirror reductions in knee joint reaction forces.

Approaches to determining occlusion pressure for blood flow restricted exercise training: Systematic review.

Low-intensity exercise with blood flow restriction (BFR) is an increasingly common method of improving muscular strength and hypertrophy, and improving aerobic fitness, in clinical and athletic populations. The aim of this systematic review was to describe common approaches to determining occlusion pressures for BFR exercise. A comprehensive literature search yielded 1389 results, of which 129 were included. Studies were predominantly randomised control trials (86.7%) with modest sample sizes (average number of 11.4 ± 6.2 participants per BFR group/s) of young adults (average age of 34.6 ± 17.9). Five different approaches for determining occlusion pressure were identified: arbitrary pressures (56.6%), percentage of limb occlusion pressure (25.6%), brachial systolic blood pressure (10.9%), perceived tightness (3.9%) and other (3%). From 2016 to 2018, the number of published papers using a percentage of limb occlusion pressure increased yearly, paralleling a decrease use of arbitrary pressures. Of the studies included in this review, the most common approach to determining occlusion pressure was using a non-individualised, arbitrary pressure. Given the safety concerns associated with arbitrary pressures, continual dissemination regarding the optimal applications of BFR for safety and efficacy is required.

Anterior cruciate ligament reconstructed individuals demonstrate slower reactions during a dynamic postural task.

INTRODUCTION: To determine whether individuals with a history of anterior cruciate ligament reconstruction (ACLR) exhibit altered neuromotor function compared to healthy controls. It was hypothesized that the ACLR group would have slower postural responses compared to healthy individuals of similar age. MATERIALS AND METHODS: Sixteen adults with a unilateral ACLR and 16 matched healthy controls participated. General assessments of neuromotor function were gathered and included measures of reaction time (both seated and postural conditions), walking ability, balance, ankle ROM, proprioception, knee joint laxity, patellar tendon reflex latency, and quadriceps strength. Data were analyzed using mixed generalized linear models with between-subject (ie, controls, ACLR) and within-subject factors (ie, affected, unaffected limb). RESULTS: Individuals with an ACLR exhibited a significant slowing of their postural reaction times compared to the control individuals. The ACLR group was slower under both the simple (ACLR: 484 ± 6.17 ms, control: 399 ± 1.95 ms) and choice reaction time conditions (ACLR: 550 ± 43 ms, control: 445 ± 43 ms). No other group differences were found in any of the other measures. CONCLUSION: Overall, ACLR individuals had a reduced ability to respond quickly under more challenging postural conditions (ie, stepping response). This finding would indicate that the impact of an ACLR is not purely mechanical and restricted to the joint. Rather, injury and reconstruction of the ACL impact neural mechanisms, altering individuals' ability to respond under challenging balance tasks.

A Normative Database of Hip and Knee Joint Biomechanics During Dynamic Tasks Using Four Functional Methods With Three Functional Calibration Tasks.

Although predicted hip joint center (HJC) locations are known to vary widely between functional methods, no previous investigation has detailed functional method-dependent hip and knee biomechanics. The purpose of this study was to define a normative database of hip joint biomechanics during dynamic movements based upon functional HJC methods and calibration tasks. Thirty healthy young adults performed arc, star arc, and two-sided calibration tasks. Motion capture and ground reaction forces were collected during walking, running, and single-leg landings (SLLs). Two sphere-fit (geometric and algebraic) and two coordinate transformation techniques were implemented using each calibration (12 total method-calibration combinations). Surprisingly, the geometric fit-two-sided model placed the HJC at the midline of the pelvis and above the iliac spines, and thus was removed from analyses. A database of triplanar hip and knee kinematics and hip moments and powers was constructed using the mean of all subjects for the eleven method-calibration combinations. A nested analysis of variance approach compared calibration [method] peak hip kinematics and kinetics. Most method differences existed between geometric fit and coordinate transformations (58 of 84 total). No arc-star arc differences were found. Thirty-two differences were found between the two-sided and arc/star arc calibrations. This database of functional method based hip and knee biomechanics serves as an important reference point for interstudy comparisons. Overall, this study illustrates that functional HJC method can dramatically impact hip biomechanics and should be explicitly detailed in future work.

Rare germline variants in known melanoma susceptibility genes in familial melanoma.

Known high-risk cutaneous malignant melanoma (CMM) genes account for melanoma risk in <40% of melanoma-prone families, suggesting the existence of additional high-risk genes or perhaps a polygenic mechanism involving multiple genetic modifiers. The goal of this study was to systematically characterize rare germline variants in 42 established melanoma genes among 144 CMM patients in 76 American CMM families without known mutations using data from whole-exome sequencing. We identified 68 rare (<0.1% in public and in-house control datasets) nonsynonymous variants in 25 genes. We technically validated all loss-of-function, inframe insertion/deletion, and missense variants predicted as deleterious, and followed them up in 1, 559 population-based CMM cases and 1, 633 controls. Several of these variants showed disease co-segregation within families. Of particular interest, a stopgain variant in TYR was present in five of six CMM cases/obligate gene carriers in one family and a single population-based CMM case. A start gain variant in the 5'UTR region of PLA2G6 and a missense variant in ATM were each seen in all three affected people in a single family, respectively. Results from rare variant burden tests showed that familial and population-based CMM patients tended to have higher frequencies of rare germline variants in albinism genes such as TYR, TYRP1, and OCA2 (P < 0.05). Our results suggest that rare nonsynonymous variants in low- or intermediate-risk CMM genes may influence familial CMM predisposition, warranting further investigation of both common and rare variants in genes affecting functionally important pathways (such as melanogenesis) in melanoma risk assessment.

Correction to: The long-term rate of change in lung function in urban professional firefighters: a systematic review.

Following publication of the original article [1], the authors flagged an error in Table 2; specifically, within the row beginning 'Aldrich et al. 2013' on page 11 of the article PDF.