Determinants of Polar versus Nematic Organization in Networks of Dynamic Microtubules and Mitotic Motors.

During cell division, mitotic motors organize microtubules in the bipolar spindle into either polar arrays at the spindle poles or a "nematic" network of aligned microtubules at the spindle center. The reasons for the distinct self-organizing capacities of dynamic microtubules and different motors are not understood. Using in vitro reconstitution experiments and computer simulations, we show that the human mitotic motors kinesin-5 KIF11 and kinesin-14 HSET, despite opposite directionalities, can both organize dynamic microtubules into either polar or nematic networks. We show that in addition to the motor properties the natural asymmetry between microtubule plus- and minus-end growth critically contributes to the organizational potential of the motors. We identify two control parameters that capture system composition and kinetic properties and predict the outcome of microtubule network organization. These results elucidate a fundamental design principle of spindle bipolarity and establish general rules for active filament network organization.

Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore.

BACKGROUND: The majority of hepatocellular carcinoma (HCC) cases occur in the presence of cirrhosis. Biomarkers of cirrhosis-associated immune dysfunction such as CD8+ T cell cytokines could aid HCC risk assessment. METHODS: CD8+ T cell cytokines were determined in pre-diagnostic serum in two studies including 315 HCC case-control pairs in the Shanghai Cohort Study (SCS) and 197 pairs in the Singapore Chinese Health Study (SCHS). Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with levels of five cytokines-soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1ß), and tumour necrosis factor alpha (TNF-α). RESULTS: sCD137 levels were significantly higher in HCC cases than controls in both cohorts (Ps < 0.001). Compared with the lowest quartile, multivariable-adjusted ORs (95% CI) of HCC for the highest sCD137 quartile were 3.79 (1.73, 8.30) in the SCS and 3.49 (1.44, 8.48) in the SCHS. The sCD137-HCC association was independent of hepatitis B seropositivity and follow-up time. No other cytokine was consistently associated with HCC risk. CONCLUSION: sCD137 was associated with higher risk of HCC in two studies nested in general population cohorts. sCD137 may be a long-term risk marker of HCC development.

Circulating IL-10 is associated with reduced risk of prostate cancer in a prospective cohort of elderly men: the MrOS Study.

PURPOSE: Prostate cancer (PCa) is the most commonly diagnosed cancer in men, resulting in a large cancer burden given a relatively higher 5-year survival rate of patients after cancer diagnosis. The underlying etiology of prostate cancer is not well understood. Chronic inflammation plays a significant role in carcinogenesis overall and may be involved in the development of PCa, but immune-related biomarker studies in prostate cancer are limited. METHODS: The associations of serum concentrations of cytokines, systemic immune biomarkers, with risk of PCa were assessed in a randomly selected sub-cohort (n = 798, mean age = 73 years) of the Osteoporotic Fractures in Men (MrOS) study, a prospective cohort of older men. At baseline, we measured serum interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), soluble receptors (SR) of IL-6 (IL-6SR) and TNF (TNFαSR1 and TNFαSR2), and IL-10. The risk of PCa was calculated for higher tertile levels of measured individual cytokines relative to the lowest tertile using Cox proportional hazards regression models. RESULTS: After an average 6 years of follow-up, 59 men developed incident PCa. Men in the middle or highest tertile of IL-10 had a statistically significant 50% lower risk of PCa compared to the lowest tertile (hazard ratio = 0.50, 95% confidence interval = 0.30-0.84). There was no significant association between any of the other cytokines measured and PCa risk. CONCLUSION: IL-10, an anti-inflammatory cytokine, was associated with lower risk of PCa. Further research of IL-10 and inflammation in relation to PCa development is warranted.

Low risk of embryonic and other cancers in PIK3CA-related overgrowth spectrum: Impact on screening recommendations.

The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.

Repeated High-Intensity Effort Activity in International Male Rugby Sevens.

ABSTRACT: Couderc, A, Gabbett, TJ, Piscione, J, Robineau, J, Peeters, A, Igarza, G, Thomas, C, Hanon, C, and Lacome, M. Repeated high-intensity effort activity in international male Rugby Sevens. J Strength Cond Res 35(6): 1720-1726, 2023-Rugby Sevens is characterized by repeated high-intensity accelerations, sprinting, and collisions, commonly referred to as repeated high-intensity effort (RHIE) activity. Although repeated acceleration and sprinting activity of Rugby Sevens has been investigated, to date, no study has investigated the repeated running and collision activity of international Rugby Sevens during competitive events. In this study, 15 elite players competed in 44 matches during the HSBC World Sevens Series. Global positioning systems and match analysis software were used to quantify the frequency of repeated running and collision efforts. High acceleration (≥2.5 m·s -2 ), high speed (above maximal aerobic speed), sprint (above 85% of maximal sprint speed), and collision efforts (tackles, ruck, and contact) were considered as high-intensity effort activities. An RHIE bout was defined as 3 or more high-intensity efforts with less than 21 seconds recovery between efforts. The difference between positional groups (forward and backs) and first and second halves was compared using magnitude-based inferential statistics. One hundred twelve individual match observations were analyzed. On average, players performed 27 high-intensity effort events across the game. The distribution of high-intensity efforts included the following: 37% collisions, 34% accelerations, 27.5% high-velocity running, and 1.5% sprints. An average of 3.7 RHIE bouts was performed per player. The difference in high-intensity efforts and number of RHIE bouts performed were trivial/small when compared between first and second halves, and between forward and back positional groups. Repeated high-intensity effort bouts play an important role in the activity profile of elite Rugby Sevens players. This study could provide a framework for performance analysts and coaches to analyze match-related performance of elite Rugby Sevens players, taking into account both the high-intensity running and collision components of the game. Coaches should implement training interventions to ensure the maintenance of RHIE performance during competitive events.

Sex-Related Differences in Oxygen Consumption Recovery After High-Intensity Rowing Exercise During Childhood and Adolescence.

PURPOSE: To determine sex-related differences in oxygen consumption (V˙O2) recovery after high-intensity exercise during childhood and adolescence. METHODS: Forty-two boys and 35 girls (10-17 y) performed a 60-second all-out test on a rowing ergometer. Postexercise V˙O2 recovery was analyzed from (1) the V˙O2 recovery time constant obtained from a biexponential model (τ1V˙O2) and (2) excess postexercise oxygen consumption calculated over a period of 8 minutes (EPOC8) and until τ1V˙O2 was reached (EPOCτ1). Multiplicative allometric modeling was used to assess the concurrent effects of body mass or lean body mass, and age on EPOC8 and EPOCτ1. RESULTS: EPOC8 increased significantly more in boys from the age of 14 years. However, the sex difference was no longer significant when EPOC8 was analyzed using an allometric model including body mass + age or lean body mass + age. In addition, despite a greater increase in EPOCτ1 in boys from the age of 14 years, τ1V˙O2 was not significantly different between sexes whatever age. CONCLUSION: While age and lean body mass accounted for the sex-related differences of EPOC during childhood and adolescence, no significant effect of age and sex was observed on the V˙O2 recovery time constant after high-intensity exercise.

Positive Effects of Pre-exercise Metabolic Alkalosis on Perceived Exertion and Post-exercise Squat Jump Performance in World-Class Cyclists.

ABSTRACT: Thomas, C, Delfour-Peyrethon, R, Dorel, S, and Hanon, C. Positive effects of pre-exercise metabolic alkalosis on perceived exertion and post-exercise squat jump performance in world-class cyclists. J Strength Cond Res 36(9): 2602-2609, 2022-This study aimed to determine the effects of pre-exercise alkalosis in world-class cyclists on their general (rate of perceived exertion [RPE]) and local (category-ratio scale [CR10]) perceived rates of exertion and acid-base status during 2 types of training sessions. Eight world-class cyclists ingested either sodium bicarbonate (BIC) or a placebo (PLA) in a double-blind and randomized order before performing 4 × 1,000 m constant-power sprints (CP) or 3 × 500 m all-out sprints (AO), with 20 minutes of recovery time between each session. For AO, the performance was assessed through the cycling sprint velocity and a squat jump test during recovery. During both tests, RPE, CR10, and acid-base status were measured. Sodium bicarbonate ingestion was effective in inducing pre-exercise alkalosis, compared with a PLA ( p < 0.05). During CP, performance and RPE were the same for BIC and PLA ( p > 0.05) with no time effect. The CR10 increased for the last sprint in PLA ( p < 0.05) but was attenuated in BIC (BIC: 6 vs. PLA: 8.2; p < 0.05), whereas there was no difference in acid-base status. During AO, RPE and CR10 increased with time, with no BIC effect, whereas blood lactate concentration was different ( p < 0.05). Sodium bicarbonate supplementation had no effect on overall repeated sprints ( p > 0.05). However, world-class athletes responded to BIC with higher squat jump performance than the PLA condition after AO ( p < 0.05). Our results suggest a positive influence of pre-exercise alkalosis in world-class cyclists on local perception of efforts after constant load sprints and an attenuation of muscle power output decline postsprint, as evidenced by improved squat jump performance after all-out cycling effort.

Impact of the Rapid Normalization of Chronic Hyperglycemia on the Receptor Activator of Nuclear Factor-Kappa B Ligand and the Osteoprotegerin System in Patients Living with Type 2 Diabetes: RANKL-GLYC Study.

The RANKL-GLYC study aims to explore the impact of the rapid correction of chronic hyperglycemia on the receptor activator of nuclear factor-kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG). RANKL and OPG are considered the main factors in the pathophysiology of Charcot neuroarthropathy, a devastating complication of the joints that remains poorly understood. The study began recruiting patients in September 2021 and ends in June 2022; the final study results are scheduled for January 2023.

No more hypoglycaemia on days with physical activity and unrestricted diet when using a closed-loop system for 12 weeks: A post hoc secondary analysis of the multicentre, randomized controlled Diabeloop WP7 trial.

A post hoc analysis of the Diabeloop WP7 multicentre, randomized controlled trial was performed to investigate the efficacy of the Diabeloop Generation-1 (DBLG1) closed-loop system in controlling the hypoglycaemia induced by physical activity (PA) in real-life conditions. Glycaemic outcomes were compared between days with and without PA in 56 patients with type 1 diabetes (T1D) using DBLG1 for 12 weeks. After the patient announces a PA, DBLG1 reduces insulin delivery and, if necessary, calculates the amount of preventive carbohydrates (CHO). Daily time spent in the interstitial glucose range less than 70 mg/dL was not significantly different between days with and without PA (2.0% ± 1.5% vs. 2.2% ± 1.1%), regardless of the intensity or duration of the PA. Preventive CHO intake recommended by the system was significantly higher in days with PA (41.1 ± 35.5 vs. 21.8 ± 28.5 g/day; P < .0001), and insulin delivery was significantly lower (31.5 ± 10.5 vs. 34.0 ± 10.5 U/day; P < .0001). The time spent in hyperglycaemia and the glycaemic variation coefficient increased significantly on days with PA. In real-life conditions, the use of DBLG1 avoids PA-induced hypoglycaemia. Insulin adjustments and preventive CHO recommendation may explain this therapeutic benefit.

Sex-related differences in accumulated O2 deficit incurred by high-intensity rowing exercise during childhood and adolescence.

PURPOSE: The aims of the present study were to determine during childhood and adolescence (i) the effect of sex on non-oxidative energy production, quantified by the accumulated oxygen deficit (AOD), and (ii) the influence of AOD on high-intensity performance. METHODS: Thirty-nine boys and 35 girls aged 10-17 years performed a 60 s all-out test on a rowing ergometer to determine AOD and mean power output (MPO). Multiplicative allometric modelling was used to assess the concurrent effects of lean body mass (LBM) and age on AOD. RESULTS: AOD significantly increased with age in both sexes (p < 0.001) with boys exhibiting significantly higher AOD than girls from the age of 14 years (10-11.9 yr: 1.9 vs 1.9 L, 12-13.9 yr: 2.4 vs 2.7 L, 14-15.9 yr: 2.8 vs 4.6 L and 16-17.9 yr: 2.9 vs 5.2 L, in girls and boys respectively, p < 0.001). However, a sex difference was no longer significant when AOD was analysed using an allometric model including age and LBM (p = 0.885). Finally, significant correlations were found between AOD and MPO in boys and girls but with lower evidence in girls (r2 = 0.41 vs. 0.89). CONCLUSION: Non-oxidative energy production increased more extensively in boys than girls from the age of 14 years. Age and LBM accounted for the sexual differentiation of AOD during childhood and adolescence. In addition, AOD was found to be a determinant factor of high-intensity performance, more particularly in boys.

Asymptomatic macrocephaly: to scan or not to scan.

BACKGROUND: Macrocephaly is a common finding in infants and is often idiopathic or familial. In the absence of clinical signs and symptoms, it can be difficult to determine when concern for underlying pathology is justified. OBJECTIVES: The objectives of this study were to determine the utility of screening head ultrasound (US) in asymptomatic infants with macrocephaly and to identify clinical factors associated with significant US findings. MATERIALS AND METHODS: A 20-year retrospective review was performed of infants undergoing head US for macrocephaly or rapidly increasing head circumference. Data collected included age, gender, head circumference at birth and at the time of US, specialty of the ordering physician, US findings, computed tomography (CT) or magnetic resonance imaging (MRI) findings, and clinical course including interventions. RESULTS: Four hundred and forty infants met inclusion criteria. Two hundred and eighty studies (64%) were found to be normal, 137 (31%) had incidental findings, 17 (3.8%) had indeterminate but potentially significant findings, and 6 (1.4%) had significant findings. Twenty of the 23 infants with indeterminate or significant findings had subsequent CT or MRI. This confirmed significant findings in eight infants (1.8%): three subdural hematomas, two intracranial tumors, two aqueductal stenoses, and one middle fossa cyst. Five of the eight infants required surgical procedures. The only statistically significant association found with having a significant finding on head US was head circumference at birth. CONCLUSION: Ultrasound is a useful initial study to evaluate infantile macrocephaly, identifying several treatable causes in our study and, when negative, effectively excluding significant pathology.

Problem-solving in clinical practice: Persisting respiratory distress in a premature infant.

The deterioration of a previously stable preterm infant is a common scenario on the neonatal unit. The the most common bacterial causes of deterioration are nosocomial infections, such as coagulase-negative Staphylococcus and Staphylococcus aureus Non-infective conditions such as pulmonary haemorrhage, anaemia of prematurity and necrotising enterocolitis may also cause preterm infants to deteriorate. This case chronicles the unusual diagnostic journey of an infant born at 27+1 weeks who deteriorated at 26 days of life and did not respond to antimicrobial therapy as anticipated.

Characteristics of Pruritus in Bullous Pemphigoid and Impact on Quality of Life: A Prospective Cohort Study.

Pruritus is a common symptom of bullous pemphigoid (BP), but has been poorly studied. The aim of this study was to analyse the characteristics of pruritus in patients with BP and its impact on their quality of life. A multicentre prospective observational study (in 15 French hospitals) was performed. A total of 60 patients were included, with a mean age of 77.4 years. Pruritus occurred daily in 85% of patients, with a mean pruritus intensity of 5.2/10. Tingling sensations were present in 72.4% of patients and burning sensations in 68.9%. Pruritus was exacerbated by stress, fatigue and xerosis. The mean ItchyQol score was 56.2/110 and the mean 5-D Itch Scale score was 16.5/25. The severity of pruritus was not related to age, sex, BP activity score, eosinophilia, or anti-BP230 and anti-BP180 autoantibodies. This study revealed that pruritus in BP is poorly tolerated and is an important cause of impaired quality of life.

Importance of dimensional changes on glycolytic metabolism during growth.

PURPOSE: The aim of the present study was to investigate (i) how glycolytic metabolism assessed by accumulated oxygen deficit (AODgly) and blood metabolic responses (lactate and pH) resulting from high-intensity exercise change during growth, and (ii) how lean body mass (LBM) influences AODgly and its relationship with blood markers. METHODS: Thirty-six 11- to 17-year olds performed a 60-s all-out test on a rowing ergometer. Allometric modelling was used to investigate the influence of LBM and LBM + maturity offset (MO) on AODgly and its relationship with the extreme post-exercise blood values of lactate ([La]max) and pH (pHmin) obtained during the recovery period. RESULTS: AODgly and [La]max increased while pHmin decreased linearly with LBM and MO (r2 = 0.46 to 0.72, p < 0.001). Moreover, AODgly was positively correlated with [La]max (r2 = 0.75, p < 0.001) and negatively correlated with pHmin (r2 = 0.77, p < 0.001). When AODgly was scaled for LBM, the coefficients of the relationships with blood markers drastically decreased by three to four times ([La]max: r2 = 0.24, p = 0.002; pHmin: r2 = 0.30, p < 0.001). Furthermore, by scaling AODgly for LBM + MO, the correlation coefficients with blood markers became even lower ([La]max: r2 = 0.12, p = 0.037; pHmin: r2 = 0.18, p = 0.009). However, MO-related additional changes accounted much less than LBM for the relationships between AODgly and blood markers. CONCLUSION: The results challenge previous reports of maturation-related differences in glycolytic energy turnover and suggest that changes in lean body mass are a more powerful influence than maturity status on glycolytic metabolism during growth.

Congenital infiltrating lipomatosis of the face with lingual mucosal neuromas associated with a PIK3CA mutation.

We report the case of a 5-year-old girl with congenital right-sided facial hemihypertrophy and right hemi-macroglossia with lingual mucosal neuromas. The segmental presentation of findings suggested the diagnosis of congenital infiltrating lipomatosis of the face (CILF), which belongs within the PIK3CA-related overgrowth spectrum (PROS). This was confirmed by genetic analysis showing a mosaic mutation in PIK3CA H1047R. CILF/PROS should be considered in the differential diagnosis of mucosal neuromas.

One-Year Outcomes in Caregivers of Critically Ill Patients.

BACKGROUND: Few resources are available to support caregivers of patients who have survived critical illness; consequently, the caregivers' own health may suffer. We studied caregiver and patient characteristics to determine which characteristics were associated with caregivers' health outcomes during the first year after patient discharge from an intensive care unit (ICU). METHODS: We prospectively enrolled 280 caregivers of patients who had received 7 or more days of mechanical ventilation in an ICU. Using hospital data and self-administered questionnaires, we collected information on caregiver and patient characteristics, including caregiver depressive symptoms, psychological well-being, health-related quality of life, sense of control over life, and effect of providing care on other activities. Assessments occurred 7 days and 3, 6, and 12 months after ICU discharge. RESULTS: The caregivers' mean age was 53 years, 70% were women, and 61% were caring for a spouse. A large percentage of caregivers (67% initially and 43% at 1 year) reported high levels of depressive symptoms. Depressive symptoms decreased at least partially with time in 84% of the caregivers but did not in 16%. Variables that were significantly associated with worse mental health outcomes in caregivers were younger age, greater effect of patient care on other activities, less social support, less sense of control over life, and less personal growth. No patient variables were consistently associated with caregiver outcomes over time. CONCLUSIONS: In this study, most caregivers of critically ill patients reported high levels of depressive symptoms, which commonly persisted up to 1 year and did not decrease in some caregivers. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00896220.).

Clinical Characteristics of Pruritus in Systemic Sclerosis Vary According to the Autoimmune Subtype.

Pruritus is a frequent symptom in systemic sclerosis (SSc), with a prevalence of 40-65%, but its pathophysiology is poorly understood. This study investigated the immunological component of pruritus. Fifty-six patients with SSc responded to a standardized questionnaire regarding both SSc disease and pruritus characteristics. Among patients with SSc, those with pruritus did not display a particular immunological profile (inflammatory, humoral, and/or cellular factors), but pruritus was, in most cases, concomitant with the development of SSc. Thus, pruritus characteristics were evaluated further, according to the detection of anti-centromere autoantibodies (ACA), into ACA+ (n = 17) and ACA- (n = 19). The ACA+ subgroup was characterized by a longer evolution of SSc and pruritus, pruritus present outside the sclerotic area, and a shorter daily duration of pruritus. In conclusion, the concomitant appearance of the 2 processes and the differences observed between ACA+ and ACA- subgroups support the presence of an immunological component in pruritus.

Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.

PURPOSE: Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. METHODS: We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. RESULTS: We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10-5). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 × 10-25), regardless of the phenotype. CONCLUSION: Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions.Genet Med advance online publication 02 February 2017.

Mean-Field Scaling of the Superfluid to Mott Insulator Transition in a 2D Optical Superlattice.

The mean-field treatment of the Bose-Hubbard model predicts properties of lattice-trapped gases to be insensitive to the specific lattice geometry once system energies are scaled by the lattice coordination number z. We test this scaling directly by comparing coherence properties of ^{87}Rb gases that are driven across the superfluid to Mott insulator transition within optical lattices of either the kagome (z=4) or the triangular (z=6) geometries. The coherent fraction measured for atoms in the kagome lattice is lower than for those in a triangular lattice with the same interaction and tunneling energies. A comparison of measurements from both lattices agrees quantitatively with the scaling prediction. We also study the response of the gas to a change in lattice geometry, and observe the dynamics as a strongly interacting kagome-lattice gas is suddenly "hole doped" by introducing the additional sites of the triangular lattice.