Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer.

No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org ). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.

Post-operative electrical muscle stimulation attenuates loss of muscle mass and function following major abdominal surgery in older adults: a split body randomised control trial.

INTRODUCTION: Significant losses of muscle mass and function occur after major abdominal surgery. Neuromuscular electrical stimulation (NMES) has been shown to reduce muscle atrophy in some patient groups, but evidence in post-operative patients is limited. This study assesses the efficacy of NMES for attenuating muscle atrophy and functional declines following major abdominal surgery in older adults. METHODS: Fifteen patients undergoing open colorectal resection completed a split body randomised control trial. Patients' lower limbs were randomised to control (CON) or NMES (STIM). The STIM limb underwent 15 minutes of quadriceps NMES twice daily on post-operative days (PODs) 1-4. Ultrasound measurements of Vastus Lateralis cross-sectional area (CSA) and muscle thickness (MT) were made preoperatively and on POD 5, as was dynamometry to determine knee extensor strength (KES). Change in CSA was the primary outcome. All outcomes were statistically analysed using linear mixed models. RESULTS: NMES significantly reduced the loss of CSA (-2.52 versus -9.16%, P < 0.001), MT (-2.76 versus -8.145, P = 0.001) and KES (-10.35 versus -19.69%, P = 0.03) compared to CON. No adverse events occurred, and patients reported that NMES caused minimal or no discomfort and felt that ~90-minutes of NMES daily would be tolerable. DISCUSSION: NMES reduces losses of muscle mass and function following major abdominal surgery, and as such, may be the promising tool for post-operative recovery. This is important in preventing long-term post-operative dependency, especially in the increasingly frail older patients undergoing major abdominal surgery. Further studies should establish the efficacy of bilateral NMES for improving patient-centred outcomes.

The time course of disuse muscle atrophy of the lower limb in health and disease.

Short, intermittent episodes of disuse muscle atrophy (DMA) may have negative impact on age related muscle loss. There is evidence of variability in rate of DMA between muscles and over the duration of immobilization. As yet, this is poorly characterized. This review aims to establish and compare the time-course of DMA in immobilized human lower limb muscles in both healthy and critically ill individuals, exploring evidence for an acute phase of DMA and differential rates of atrophy between and muscle groups. MEDLINE, Embase, CINHAL and CENTRAL databases were searched from inception to April 2021 for any study of human lower limb immobilization reporting muscle volume, cross-sectional area (CSA), architecture or lean leg mass over multiple post-immobilization timepoints. Risk of bias was assessed using ROBINS-I. Where possible meta-analysis was performed using a DerSimonian and Laird random effects model with effect sizes reported as mean differences (MD) with 95% confidence intervals (95% CI) at various time-points and a narrative review when meta-analysis was not possible. Twenty-nine studies were included, 12 in healthy volunteers (total n = 140), 18 in patients on an Intensive Therapy Unit (ITU) (total n = 516) and 3 in patients with ankle fracture (total n = 39). The majority of included studies are at moderate risk of bias. Rate of quadriceps atrophy over the first 14 days was significantly greater in the ITU patients (MD -1.01 95% CI -1.32, -0.69), than healthy cohorts (MD -0.12 95% CI -0.49, 0.24) (P < 0.001). Rates of atrophy appeared to vary between muscle groups (greatest in triceps surae (-11.2% day 28), followed by quadriceps (-9.2% day 28), then hamstrings (-6.5% day 28), then foot dorsiflexors (-3.2% day 28)). Rates of atrophy appear to decrease over time in healthy quadriceps (-6.5% day 14 vs. -9.1% day 28) and triceps surae (-7.8% day 14 vs. -11.2% day 28), and ITU quadriceps (-13.2% day 7 vs. -28.2% day 14). There appears to be variability in the rate of DMA between muscle groups, and more rapid atrophy during the earliest period of immobilization, indicating different mechanisms being dominant at different timepoints. Rates of atrophy are greater amongst critically unwell patients. Overall evidence is limited, and existing data has wide variability in the measures reported. Further work is required to fully characterize the time course of DMA in both health and disease.

Motor unit dysregulation following 15 days of unilateral lower limb immobilisation.

Disuse atrophy, caused by situations of unloading such as limb immobilisation, causes a rapid yet diverging reduction in skeletal muscle function when compared to muscle mass. While mechanistic insight into the loss of mass is well studied, deterioration of muscle function with a focus towards the neural input to muscle remains underexplored. This study aimed to determine the role of motor unit adaptation in disuse-induced neuromuscular deficits. Ten young, healthy male volunteers underwent 15 days of unilateral lower limb immobilisation with intramuscular electromyography (iEMG) bilaterally recorded from the vastus lateralis (VL) during knee extensor contractions normalised to maximal voluntary contraction (MVC), pre and post disuse. Muscle cross-sectional area was determined by ultrasound. Individual MUs were sampled and analysed for changes in motor unit (MU) discharge and MU potential (MUP) characteristics. VL CSA was reduced by approximately 15% which was exceeded by a two-fold decrease of 31% in muscle strength in the immobilised limb, with no change in either parameter in the non-immobilised limb. Parameters of MUP size were reduced by 11% to 24% with immobilisation, while neuromuscular junction (NMJ) transmission instability remained unchanged, and MU firing rate decreased by 8% to 11% at several contraction levels. All adaptations were observed in the immobilised limb only. These findings highlight impaired neural input following immobilisation reflected by suppressed MU firing rate which may underpin the disproportionate reductions of strength relative to muscle size. KEY POINTS: Muscle mass and function decline rapidly in situations of disuse such as bed rest and limb immobilisation. The reduction in muscle function commonly exceeds that of muscle mass, which may be associated with the dysregulation of neural input to muscle. We have used intramuscular electromyography to sample individual motor unit and near fibre potentials from the vastus lateralis following 15 days of unilateral limb immobilisation. Following disuse, the disproportionate loss of muscle strength when compared to size coincided with suppressed motor unit firing rate. These motor unit adaptations were observed at multiple contraction levels and in the immobilised limb only. Our findings demonstrate neural dysregulation as a key component of functional loss following muscle disuse in humans.

Dressings and topical agents for the management of open wounds after surgical treatment for sacrococcygeal pilonidal sinus.

BACKGROUND: Sacrococcygeal pilonidal sinus disease is a common debilitating condition that predominantly affects young adults, with a profound impact on their activities of daily living. The condition is treated surgically, and in some cases the wound in the natal cleft is left open to heal by itself. Many dressings and topical agents are available to aid healing of these wounds. OBJECTIVES: To assess the effects of dressings and topical agents for the management of open wounds following surgical treatment for sacrococcygeal pilonidal sinus in any care setting. SEARCH METHODS: In March 2021, we searched the Cochrane Wounds Specialised Register, CENTRAL, MEDLINE, Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and we scanned reference lists of included studies, reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We included parallel-group randomised controlled trials (RCTs) only. We included studies with participants who had undergone any type of sacrococcygeal pilonidal sinus disease surgery and were left with an open wound. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 11 RCTs comprising 932 participants. Two studies compared topical negative pressure wound therapy (TNPWT) with conventional open wound healing, two studies compared platelet-rich plasma with sterile absorbent gauze, and the other seven studies compared various dressings and topical agents. All studies were at high risk of bias in at least one domain, whilst one study was judged to be at low risk of bias in all but one domain. All studies were conducted in secondary care. Mean participant ages were between 20 and 30 years, and nearly 80% of participants were male. No studies provided data on quality of life, cost-effectiveness, pain at first dressing change or proportion of wounds healed at 6 or 12 months, and very few adverse effects were recorded in any study. It is unclear whether TNPWT reduces time to wound healing compared with conventional open wound healing (comparison 1), as the certainty of evidence is very low. The two studies provided conflicting results, with one study showing benefit (mean difference (MD) -24.01 days, 95% confidence interval (CI) -35.65 to -12.37; 19 participants), whilst the other reported no difference. It is also unclear whether TNPWT has any effect on the proportion of wounds healed by 30 days (risk ratio (RR) 3.60, 95% CI 0.49 to 26.54; 19 participants, 1 study; very low-certainty evidence). Limited data were available for our secondary outcomes time to return to normal daily activities and recurrence rate; we do not know whether TNPWT has any effect on these outcomes. Lietofix cream may increase the proportion of wounds that heal by 30 days compared with an iodine dressing (comparison 4; RR 8.06, 95% CI 1.05 to 61.68; 205 participants, 1 study; low-certainty evidence). The study did not provide data on time to wound healing. We do not know whether hydrogel dressings reduce time to wound healing compared with wound cleaning with 10% povidone iodine (comparison 5; MD -24.54 days, 95% CI -47.72 to -1.36; 31 participants, 1 study; very low-certainty evidence). The study did not provide data on the proportion of wounds healed. It is unclear whether hydrogel dressings have any effect on adverse effects as the certainty of the evidence is very low. Platelet-rich plasma may reduce time to wound healing compared with sterile absorbent gauze (comparison 6; MD -19.63 days, 95% CI -34.69 to -4.57; 210 participants, 2 studies; low-certainty evidence). No studies provided data on the proportion of wounds healed. Platelet-rich plasma may reduce time to return to normal daily activities (MD -15.49, 95% CI -28.95 to -2.02; 210 participants, 2 studies; low-certainty evidence). Zinc oxide mesh may make little or no difference to time to wound healing compared with placebo (comparison 2; median 54 days in the zinc oxide mesh group versus 62 days in the placebo mesh group; low-certainty evidence). We do not know whether zinc oxide mesh has an effect on the proportion of wounds healed by 30 days as the certainty of the evidence is very low (RR 2.35, 95% CI 0.49 to 11.23). It is unclear whether gentamicin-impregnated collagen sponge reduces time to wound healing compared with no dressing (comparison 7; MD -1.40 days, 95% CI -5.05 to 2.25; 50 participants, 1 study; very low-certainty evidence). The study did not provide data on the proportion of wounds healed. Dialkylcarbamoyl chloride (DACC)-coated dressings may make little or no difference to time to wound healing compared with alginate dressings (comparison 8; median 69 (95% CI 62 to 72) days in the DACC group versus 71 (95% CI 69 to 85) days in the alginate group; 1 study, 246 participants; low-certainty evidence). One study compared a polyurethane foam hydrophilic dressing with an alginate dressing (comparison 3) whilst another study compared a hydrocolloid dressing with an iodine dressing (comparison 9). It is unclear whether either intervention has any effect on time to wound healing as the certainty of evidence is very low. AUTHORS' CONCLUSIONS: At present, the evidence that any of the dressings or topical agents contained in this review have a benefit on time to wound healing, the proportion of wounds that heal at a specific time point or on any of the secondary outcomes of our review ranges from low certainty to very low certainty. There is low-certainty evidence on the benefit on wound healing of platelet-rich plasma from two studies and of Lietofix cream and hydrogel dressings from single studies. Further studies are required to investigate these interventions further.

Atrophy Resistant vs. Atrophy Susceptible Skeletal Muscles: "aRaS" as a Novel Experimental Paradigm to Study the Mechanisms of Human Disuse Atrophy.

OBJECTIVE: Disuse atrophy (DA) describes inactivity-induced skeletal muscle loss, through incompletely defined mechanisms. An intriguing observation is that individual muscles exhibit differing degrees of atrophy, despite exhibiting similar anatomical function/locations. We aimed to develop an innovative experimental paradigm to investigate Atrophy Resistant tibialis anterior (TA) and Atrophy Susceptible medial gastrocnemius (MG) muscles (aRaS) with a future view of uncovering central mechanisms. METHOD: Seven healthy young men (22 ± 1 year) underwent 15 days unilateral leg immobilisation (ULI). Participants had a single leg immobilised using a knee brace and air-boot to fix the leg (75° knee flexion) and ankle in place. Dual-energy X-ray absorptiometry (DXA), MRI and ultrasound scans of the lower leg were taken before and after the immobilisation period to determine changes in muscle mass. Techniques were developed for conchotome and microneedle TA/MG muscle biopsies following immobilisation (both limbs), and preliminary fibre typing analyses was conducted. RESULTS: TA/MG muscles displayed comparable fibre type distribution of predominantly type I fibres (TA 67 ± 7%, MG 63 ± 5%). Following 15 days immobilisation, MG muscle volume (-2.8 ± 1.4%, p < 0.05) and muscle thickness decreased (-12.9 ± 1.6%, p < 0.01), with a positive correlation between changes in muscle volume and thickness (R2 = 0.31, p = 0.038). Importantly, both TA muscle volume and thickness remained unchanged. CONCLUSION: The use of this unique "aRaS" paradigm provides an effective and convenient means by which to study the mechanistic basis of divergent DA susceptibility in humans, which may facilitate new mechanistic insights, and by extension, mitigation of skeletal muscle atrophy during human DA.

Impact of age and treatment institution type on outcomes of patients treated for chronic lymphocytic leukemia in British Columbia, Canada.

Older age has been shown to adversely impact overall survival (OS) in chronic lymphocytic leukemia (CLL) however, prior population-based studies did not analyze the impact of cytogenetic abnormalities or were prior to the availability of ibrutinib. OBJECTIVES: i) We sought to compare outcomes of patients based on their age at treatment to examine if older age has an impact on OS in patients who were treated during the period when fludarabine-rituximab was the standard upfront therapy and when ibrutinib was first introduced and ii) compare outcomes based on whether the patient received primary treatment at an academic or community-based centre. METHODS: The BC Provincial CLL Database, a population-based databasewas used to include patients who have received treatment in British Columbia (BC), Canada between 2004 and 2016. RESULTS: A total of 1122 patients were included (<70 years at treatment, n = 589) with median age at diagnosis 66 years. Younger patients had higher Rai stage (55% vs. 44% stage I-II, p < 0.001), higher lymphocyte count at diagnosis (13 × 109/L vs. 10 × 109/L, p = 0.004), greater proportion with B-symptoms at diagnosis (15% vs 10%, p = 0.004), shorter time from diagnosis to treatment (13.9 months vs. 21.4 months, p = 0.001), higher proportion treated at an academic centre (79% vs. 69%, p < 0.001) and more were treated with fludarabine-rituximab or FCR (69% vs. 42%, p < 0.001) compared to older patients. Older patients had both a significantly (p < 0.001) shorter OS from treatment start (4.7 years) and disease specific survival (8.1 years) than younger patients (median OS and DSS not reached). Of interest, there was no difference in OS between patients treated at an academic centre or community centre (p = 0.087). First-line treatment with chemoimmunotherapy improved OS (HR 0.465, 95% CI: 0.381-.567). CONCLUSIONS: Older age but not treatment-institution type adversely impacts overall survival and CLL survival in treated patients in BC.

The impact of acute beta-hydroxy-beta-methylbutyrate (HMB) ingestion on glucose and insulin kinetics in young and older men.

Insulin resistance (IR) is a key feature in the development of numerous metabolic diseases. The cornerstone for treatment for IR remains diet and exercise, however these have poor rates of adherence. Beta-hydroxy-beta-methylbutyrate (HMB) is a nutraceutical with contentious effects on IR in animal models. The aim of this study was to evaluate the impact of acute HMB on IR in humans during an oral glucose tolerance test (OGTT). Young and older male volunteers underwent two 75 g OGTT with or without 3 g HMB. In young men, HMB significantly reduced the insulin area-under-the-curve (AUC), with no difference in glucose AUC, resulting in a numerical increase in the Cederholm index of insulin sensitivity. In older men, HMB had no effect on insulin or glucose responses. In conclusion, acute HMB may improve IR following a glucose load in young men; however, this does not appear to be sustained into older age.

Comparison of real-world treatment patterns in chronic lymphocytic leukemia management before and after availability of ibrutinib in the province of British Columbia, Canada.

We performed a retrospective study comparing treatment patterns and overall survival (OS) in chronic lymphocytic leukemia (CLL) patients with the advent of ibrutinib to provide current real-world data. METHODS: Using a provincial population-based database, we analyzed CLL patients who received upfront treatment in British Columbia before ibrutinib availability (1984-2014), during ibrutinib access for: relapse only (2014-2015) and for upfront treatment of patients (with 17p deletion or unfit for chemotherapy) (2015-2016). Analysis included up to third-line treatment. RESULTS: Of 1729 patients meeting inclusion criteria (median age, 66 years; 1466, period 1; 140, period 2; 123, period 3), FR was the most common first-line therapy (35.8 %, 54.3 % and 40.7 %, periods 1-3, respectively) and 18.7 % received ibrutinib upfront in period 3. The most common therapies in relapse were chemoimmunotherapy (36.1 % and 55.6 %, periods 1 and 2, second-line; 29.2 %, period 1, third-line) and ibrutinib (69.8 %, period 3, second-line; 46.4 % and 70.3 %, periods 2 and 3, third-line). OS improved for patients treated in periods 2-3 over period 1 (median OS not reached vs. 11.9 years, p < 0.001; no difference in OS for periods 2-3, p = 0.385). CONCLUSION: Ibrutinib has replaced chemoimmunotherapy as the preferred therapy in relapse. Overall survival has improved over time with access to ibrutinib.

Surgical interventions for the treatment of sacrococcygeal pilonidal sinus disease in children: A systematic review and meta-analysis.

BACKGROUND: Pilonidal sinus disease (PNS) is not uncommon in children. Controversy remains over the best treatment and there is limited evidence. This systematic review and meta-analysis aims to establish which techniques have the best outcomes in children. METHODS: MEDLINE, EMBASE and CENTRAL databases were searched. Studies reporting treatment outcomes for PNS in children were included. RESULTS: Open healing has pooled risk of recurrence of 26% (95%CI 15-38%), risk of wound complication of 21% (9-36%) and wound healing ranged from 38-92 days. Midline primary closure has pooled risk of recurrence of 12% (8-18%), risk of wound complication of 30% (19-46%) and wound healing ranged from 8 to 32 days. Off-midline primary closure has pooled risk of recurrence of 6% (1-15%), risk of wound complication of 14% (6-25%) and wound healing was 27 days. VAC therapy has pooled risk of recurrence of 20% (0-65%) and wound healing ranged from 38 to 92 days. Minimally invasive techniques has pooled risk of recurrence of 7% (1-16%) and wound healing ranged from 21-30 days. Marsupialisation has pooled risk of recurrence of 6% (0-22%), and wound healing ranged from 6 to 41 days. CONCLUSION: Evidence for management of PNS in children is poor. Off-midline primary closure, minimally invasive techniques, and marsupialisation have the best outcomes. LEVEL OF EVIDENCE RATING: IV.