The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

Aerobically trained older adults show impaired resting, but preserved exercise-induced circulating progenitor cell count, which was not improved by sprint interval training.

Older adults exhibit a reduced number and function of CD34 + circulating progenitor cells (CPC), a known risk factor for cardiovascular disease. Exercise promotes the mobilisation of CPCs from bone marrow, so whether ageing per se or physical inactivity in older age reduces CPCs is unknown. Thus, this study examined the effect of age on resting and exercise-induced changes in CPCs in aerobically trained adults and the effect of 8 weeks of sprint interval training (SIT) on resting and exercise-induced CPCs in older adults. Twelve young (22-34 years) and nine older (63-70 years) adults participated in the study. Blood was sampled pre and immediately post a graded exercise test to exhaustion in both groups. Older participants repeated the process after 8 weeks of SIT (3 × 20 s 'all-out' sprints, 2 × a week). Total CPCs (CD34+) and endothelial progenitor cells (EPCs: CD34+KDR+) were determined by flow cytometry. Older adults exhibited lower basal total CD34+ CPCs (828 ± 314 vs. 1186 ± 272 cells·mL-1, p = 0.0149) and CD34+KDR+ EPCs (177 ± 128 vs. 335 ± 92 cells·mL-1, p = 0.007) than younger adults. The maximal exercise test increased CPCs in young (CD34+: p = 0.004; CD34+KDR+: p = 0.017) and older adults (CD34+: p < 0.001; CD34+KDR+: p = 0.008), without difference between groups (p = 0.211). SIT did not alter resting or exercise-induced changes in CPCs in the older cohort (p > 0.232). This study suggests age per se does not impair exercise-induced CPC counts, but does lower resting CPC counts.

The Cancer Research UK Stratified Medicine Programme as a model for delivering personalised cancer care.

Genomic screening is routinely used to guide the treatment of cancer patients in many countries. However, several multi-layered factors make this effort difficult to deliver within a clinically relevant timeframe. Here we share the learnings from the CRUK-funded Stratified Medicine Programme for advanced NSCLC patients, which could be useful to better plan future studies.

Exercise-induced skeletal muscle angiogenesis: impact of age, sex, angiocrines and cellular mediators.

Exercise-induced skeletal muscle angiogenesis is a well-known physiological adaptation that occurs in humans in response to exercise training and can lead to endurance performance benefits, as well as improvements in cardiovascular and skeletal tissue health. An increase in capillary density in skeletal muscle improves diffusive oxygen exchange and waste extraction, and thus greater fatigue resistance, which has application to athletes but also to the general population. Exercise-induced angiogenesis can significantly contribute to improvements in cardiovascular and metabolic health, such as the increase in muscle glucose uptake, important for the prevention of diabetes. Recently, our understanding of the mechanisms by which angiogenesis occurs with exercise has grown substantially. This review will detail the biochemical, cellular and biomechanical signals for exercise-induced skeletal muscle angiogenesis, including recent work on extracellular vesicles and circulating angiogenic cells. In addition, the influence of age, sex, exercise intensity/duration, as well as recent observations with the use of blood flow restricted exercise, will also be discussed in detail. This review will provide academics and practitioners with mechanistic and applied evidence for optimising training interventions to promote physical performance through manipulating capillarisation in skeletal muscle.

Imaging breast cancer using hyperpolarized carbon-13 MRI.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.

Survivorship of shoulder arthroplasty in young patients with osteoarthritis: an analysis of the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: The treatment of shoulder osteoarthritis in the young patient remains challenging. The higher functional demands and higher expectations of the young patient cohort are often coupled with increased failure and revision rates. Consequently, shoulder surgeons are faced with a unique challenge with implant selection. The aim of this study was to compare the survivorship and reasons for revision of 5 classes of shoulder arthroplasty in patients aged <55 years with a primary diagnosis of osteoarthritis by use of data from a large national arthroplasty registry. METHODS: The study population included all primary shoulder arthroplasty procedures undertaken for osteoarthritis in patients aged <55 years and reported to the registry between September 1999 and December 2021. Procedures were grouped into the following classes: total shoulder arthroplasty (TSA), hemiarthroplasty resurfacing (HRA), hemiarthroplasty stemmed metallic head (HSMH), hemiarthroplasty stemmed pyrocarbon head (HSPH), and reverse total shoulder arthroplasty (RTSA). The outcome measure was the cumulative percent revision, which was defined using Kaplan-Meier estimates of survivorship to describe the time to the first revision. Hazard ratios (HRs) were calculated from Cox proportional hazards models, adjusting for age and sex, to compare revision rates among groups. RESULTS: There were 1564 shoulder arthroplasty procedures in patients aged <55 years, of which 361 (23.1%) were HRA, 70 (4.5%) were HSMH, 159 (10.2%) were HSPH, 714 (45.7%) were TSA, and 260 (16.6%) were RTSA. HRA had a higher rate of revision than RTSA after 1 year (HRA = 2.51 (95% CI 1.30, 4.83), P = .005), with no difference prior to that time. In addition, HSMH had a higher rate of revision than RTSA for the entire period (HR, 2.69 [95% confidence interval, 1.28-5.63], P = .008). There was no significant difference in the rate of revision for HSPH and TSA when they were compared with RTSA. Glenoid erosion was the most common cause of revision for HRA (28.6% of revisions) and HSMH (50%). Instability/dislocation was the leading cause of revision for RTSA (41.7%) and HSPH (28.6%), and for TSA, the majority of revisions were for either instability/dislocation (20.6%) or loosening (18.6%). CONCLUSION: These results should be interpreted within the context of the lack of availability of long-term data on RTSA and HSPH stems. RTSA outperforms all implants regarding revision rates at mid-term follow-up. The high early dislocation rate associated with RTSA, as well as the lack of revision options available to address this, indicates that careful selection of patients and a greater appreciation of anatomic risk factors are needed in the future.

Co-expression of TNF receptors 1 and 2 on melanomas facilitates soluble TNF-induced resistance to MAPK pathway inhibitors.

BACKGROUND: The effectiveness of MAPK pathway inhibitors (MAPKi) used to treat patients with BRAF-mutant melanoma is limited by a range of resistance mechanisms, including soluble TNF (solTNF)-mediated NF-kB signaling. solTNF preferentially signals through type-1 TNF receptor (TNFR1), however, it can also bind to TNFR2, a receptor that is primarily expressed on leukocytes. Here, we investigate the TNFR2 expression pattern on human BRAFV600E+ melanomas and its role in solTNF-driven resistance reprogramming to MAPKi. METHODS: Flow cytometry was used to test TNFR1, TNFR2 and CD271 expression on, as well as NF-kB phosphorylation in human BRAF-mutant melanoma. The ability of melanoma cell lines to acquire MAPKi resistance in response to recombinant or macrophage-derived TNF was evaluated using the MTT cytotoxicity assay. Gene editing was implemented to knock out or knock in TNF receptors in melanoma cell lines. Knockout and knock-in cell line variants were employed to assess the intrinsic roles of these receptors in TNF-induced resistance to MAPKi. Multicolor immunofluorescence microscopy was utilized to test TNFR2 expression by melanoma in patients receiving MAPKi therapy. RESULTS: TNFR1 and TNFR2 are co-expressed at various levels on 4/7 BRAFV600E+ melanoma cell lines evaluated in this study. In vitro treatments with solTNF induce MAPKi resistance solely in TNFR2-expressing BRAFV600E+ melanoma cell lines. TNFR1 and TNFR2 knockout and knock-in studies indicate that solTNF-mediated MAPKi resistance in BRAFV600E+ melanomas is predicated on TNFR1 and TNFR2 co-expression, where TNFR1 is the central mediator of NF-kB signaling, while TNFR2 plays an auxiliary role. solTNF-mediated effects are transient and can be abrogated with biologics. Evaluation of patient specimens indicates that TNFR2 is expressed on 50% of primary BRAFV600E+ melanoma cells and that MAPKi therapy may lead to the enrichment of TNFR2-expressing tumor cells. CONCLUSIONS: Our data suggest that TNFR2 is essential to solTNF-induced MAPKi resistance and a possible biomarker to identify melanoma patients that can benefit from solTNF-targeting therapies.

Traumatic Nondissociative Carpal Instability: A Case Series.

PURPOSE: We report 8 cases of acute or subacute unilateral nondissociative carpal instability (CIND) in the context of nondisplaced scaphoid fractures. METHODS: Eight patients from 3 centers developed abnormal volar intercalated segment instability (VISI) or dorsal intercalated segment instability (DISI) following the diagnosis of a nondisplaced scaphoid fracture. An operative inspection in each patient confirmed intact scapholunate and lunotriquetral interosseous ligaments. We outline the demographic characteristics of our patient cohort, radiologic and operative findings of CIND-DISI and CIND-VISI, and the outcomes of acute and delayed treatment. RESULTS: Two patients were diagnosed with CIND-DISI and 6 with CIND-VISI associated with ipsilateral nondisplaced scaphoid fractures. The average time from injury to diagnosis of CIND was 11 weeks, and the mean clinical and radiographic follow-up was 18 months. Rapid healing of the scaphoid fractures was achieved in all patients (4 open reduction internal fixation, 4 cast). All patients underwent surgery to improve proximal carpal row alignment: in 3 of the 4 patients who were diagnosed and treated surgically within 12 weeks of injury, the radiolunate angle (RLA) was successfully restored. A contracture release and ligament repair or reconstruction with tendon graft 12 or more weeks following injury was unsuccessful in restoring proximal row alignment in all 4 patients. Two patients in the delayed treatment group required secondary surgery for partial fusion. CONCLUSIONS: Based on the arthroscopic, imaging, and operative findings, we propose that the ligamentous restraints to CIND-VISI are dorsal at the radiocarpal joint and volar at the midcarpal joint. Conversely, the ligamentous restraints to CIND-DISI are dorsal at the midcarpal joint and volar at both the radiocarpal and midcarpal joints. In our series, a delayed diagnosis and late reconstructive surgery were associated with no improvement in RLA. We recommend early recognition of traumatic CIND and prompt treatment of injured ligaments prior to the development of a fixed deformity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Mid-term outcomes of pyrolytic carbon humeral resurfacing hemiarthroplasty compared with metal humeral resurfacing and metal stemmed hemiarthroplasty for osteoarthritis in young patients: analysis from the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: The optimal surgical management of glenohumeral osteoarthritis in young patients remains an unsolved problem. Humeral resurfacing hemiarthroplasty and stemmed hemiarthroplasty using metallic heads are 2 surgical options that avoid the complications of loosening or wear of the glenoid component seen in total shoulder arthroplasty. Despite the potential benefits, improvement in survivorship has not been demonstrated from joint registry studies or other studies at mid-term follow-up. This is predominantly because of glenoid erosion and pain that occur when the metal resurfaced head articulates with the native glenoid. The use of pyrolytic carbon (pyrocarbon) as a resurfacing material has been proposed as an alternative bearing surface thought to reduce glenoid erosion owing to a marked reduction in wear rates in vitro. This study aimed to compare the survivorship of shoulder hemi-resurfacing using pyrocarbon with shoulder hemi-resurfacing and stemmed hemiarthroplasty using metallic heads. METHODS: Data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) were analyzed for all patients aged <55 years who had undergone a primary shoulder replacement for osteoarthritis from April 16, 2004, to December 31, 2019. The outcomes of shoulder procedures using pyrocarbon hemi-resurfacing were compared with procedures using metal hemi-resurfacing and metal stemmed hemiarthroplasty. The reasons for revision in each arthroplasty class were analyzed. The analyses were undertaken using Kaplan-Meier estimates of survivorship and hazard ratios (HRs) from Cox proportional hazards models. RESULTS: We analyzed 393 primary shoulder procedures, of which 163 were pyrocarbon hemi-resurfacing procedures, 163 were metal hemi-resurfacing procedures, and 67 were metal stemmed hemiarthroplasties.The cumulative percentage of revision at 6 years was 8.9% for pyrocarbon hemi-resurfacing, 17.1% for metal hemi-resurfacing, and 17.5% for metal stemmed hemiarthroplasty. Pyrocarbon hemi-resurfacing prostheses had a statistically lower revision rate than other hemi-resurfacing prostheses (HR, 0.41; 95% confidence interval, 0.18-0.93; P = .032). Pain, prosthesis fracture, and infection were the key reasons for revision. No pyrocarbon hemi-resurfacing cases were revised for glenoid erosion. In male patients, pyrocarbon humeral resurfacing had a lower cumulative percentage of revision compared with metal stemmed hemiarthroplasty (HR, 0.32; 95% confidence interval, 0.11-0.93; P = .037). CONCLUSION: Pyrocarbon humeral resurfacing arthroplasty had statistically lower revision rates at mid-term follow-up in patients aged <55 years compared with other hemi-resurfacing procedures.

Outcomes following out-of-hospital cardiac arrest in the aeromedical retrieval population of the remote Top End of the Northern Territory, Australia.

OBJECTIVE: Out-of-hospital cardiac arrest is an event with an extremely poor prognosis. There is limited literature on the outcomes for regional Australia, with none specifically addressing remote populations. We aimed to assess out-of-hospital cardiac arrest outcomes in the aeromedical retrieval population of the Top End Medical Retrieval Service. DESIGN: We retrospectively identified all cardiac arrests, deaths and patients who had cardiopulmonary resuscitation within the aeromedical retrieval database for a 5-year period from January 2012 to December 2016. SETTING: Retrieval patients across the Top End of the Northern Territory, Australia. PARTICIPANTS: All patients within the cohort with a non-traumatic out-of-hospital cardiac arrest. MAIN OUTCOME MEASURES: Data were collected on outcomes as per Utstein definitions, along with patient demographics, retrieval timings and interventions. RESULTS: Seventy-five patients suffering cardiac arrest were identified, with 58 having a non-traumatic arrest in an out-of-hospital setting. The median age of the cohort was 40 years, and 53% had an initial shockable rhythm. Return of spontaneous circulation was achieved in 55% and 43% survived to hospital. The survival to hospital discharge and 28 days were 31% and 29%, respectively. CONCLUSIONS: Although the study has a small sample size and limitations on generalisability due to the restricted nature of the cohort selection, the results suggest a 28-day survival rate is potentially comparable to other regions of Australia and the rest of the world. Further research needs to be undertaken in out-of-hospital cardiac arrest in remote regions to establish a true population-based cohort and ascertain where improvements can be made.

Single-cell analyses of human pancreas: characteristics of two populations of acinar cells in chronic pancreatitis.

Chronic pancreatitis (CP) is a complex inflammatory disorder with numerous associated genetic and environmental risk factors. The most distressing characteristic of CP is recalcitrant pain, often requiring surgical resection including total pancreatectomy with islet autotransplantation (TPIAT). We studied five consented subjects undergoing pancreatic resection and processed isolated cells for single-cell RNA sequencing (scRNA-Seq). Using high-dimensional transcriptomic cluster analysis, we identified 11 unique cell clusters in the pancreas tissue. These cell clusters include a cluster of undifferentiated/dedifferentiated cells and two unique clusters of acinar cells, one of which appears to be in a transitional stage. To determine the cellular response to protease inhibitor and stimulation, we treated aliquots of cells from one subject with a protease inhibitor cocktail with and without bethanechol (a muscarinic receptor agonist) at 100 and 400 µM and compared gene expression profiles. The protease inhibitors appeared to reduce cell stress. Pancreatic digestive enzymes and islet hormones were upregulated in both doses of bethanechol-treated cells compared with naïve cells. High-dose bethanechol appeared to be toxic and consistent with hyperstimulation. These studies demonstrate the feasibility of investigating human acinar cell physiology at the single-cell level and initial evidence that these cells retain responsiveness to agonist stimulation with predicted second messenger and transcriptomic responses.NEW & NOTEWORTHY We conducted single cell RNA sequencing on pancreas tissue from five individuals. We identified eleven unique cell clusters including a large population of dedifferentiated cells as well as two unique clusters of acinar cells, one of which appears to exist in a transitional state. We also examined the cellular response of pancreas tissue to stimulation and identified affected genes and pathways, including pancreatic digestive enzymes.

Direct Target Site Identification of a Sulfonyl-Triazole Covalent Kinase Probe by LC-MS Chemical Proteomics.

Chemical proteomics is widely used for the global investigation of protein activity and binding of small molecule ligands. Covalent probe binding and inhibition are assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to gain molecular information on targeted proteins and probe-modified sites. The identification of amino acid sites modified by large complex probes, however, is particularly challenging because of the increased size, hydrophobicity, and charge state of peptides derived from modified proteins. These studies are important for direct evaluation of proteome-wide selectivity of inhibitor scaffolds used to develop targeted covalent inhibitors. Here, we disclose reverse-phase chromatography and MS dissociation conditions tailored for binding site identification using a clickable covalent kinase inhibitor containing a sulfonyl-triazole reactive group (KY-26). We applied this LC-MS/MS strategy to identify tyrosine and lysine sites modified by KY-26 in functional sites of kinases and other ATP-/NAD-binding proteins (>65 in total) in live cells. Our studies revealed key bioanalytical conditions to guide future chemical proteomic workflows for direct target site identification of complex irreversible probes and inhibitors.

Exercise acutely increases vitamin D receptor expression in T lymphocytes in vitamin D-deficient men, independent of age.

NEW FINDINGS: What is the central question of this study? Does exercise affect vitamin D receptor expression in T lymphocytes in young, middle-aged and older adults? What is the main finding and its importance? Moderate-intensity cycling exercise increases vitamin D receptor expression in vitamin D-deficient men, independent of age, presenting a strategy to combat the prevalence of vitamin D deficiency. ABSTRACT: Vitamin D plays a key role in the modulation of the immune system, mediated through the intracellular vitamin D receptor (VDR). Exercise has been shown to influence the activity and availability of the VDR. The aim of this study was to investigate the effect of age on basal immune cell (T-lymphocyte) VDR expression and the subsequent effect of acute aerobic exercise to modulate VDR expression in peripheral T cells. Thirty-five men were included in the study (mean ± SD: age 44 ± 17 years and body mass index 25.7 ± 3.1 kg/m2 ), separated into three age groups: 18-30 (n = 12), 31-45 (n = 11) and 60-75 years (n = 12). Participants completed two trials [control (CON) and aerobic exercise (AE)], with blood samples collected pre- and postexercise (0, 1 and 3 h). Peripheral blood T cells were isolated and analysed for VDR expression by flow cytometry. The results show that advanced age is associated with lower VDR expression in T cells (882 ± 274, 796 ± 243 and 594 ± 174 geomean in the 18-30, 31-45 and 60-75 year age groups, respectively). Acute AE was successful at acutely increasing VDR expression in T cells, irrespective of age. Advanced age corresponds to a lower T-cell VDR expression, which might be responsible for age-associated development of chronic conditions and autoimmunity. Exercise was successful in increasing VDR expression in T cells irrespective of age and independent of exercise-induced T-cell mobilization.

Rehabilitation following surgery for flexor tendon injuries of the hand.

BACKGROUND: Various rehabilitation treatments may be offered following surgery for flexor tendon injuries of the hand. Rehabilitation often includes a combination of an exercise regimen and an orthosis, plus other rehabilitation treatments, usually delivered together. The effectiveness of these interventions remains unclear. OBJECTIVES: To assess the effects (benefits and harms) of different rehabilitation interventions after surgery for flexor tendon injuries of the hand. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, MEDLINE, Embase, two additional databases and two international trials registries, unrestricted by language. The last date of searches was 11 August 2020. We checked the reference lists of included studies and relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared any postoperative rehabilitation intervention with no intervention, control, placebo, or another postoperative rehabilitation intervention in individuals who have had surgery for flexor tendon injuries of the hand. Trials comparing different mobilisation regimens either with another mobilisation regimen or with a control were the main comparisons of interest. Our main outcomes of interest were patient-reported function, active range of motion of the fingers, and number of participants experiencing an adverse event. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data, assessed risk of bias and assessed the quality of the body of evidence for primary outcomes using the GRADE approach, according to standard Cochrane methodology. MAIN RESULTS: We included 16 RCTs and one quasi-RCT, with a total of 1108 participants, mainly adults. Overall, the participants were aged between 7 and 72 years, and 74% were male. Studies mainly focused on flexor tendon injuries in zone II. The 17 studies were heterogeneous with respect to the types of rehabilitation treatments provided, intensity, duration of treatment and the treatment setting. Each trial tested one of 14 comparisons, eight of which were of different exercise regimens. The other trials examined the timing of return to unrestricted functional activities after surgery (one study); the use of external devices applied to the participant to facilitate mobilisation, such as an exoskeleton (one study) or continuous passive motion device (one study); modalities such as laser therapy (two studies) or ultrasound therapy (one study); and a motor imagery treatment (one study). No trials tested different types of orthoses; different orthosis wearing regimens, including duration; different timings for commencing mobilisation; different types of scar management; or different timings for commencing strengthening. Trials were generally at high risk of bias for one or more domains, including lack of blinding, incomplete outcome data and selective outcome reporting. Data pooling was limited to tendon rupture data in a three trial comparison. We rated the evidence available for all reported outcomes of all comparisons as very low-certainty evidence, which means that we have very little confidence in the estimates of effect. We present the findings from three exercise regimen comparisons, as these are commonly used in clinical current practice. Early active flexion plus controlled passive exercise regimen versus early controlled passive exercise regimen (modified Kleinert protocol) was compared in one trial of 53 participants with mainly zone II flexor tendon repairs. There is very low-certainty evidence of no clinically important difference between the two groups in patient-rated function or active finger range of motion at 6 or 12 months follow-up. There is very low-certainty evidence of little between-group difference in adverse events: there were 15 overall. All three tendon ruptures underwent secondary surgery. An active exercise regimen versus an immobilisation regimen for three weeks was compared in one trial reporting data for 84 participants with zone II flexor tendon repairs. The trial did not report on self-rated function, on range of movement during three to six months or numbers of participants experiencing adverse events. The very low-certainty evidence for poor (under one-quarter that of normal) range of finger movement at one to three years follow-up means we are uncertain of the finding of zero cases in the active group versus seven cases in the immobilisation regimen. The same uncertainty applies to the finding of little difference between the two groups in adverse events (5 tendon ruptures in the active group versus 10 probable scar adhesion in the immobilisation group) indicated for surgery. Place and hold exercise regimen performed within an orthosis versus a controlled passive regimen using rubber band traction was compared in three heterogeneous trials, which reported data for a maximum of 194 participants, with mainly zone II flexor tendon repairs. The trials did not report on range of movement during three to six months, or numbers of participants experiencing adverse events. There was very low-certainty evidence of no difference in self-rated function using the Disability of the Arm, Shoulder and Hand (DASH) functional assessment between the two groups at six months (one trial) or at 12 months (one trial). There is very low-certainty evidence from one trial of greater active finger range of motion at 12 months after place and hold. Secondary surgery data were not available; however, all seven recorded tendon ruptures would have required surgery. All the evidence for the other five exercise comparisons as well as those of the other six comparisons made by the included studies was incomplete and, where available, of very low-certainty. AUTHORS' CONCLUSIONS: There is a lack of evidence from RCTs on most of the rehabilitation interventions used following surgery for flexor tendon injuries of the hand. The limited and very low-certainty evidence for all 14 comparisons examined in the 17 included studies means that we have very little confidence in the estimates of effect for all outcomes for which data were available for these comparisons. The dearth of evidence identified in this review points to the urgent need for sufficiently powered RCTs that examine key questions relating to the rehabilitation of these injuries. A consensus approach identifying these and establishing minimum study conduct and reporting criteria will be valuable. Our suggestions for future research are detailed in the review.

Accuracy of magnetic resonance imaging of the wrist for clinically important lesions of the major interosseous ligaments and triangular fibrocartilage complex; correlation with radiocarpal arthroscopy.

OBJECTIVE: To demonstrate the utility of MRI in separating clinically relevant from minor or incidental lesions of the triangular fibrocartilage complex and the major interosseous ligaments in the wrist. MATERIALS AND METHODS: In this retrospective study, we identified 89 patients and correlated MRI finding with subsequent arthroscopy. Triangular fibrocartilage complex abnormalities have been subdivided into disc lesions-central and radial-or ulnar-sided tears according to MRI appearances and surgical findings as the clinical and surgical approach is very different. Interosseous ligament tears were subdivided into partial or complete, highlighting the principle of recognising surgically relevant lesions. RESULTS: For simple central to radial tears and perforations of the triangular fibrocartilage complex, MRI was 98.3% accurate. MRI identified all peripheral triangular fibrocartilage complex tears seen at arthroscopy; however, the specificity of 66.7% may reflect partly the use of arthroscopy limited to the radiocarpal joint. MRI proved 95.4% accurate for surgically relevant scapholunate interosseous ligament tears and was highly accurate at separating limited from complete lunotriquetral interosseous ligament tears showing 100% accuracy for complete tears. CONCLUSIONS: The study shows excellent correlation between MRI and arthroscopic findings that determine surgical relevance with a very high sensitivity for triangular fibrocartilage complex lesions and accurate separation of minor versus surgically relevant ligamentous tears.

Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation.

Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFß and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFß/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFß/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFß/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.

CaMKII exacerbates heart failure progression by activating class I HDACs.

BACKGROUND: Persistent cardiac Ca2+/calmodulin dependent Kinase II (CaMKII) activation plays an essential role in heart failure development. However, the molecular mechanisms underlying CaMKII induced heart failure progression remains incompletely understood. Histone deacetylases (HDACs) are critical for transcriptional responses to stress, and contribute to expression of pathological genes causing adverse ventricular remodeling. Class I HDACs, including HDAC1, HDAC2 and HDAC3, promote pathological cardiac hypertrophy, whereas class IIa HDACs suppress cardiac hypertrophy. While it is known that CaMKII deactivates class IIa HDACs to enhance cardiac hypertrophy, the role of CaMKII in regulating class I HDACs during heart failure progression is unclear. METHODS AND RESULTS: CaMKII increases the deacetylase activity of recombinant HDAC1, HDAC2 and HDAC3 via in vitro phosphorylation assays. Phosphorylation sites on HDAC1 and HDAC3 are identified with mass spectrometry. HDAC1 activity is also increased in cardiac-specific CaMKIIδC transgenic mice (CaMKIIδC-tg). Beyond post-translational modifications, CaMKII induces HDAC1 and HDAC3 expression. HDAC1 and HDAC3 expression are significantly increased in CaMKIIδC-tg mice. Inhibition of CaMKII by overexpression of the inhibitory peptide AC3-I in the heart attenuates the upregulation of HDAC1 after myocardial infarction surgery. Importantly, a potent HDAC1 inhibitor Quisinostat improves downregulated autophagy genes and cardiac dysfunction in CaMKIIδC-tg mice. In addition to Quisinostat, selective class I HDACs inhibitors, Apicidin and Entinostat, HDAC3 specific inhibitor RGFP966, as well as HDAC1 and HDAC3 siRNA prevent CaMKII overexpression induced cardiac myocyte hypertrophy. CONCLUSION: CaMKII activates class I HDACs in heart failure, which may be a central mechanism for heart failure progression. Selective class I HDACs inhibition may be a novel therapeutic avenue to alleviate CaMKII hyperactivity induced cardiac dysfunction.

Potential Cellular and Biochemical Mechanisms of Exercise and Physical Activity on the Ageing Process.

Exercise in young adults has been consistently shown to improve various aspects of physiological and psychological health but we are now realising the potential benefits of exercise with advancing age. Specifically, exercise improves cardiovascular, musculoskeletal, and metabolic health through reductions in oxidative stress, chronic low-grade inflammation and modulating cellular processes within a variety of tissues. In this this chapter we will discuss the effects of acute and chronic exercise on these processes and conditions in an ageing population, and how physical activity affects our vasculature, skeletal muscle function, our immune system, and cardiometabolic risk in older adults.

Health-care providers' perspectives on factors influencing return-to-work after surgery for nontraumatic conditions of the upper extremity.

STUDY DESIGN: This study is a descriptive survey. INTRODUCTION: Health care providers (HCPs) are key stakeholders who facilitate workers' return to work (RTW) following upper extremity surgery. Hand therapists play a major role in this process, yet we do not know if and/or how their perspectives differ from other HCPs. PURPOSE OF THE STUDY: This study examined HCPs' opinion on factors that influence RTW after surgery for nontraumatic upper extremity conditions and whether HCPs from different disciplines differed in their opinion. METHODS: HCPs (occupational therapists, physiotherapists, hand therapists, exercise physiologists, psychologists, surgeons, and general practitioners) completed a survey rating 50 factors on a worker's ability to RTW. Each factor was scored using a 5-point Likert scale from "not" to "extremely" influential, which was later dichotomised. Agreement was indicated at 75%. The level of disagreement between disciplines was examined. RESULTS: Respondents (n = 787) identified 20 factors being influential on RTW. They are (in order from highest to lowest) poor pain coping (the highest, >85% of respondents), postoperative psychological state, RTW self-efficacy, employer/supervisor's support, employer's unwillingness for job modification, recovery expectations, job satisfaction, suitable duties availability, whether the job can be modified, and mood disorder diagnosis. There was agreement that two factors do not influence RTW, gender, and preemployment medical assessment. There was disagreement (P < .05) between HCP disciplines on six factors (obesity, comorbidities, doctors' RTW recommendation, diagnosis, fitness, income). There were no consistent patterns with respect to which professions disagreed across all six factors. Hand therapists differed from the other disciplines for three of the factors including diagnosis, comorbidities, and doctor's recommendation for RTW. DISCUSSION: The factors that stakeholders agreed as having the greatest influence were mainly related to the worker (pain and psychological factors) and the workplace and are amenable to RTW interventions. CONCLUSION: Interventions facilitating RTW and future research should consider the factors identified by HCPs in this study.

The Lister's tubercle trapdoor: a minimally invasive technique for harvesting cancellous bone from the distal radius.

Bone graft harvest from the distal radius, immediately proximal to the Lister's tubercle, is a common technique in upper limb surgery. Here, we present a minimally invasive technique to harvest bone graft using a replaceable, well vascularized access trapdoor. The hinged trapdoor technique allows a small incision over Lister's tubercle and does not violate the fibro-osseous tunnel of the third compartment. Nearby structures like the superficial radial nerve, extensor carpi radialis brevis and extensor pollicis longus are safely protected throughout. Closure of the trapdoor creates a smooth surface and therefore little or no surrounding trauma.