Factors influencing risk-based care of the childhood cancer survivor in the 21st century.

The population of adult survivors of childhood cancer continues to grow as survival rates improve. Although it is well established that these survivors experience various complications and comorbidities related to their malignancy and treatment, this risk is modified by many factors that are not directly linked to their cancer history. Research evaluating the influence of patient-specific demographic and genetic factors, premorbid and comorbid conditions, health behaviors, and aging has identified additional risk factors that influence cancer treatment-related toxicity and possible targets for intervention in this population. Furthermore, although current long-term follow-up guidelines comprehensively address specific therapy-related risks and provide screening recommendations, the risk profile of the population continues to evolve with ongoing modification of treatment strategies and the emergence of novel therapeutics. To address the multifactorial modifiers of cancer treatment-related health risk and evolving treatment approaches, a patient-centered and risk-adapted approach to care that often requires a multidisciplinary team approach, including medical and behavioral providers, is necessary for this population. CA Cancer J Clin 2018;68:133-152. © 2018 American Cancer Society.

Fine-scaled climate variation in equatorial Africa revealed by modern and fossil primate teeth.

Variability in resource availability is hypothesized to be a significant driver of primate adaptation and evolution, but most paleoclimate proxies cannot recover environmental seasonality on the scale of an individual lifespan. Oxygen isotope compositions (δ18O values) sampled at high spatial resolution in the dentitions of modern African primates (n = 2,352 near weekly measurements from 26 teeth) track concurrent seasonal precipitation, regional climatic patterns, discrete meteorological events, and niche partitioning. We leverage these data to contextualize the first δ18O values of two 17 Ma Afropithecus turkanensis individuals from Kalodirr, Kenya, from which we infer variably bimodal wet seasons, supported by rainfall reconstructions in a global Earth system model. Afropithecus' δ18O fluctuations are intermediate in magnitude between those measured at high resolution in baboons (Papio spp.) living across a gradient of aridity and modern forest-dwelling chimpanzees (Pan troglodytes verus). This large-bodied Miocene ape consumed seasonally variable food and water sources enriched in 18O compared to contemporaneous terrestrial fauna (n = 66 fossil specimens). Reliance on fallback foods during documented dry seasons potentially contributed to novel dental features long considered adaptations to hard-object feeding. Developmentally informed microsampling recovers greater ecological complexity than conventional isotope sampling; the two Miocene apes (n = 248 near weekly measurements) evince as great a range of seasonal δ18O variation as more time-averaged bulk measurements from 101 eastern African Plio-Pleistocene hominins and 42 papionins spanning 4 million y. These results reveal unprecedented environmental histories in primate teeth and suggest a framework for evaluating climate change and primate paleoecology throughout the Cenozoic.

Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.

Vascular Adaptation to Exercise in Humans: Role of Hemodynamic Stimuli.

On the 400th anniversary of Harvey's Lumleian lectures, this review focuses on "hemodynamic" forces associated with the movement of blood through arteries in humans and the functional and structural adaptations that result from repeated episodic exposure to such stimuli. The late 20th century discovery that endothelial cells modify arterial tone via paracrine transduction provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the interrelationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions, and the implications for human health. Exercise modifies blood flow, luminal shear stress, arterial pressure, and tangential wall stress, all of which can transduce changes in arterial function, diameter, and wall thickness. There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute to the well-established decrease in cardiovascular risk attributed to physical activity.

Assisted reproductive technology use and outcomes in childhood cancer survivors.

BACKGROUND: Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. METHODS: Five-year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. RESULTS: Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10 years [range, 0-20 years]; median years of follow-up after age 18 years, 11 years [range, 2-11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p = .39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p = .33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20-0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15-0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide-equivalent dose, ≥8000 mg/m2 vs. none; RR, 1.04; 95% CI, 0.52-2.05). CONCLUSIONS: Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population.

Cardiac functional adaptation to resistance and endurance exercise training: a randomized crossover study.

Few training studies have assessed the impact of different modes of exercise on changes in cardiac function. This study investigated changes in left ventricular (LV) systolic and diastolic function following endurance (END) and resistance (RES) training in healthy participants. Sixty-four individuals participated in a randomized crossover design trial, involving 12 wk of END and RES training, separated by a 12-wk washout. Echocardiograms assessed systolic function [ejection fraction (EF) and global longitudinal strain (GLS)], diastolic function [mitral valve early velocity (E), tissue Doppler velocity (e'), their ratio (E/e')], and left atrial volume indexed to body surface area (LA ESVi). LV mass (LVM) increased with both RES (Δ5.3 ± 11.9, P = 0.001) and END (Δ7.5 ± 13.9, P < 0.001). Once adjusted for lean body mass (LVMi), changes remained significant following END. E/e' improved following END (Δ-0.35 ± 0.98, P = 0.011) not RES (Δ0.35 ± 1.11, P =0.157; P = 0.001 between modes). LA ESVi increased with END (Δ2.0 ± 6.1, P = 0.019) but not RES (Δ1.7 ± 5.7, P = 0.113). EF and GLS were not impacted significantly by either mode of training. Adaptation in LVM and LA volumes, as well as diastolic function, was exercise mode specific. Twelve weeks of intensive END increased LVM, LA volumes, and increased diastolic function. Following RES, LVM increased, although this was attenuated after accounting for changes in lean body mass. There were no changes in systolic function following either mode of exercise training.NEW & NOTEWORTHY Different types of exercise training induce distinct physiological adaptations however few exercise training studies have assessed the impact of different modes of exercise on cardiac function. This study investigated changes in left ventricular systolic and diastolic function following exercise training. Participants completed both endurance and resistance training separated by a 12-wk washout period so each participant is their own control. We present adaptations in cardiac structure and diastolic function are exercise mode specific.

Sleep disruption and sleep position: Increased wake frequency in supine predicts lateral position preference.

Little is known about the physiological and biomechanical factors that determine individual preferences in lying posture during sleep. This study investigated relationships between position preference and position-specific arousals, awakenings, limb movements and limb movement arousals to explore the mechanisms by which biomechanical factors influence position preference. Forty-one mature-aged adults underwent 2 nights of at-home polysomnography ~2 weeks apart, on a standardised firm foam mattress, measuring nocturnal sleep architecture and position. The lateral supine ratio and restlessness indices specific to lateral and supine positions including limb movement index, limb movement arousal index, arousal index, wake index, respiratory arousal index and apnea-hypopnea index were calculated and analysed via linear mixed-effects regression. In the supine position, all restlessness indices were significantly increased compared with the lateral position, including a 379% increase in respiratory arousals (ß = 7.0, p < 0.001), 108% increase in arousal index (ß = 10.3, p < 0.001) and 107% increase in wake index (ß = 2.5, p < 0.001). Wake index in the supine position increased significantly with more lateral sleep (ß = 1.9, p = 0.0013), and significant correlation between lateral supine ratio polysomnography 1 and lateral supine ratio polysomnography 2 (ß = 0.95, p < 0.001) indicated strong consistency in sleep preference. Overall, the findings suggest that some individuals have low tolerance to supine posture, represented by a comparatively high wake index in the supine position, and that these individuals compensate by sleeping a greater proportion in the lateral position.

Pigmented villonodular synovitis/giant cell tumor in the knee.

PURPOSE OF REVIEW: Pigmented villonodular synovitis (PVNS) is a rare diagnosis in pediatric patients and commonly presents with symptoms of swelling and pain. Early diagnosis is important to prevent secondary degeneration into the subchondral bone. This review will analyze the etiology, clinical signs/symptoms, diagnosis, treatment, and recent literature on PVNS in the pediatric population. RECENT FINDINGS: Many theories of PVNS etiology have been described in the literature; however, an inflammatory response has been most widely accepted. PVNS can occur in any joint, but most commonly in the knee. The most common treatment for PVNS is synovectomy, and long-term follow-up is necessary to detect disease persistence or recurrence. SUMMARY: Although uncommon, PVNS does occur in the pediatric population and this diagnosis should be included in the differential of atraumatic joint swelling and pain.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

The effects of water temperature on cerebral blood flow during aquatic exercise.

PURPOSE: Recent studies suggest that episodic increases in cerebral blood flow (CBF) may contribute to the improvement in brain health associated with exercise training. Optimising CBF during exercise may enhance this benefit. Water immersion in ~ 30-32 °C augments CBF at rest and during exercise; however, the impact of water temperature on the CBF response has not been investigated. We hypothesised that cycle ergometry in water would increase CBF compared to land-based exercise, and that warm water would attenuate the CBF benefits. METHODS: Eleven young heathy participants (nine males; 23.8 ± 3.1 yrs) completed 30 min of resistance-matched cycle exercise in three separate conditions; non-immersion (Land), 32 °C and 38 °C water immersion up to the level of the waist. Middle cerebral artery velocity (MCAv), blood pressure, and respiratory measures were assessed throughout the exercise bouts. RESULTS: Core temperature was significantly higher in the 38 °C immersion than 32 °C (+ 0.84 ± 0.24 vs + 0.04 ± 0.16, P < 0.001), whilst mean arterial pressure was lower during 38 °C exercise compared to Land (84 ± 8 vs 100 ± 14 mmHg, P < 0.001) and 32 °C (92 ± 9, P = 0.03). MCAv was higher in 32 °C immersion compared to the Land and 38 °C conditions throughout the exercise bout (68 ± 10 vs 64 ± 11 vs 62 ± 12 cm/s, P = 0.03 and P = 0.02, respectively). CONCLUSION: Our findings suggest that cycle exercise in warm water attenuates the beneficial impact of water immersion on CBF velocity due to redistribution of blood flow to subserve thermoregulatory demand. Our findings suggest that, whilst water-based exercise can have beneficial effects on cerebrovascular function, water temperature is a key determinant of this benefit.

Effect of low-volume combined aerobic and resistance high-intensity interval training on vascular health in people with type 2 diabetes: a randomised controlled trial.

PURPOSE: We compared the effects of low-volume combined aerobic and resistance high-intensity interval training (C-HIIT), combined moderate-intensity continuous training (C-MICT) and waitlist control (CON) on vascular health after 8-weeks of supervised training, and an additional 10-months of self-directed training, in adults with type 2 diabetes (T2D). METHODS: Sixty-nine low active adults with T2D were randomised to 8-weeks of supervised C-HIIT (3 times/week, 78-min/week), C-MICT (current exercise guidelines, 4 times/week, 210-min/week) or CON. CON underwent usual care for 8-weeks before being re-randomised to C-HIIT or C-MICT. This was followed by 10-months of self-directed training for participants in C-HIIT and C-MICT. Vascular outcomes were evaluated at baseline, 8-weeks, and 12-months. RESULTS: After 8-weeks, supervised C-HIIT significantly improved relative flow-mediated dilation (FMD) compared with CON (mean difference [MD] 0.8% [0.1, 1.4], p = 0.025). Although not significantly different from CON, the magnitude of change in relative FMD following 8-weeks of supervised C-MICT was similar (MD 0.8% [-0.1, 1.7], p = 0.080). There were no differences in haemodynamic indices, carotid-femoral pulse wave velocity (cfPWV), or aortic reservoir pressure between groups at 8-weeks. After 12-months, there was a significant reduction in haemodynamic indices (time effect, p < 0.05) for both C-HIIT and C-MICT, with no between-group difference. The reduction in cfPWV over 12-months was significantly greater in C-MICT than C-HIIT (group × time effect, p = 0.018). There was no difference in FMD over time or between groups at 12-months. CONCLUSIONS: Short-term supervised C-HIIT and C-MICT both increased brachial artery FMD compared with CON. Long-term C-HIIT and C-MICT were beneficial for improving haemodynamic indices, but not brachial artery FMD. C-MICT was superior to C-HIIT for improving cfPWV at 12-months. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier ACTRN12615000475549.

No Association Between Growth Hormone Therapy and Upper Extremity Physeal Tension Injuries: A Matched Case-control Study.

BACKGROUND: Recent evidence has identified a strong association between growth hormone therapy and physeal injuries in the lower extremity; however, few studies have investigated this association in the upper extremity. QUESTIONS/PURPOSES: (1) Do pediatric patients with physeal tension injuries of the shoulder and elbow have higher odds of having exposure to recombinant growth hormone therapy than matched controls? (2) Are the odds of having exposure to recombinant growth hormone therapy in physeal tension injuries different when stratified by shoulder and elbow injuries? METHODS: Using a matched case-control study design, patients between 4 and 18 years of age treated at a large, urban, academic center from February 1, 2016, to November 6, 2023, were identified by ICD-10 codes using EPIC SlicerDicer, an electronic medical record-based data mining tool. Patients diagnosed with physeal tension injuries in the shoulder or elbow were included in the case group, and those with midshaft radius, metaphyseal radius, or both-bone forearm fractures were included in the control group. A total of 618 patients with physeal injuries and 1244 with non-physeal fractures were identified and screened for inclusion. After further chart review to confirm diagnoses, 46% (283) of patients with physeal injuries and 54% (670) of patients with non-physeal fractures were included. A further 6% (16) of patients with physeal injuries and 2% (15) of patients with non-physeal injuries were excluded due concomitant dislocations or missing data, resulting in 267 eligible patients with physeal injuries and 655 eligible patients with non-physeal fractures. Two patients with concurrent elbow and shoulder physeal injuries were additionally excluded from stratified analyses. Patients with physeal injuries and non-physeal fractures were 1:1 matched by age ± 0.5 years, sex, and BMI ± 2 kg/m2. In all, 522 patients were included in the analysis, including 261 patients with physeal injuries and 261 with non-physeal fractures. The mean ± SD ages for both patient groups was 13 ± 2 years (p = 0.44), 88% (229 of 261) of all participants were male, and the mean BMIs were 19.9 ± 3.0 kg/m2 and 19.4 ± 3.0 kg/m2 (p = 0.11), respectively. Growth hormone exposure was compared between patients with physeal injuries and non-physeal fractures using a conditional logistic regression model. RESULTS: Overall, 4% (10 of 261) of patients with physeal injuries had exposure to growth hormone therapy as compared with 2% (4 of 261) of patients with non-physeal fractures (OR 2.5 [95% confidence interval 0.8 to 8.0]). Subgroup analyses of shoulder and elbow injuries demonstrated no difference in growth hormone exposure between patients with physeal injuries and non-physeal fractures (OR 2 [95% CI 0.4 to 10.2] and OR 3 [95% CI 0.6 to 14.9], respectively). CONCLUSION: In light of these results, clinicians may not need to advise precaution against sports or other activities that put the upper extremity physes under stress when treating patients with growth hormone supplementation therapy. Future multicenter studies, however, are indicated to further investigate for the existence of any subtle association between growth hormone therapy and upper extremity physeal injuries relative to the large association previously noted in the lower extremity in pediatric and adolescent patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

Simultaneous MPFL reconstruction and guided growth result in low rates of recurrent patellofemoral instability.

PURPOSE: Implant-mediated guided growth (IMGG) is used to address coronal plane deformity in skeletally immature patients. Few studies have reported on IMGG and simultaneous medial patellofemoral ligament (MPFL) reconstruction for paediatric patients with concurrent genu valgum and patellofemoral instability (PFI). This study aimed to report on the outcomes of these simultaneous procedures. MATERIALS AND METHODS: This was a retrospective review of paediatric patients undergoing simultaneous MPFL reconstruction and IMGG between 2016 and 2023. Mechanical lateral distal femoral angle (mLDFA), hip-knee-ankle angle (HKA) and mechanical axis deviation (MAD) were measured on full-length hip-to-ankle plain radiographs. Measurements were taken preoperatively, prior to implant removal and/or at final follow-up with minimum 1-year clinical follow-up. RESULTS: A total of 25 extremities in 22 patients (10 female) underwent simultaneous IMGG and MPFL reconstruction. The mean age at surgery was 12.6 ± 1.7 years. The mean duration of implant retention was 18.6 ± 11.3 months. Nineteen extremities (76%) underwent implant removal by final follow-up. Preoperative HKA corrected from a mean of 5.8 ± 2.3° to -0.8 ± 4.5° at implant removal or final follow-up (p < 0.001), with mLDFA and MAD similarly improving (both p < 0.001). HKA corrected a mean of 0.7 ± 0.9° per month, while mLDFA and MAD corrected a mean of 0.5 ± 0.6°/month and 2 ± 3 mm/month, respectively. At the time of implant removal or final follow-up, 88% of patients demonstrated alignment within 5° of neutral. Only one extremity experienced subsequent PFI (4%). For 14 patients who underwent implant removal with further imaging at a mean of 7.8 ± 4.9 months, only one patient (7%) had a valgus rebound to an HKA > 5°. CONCLUSION: Simultaneous MPFL reconstruction and IMGG provided successful correction of lower extremity malalignment with only one recurrence of PFI. This approach is a reliable surgical option for skeletally immature patients with genu valgum and PFI. LEVEL OF EVIDENCE: Level 4 case series.

Measurement of TT-TG can change with sequential MRIs due to variations in tibiofemoral rotation in patellofemoral instability patients.

PURPOSE: There are various anatomic risk factors for patellofemoral instability (PFI) that help guide surgical treatment, including the tibial tubercle to trochlear groove (TT-TG) distance. However, no study has analysed the temporal changes in TT-TG prior to surgical intervention. This study sought to understand the variations in TT-TG over time for pediatric patients suffering from PFI prior to surgical intervention. The authors hypothesised that the TT-TG would substantially change between time points. METHODS: Patients undergoing medial patellofemoral ligament (MPFL) reconstruction between 2014 and 2019 by one of two fellowship-trained orthopaedic surgeons were identified. Patients were included if they had two preoperative magnetic resonance imaging (MRI) performed on the same knee within 7.5 months of each other prior to any surgical intervention and had an initial TT-TG greater than 10 mm. RESULTS: After considering 251 patients for inclusion, 21 patients met the final inclusion criteria. The mean age was 14.5 ± 2.5 years and 61.9% were female. TT-TG was initially noted to be 15.1 ± 1.8 mm. At mean time after sequential MRIs of 5.0 ± 1.9 months, TT-TG was noted to be 16.7 ± 3.2 mm. The differences between initial and subsequent TT-TG ranged from a 21.2% decrease to a 61.1% increase, with a mean difference of an 11.3% increase. Comparison between initial and subsequent TT-TG values demonstrated a significant difference (p = 0.017). Change in tibiofemoral rotation ranged from -9.2° to 7.5°. When comparing the change in TT-TG to change in tibiofemoral rotation, a significant correlation was found (p = 0.019). CONCLUSION: Despite only a mean time between MRIs of 5 months, variations in TT-TG ranged from a decrease of 21.2% to an increase of 61.1%. The significant relationship between the changes in TT-TG and changes in tibiofemoral rotation between MRIs suggest that TT-TG measurements may vary due to variations in tibiofemoral rotation at the time of individual MRIs. LEVEL OF EVIDENCE: Level IV.

Hemiepiphysiodesis for Genu Valgum in Patients With Multiple Hereditary Exostoses.

BACKGROUND: Genu valgum is a well-known feature of multiple hereditary exostoses (MHE). Though prior reports have demonstrated successful treatment with hemiepiphysiodesis, details regarding the correction rate and comparison to an idiopathic population are lacking. This study aimed to detail our institution's experience with guided growth of the knee in patients with MHE and compare this to an idiopathic population. METHODS: All pediatric patients (age 18 and younger) with MHE who underwent lower extremity hemiepiphysiodesis at a tertiary care medical center between January 2016 and December 2022 were retrospectively reviewed. Preoperative and postoperative mechanical lateral distal femoral angle (mLDFA) and medial proximal tibial angle (MPTA, the primary outcomes) were measured in addition to mechanical axis deviation (MAD) and hip-knee-ankle angle (HKA). Patients were 1:2 matched based on age, sex, and physes instrumented to a cohort with idiopathic genu valgum. RESULTS: A total of 21 extremities in 16 patients with MHE underwent hemiepiphysiodesis of the distal femur, proximal tibia, and/or distal tibia. The mean age at surgery was 11.7±2.2 years. Mean MAD corrected from zone 1.9±0.7 to -0.3±1.5, while mLDFA corrected from 83.4±2.9 to 91.7±5.2 degrees and MPTA corrected from 95.3±3.6 to 90.5±4.0 degrees in distal femurs and proximal tibias undergoing guided growth, respectively. Three extremities (14.3%) experienced overcorrection ≥5 degrees managed with observation. There were no differences in correction rates per month for mLDFA (0.54±0.34 vs. 0.51±0.29 degrees, P =0.738) or MPTA (0.31±0.26 vs. 0.50±0.59 degrees, P =0.453) between MHE and idiopathic groups. For 11 extremities in the MHE group with open physes at hardware removal, they experienced a mean recurrence of HKA of 4.0±3.4 degrees at 19-month follow-up. CONCLUSION: Hemiepiphysiodesis corrects lower extremity malalignment in patients with MHE at a similar rate compared with an idiopathic coronal plane deformity population. Rebound deformity of 4 degrees at 19 months after hardware removal in patients with remaining open growth plates should make surgeons conscious of the remaining growth potential when planning deformity correction. LEVEL OF EVIDENCE: Level III.

Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699.

Sex differences in cardiovascular risk factor responses to resistance and endurance training in younger subjects.

This study compared differences in cardiovascular (CV) risk factor responses between males and females following endurance (END) and resistance (RES) training. We present the frequency of responders to each training modality and the magnitude of response. Using a randomized crossover design, 68 healthy adults [age: female (F): 24.5 ± 4.6; male (M): 27.3 ± 6.6] completed 3 mo of RES and END, with 3 mo washout. Peak oxygen consumption (V̇o2peak), strength, body composition, blood pressure, glucose, insulin, and lipids were measured. V̇o2peak (L/min) significantly increased in both sexes following END, but not RES. The magnitude of change was larger in males (F: +0.20 L/min; M: +0.32 L/min), although this did not achieve statistical significance (P = 0.051). Strength significantly increased in both sexes following RES (P < 0.01), with a larger increase in males (Leg press: F: +39 kg; M: +63 kg; P < 0.05). Lean mass significantly increased in both sexes (P < 0.01) following RES and fat mass decreased in females following END (P = 0.019). The change in C-reactive protein following END was significantly different between sexes (F: -0.4 mg/L; M: +0.5 mg/L; P = 0.035). There were no differences between sexes in the proportion of individuals who responded positively to any variable following RES or END; differences between sexes were due to the magnitude of change. Males had a larger increase in V̇o2peak following END and strength following RES. There were no sex differences in other CV risk factors. This suggests differences in physiological responses to strength and V̇o2peak may not translate to changes in CV risk in healthy subjects.NEW & NOTEWORTHY This study investigated sex differences in cardiovascular risk factors in response to different exercise training modalities. Males had a larger improvement in peak oxygen consumption following endurance training and strength following resistance training compared with females. These changes in peak oxygen consumption and strength did not translate to changes in other cardiovascular risk factors. Despite the greater magnitude of change in males, there were no sex differences in the proportion of individuals who responded to training.

The effects of water-based circuit exercise training on vascular function in people with coronary heart disease.

Impaired endothelial function in people with coronary heart disease (CHD) is associated with increased mortality. Water immersion can increase peripheral artery shear stress which may provide an additional stimulus to the endothelium during exercise. This study compared the effects of water-based circuit exercise training (WEX) and gym-based circuit exercise training (GEX) on vascular function in people with stable CHD. Participants were randomized to 12 wk of WEX (n = 20), GEX (n = 20), or a control group (usual activities; n = 12). Endothelium-dependent flow-mediated dilation (FMD) and glyceryl trinitrate-mediated dilation (GTN) of the brachial artery were assessed pre- and postintervention. FMD increased following WEX [4.0% (3.0%-5.1%) to 5.3% (4.1%-6.5%); P = 0.016], but was unchanged following GEX [4.9% (3.8%-5.9%) to 5.0% (3.8%-6.1%); P = 0.822]. There were no between-group differences in the change in FMD and no significant changes in GTN-mediated dilation percentage. Triglycerides decreased following GEX [1.2 mmol·L-1 (1.0-1.4 mmol·L-1) to 1.0 mmol·L-1 (0.8-1.3 mmol·L-1); P = 0.022], but there were no further differences in lipid profiles. WEX improved endothelial function of the brachial artery in people with stable CHD, suggesting that WEX is an effective alternative to gym-based exercise in people living with CHD, which may specifically address vascular health.NEW & NOTEWORTHY This study found that 12 wk of water-based circuit exercise training was well tolerated and improved vascular endothelial function in people with stable coronary heart disease. However, there was no effect on endothelium-independent function. Water-based exercise appears to be an effective alternative to gym-based exercise for people with coronary heart disease, which has specific benefits to vascular health and function.

Effects of exercise during water immersion on arterial function in humans.

Flow-mediated dilation (FMD) provides a valid bioassay of vascular function in humans. Although water immersion induces hemodynamic effects that modify brachial artery shear stress, it is unclear whether water-based exercise modifies FMD. We hypothesized that exercise in 32°C water would decrease brachial artery shear and FMD relative to land-based exercise, whereas exercise in 38°C would increase brachial shear and FMD. Ten healthy participants (8 males; 23.9 ± 3.3 yr) completed 30 min of resistance-matched cycle exercise in three separate conditions: on land and in 32°C and 38°C water. Brachial artery shear rate area under the curve (SRAUC) was measured throughout each condition, with FMD measured pre- and postexercise. Brachial SRAUC increased during exercise in all conditions and was highest across the 38°C condition compared with Land and 32°C conditions (38°C: 27,507 ± 8,350 vs. Land: 9,908 ± 4,738 vs. 32°C: 13,840 ± 5,861 1/s, P < 0.001). Retrograde diastolic shear was greater during 32°C than both Land and 38°C conditions (32°C:-3,869 ± 2,198 vs. Land:-1,602 ± 1,334 vs. 32°C:-1,036 ± 1,754, P < 0.01). FMD increased as a result of 38°C (6.2 ± 1.9 vs. 8.5 ± 2.7%, P = 0.03), with no change in the Land exercise (6.3 ± 2.4 vs. 7.7 ± 2.4%, P = 0.10) or 32°C condition (6.4 ± 3.2 vs. 6.7 ± 3.2%, P = 0.99). Our findings indicate that cycle exercise in hot water attenuates retrograde shear, increases antegrade shear, and FMD. Exercise in 32°C water induces central hemodynamic changes relative to land-based exercise, but these do not translate to increases in FMD in either condition, likely due to the impact of increased retrograde shear. Our findings indicate that modification of shear has direct acute impacts on endothelial function in humans.

A noninvasive method for whole-genome skin methylome profiling.

BACKGROUND: Ageing, disease and malignant transformation of the skin are associated with changes in DNA methylation. So far, mostly invasive methodologies such as biopsies have been applied in collecting DNA methylation signatures. Tape stripping offers a noninvasive option for skin diagnostics. It enables the easy but robust capture of biologic material in large numbers of participants without the need for specialized medical personnel. OBJECTIVES: To design and validate a methodology for noninvasive skin sample collection using tape stripping for subsequent DNA -methylation analysis. METHODS: A total of 175 participants were recruited and provided tape-stripping samples from a sun-exposed area; 92 provided matched tape-stripping samples from a sun-protected area, and an additional 5 provided matched skin-shave biopsies from the same area. Using -enzymatic conversion and whole-genome Illumina sequencing, we generated genome-wide DNA methylation profiles that were used to evaluate the feasibility of noninvasive data acquisition, to compare with established sampling approaches and to investigate biomarker identification for age and ultraviolet (UV) exposure. RESULTS: We found that tape-stripping samples showed strong concordance in their global DNA methylation landscapes to those of conventional invasive biopsies. Moreover, we showed sample reproducibility and consistent global methylation profiles in skin tape-stripping samples collected from different areas of the body. Using matched samples from sun-protected and sun-exposed areas of the body we were able to validate the capacity of our method to capture the effects of environmental changes and ageing in a cohort covering various ages, ethnicities and skin types. We found DNA methylation changes on the skin resulting from UV exposure and identified significant age-related hypermethylation of CpG islands, with a pronounced peak effect at 50-55 years of age, including methylation changes in well-described markers of ageing. CONCLUSIONS: These data demonstrate the feasibility of using tape stripping combined with whole-genome sequencing as a noninvasive approach to measuring DNA methylation changes in the skin. In addition, they outline a viable experimental framework for the use of skin tape stripping, particularly when it is performed in large cohorts of patients to identify biomarkers of skin ageing, UV damage and, possibly, to track treatment response to therapeutic interventions.