Effectiveness of postsurgical rehabilitation following lumbar disc herniation surgery: A systematic review.

Introduction: The effectiveness of post-surgical rehabilitation following lumbar disc herniation (LDH) surgery is unclear. Research question: To investigate the effectiveness and safety of rehabilitation interventions initiated within three months post-surgery for adults treated surgically for LDH. Material and methods: This systematic review searched seven databases from inception to November 2023. Independent reviewers screened studies, assessed and extracted data, and rated the certainty of the evidence using the GRADE approach. Results: This systematic review retrieved 20,531 citations and included 25 randomized controlled trials. The high certainty evidence suggests that adding Pilates exercise to routine care and cognitive behavioral therapy may improve function immediately post-intervention (1 RCT), and that adding whole-body magnetic therapy to exercise, pharmacological and aquatic therapy may reduce low back pain intensity (1 RCT) immediately post-intervention. Compared to placebo, pregabalin did not reduce low back pain or leg pain intensity (1 RCT) (moderate to high certainty evidence). We found no differences between: 1) behavioral graded activity vs. physiotherapy (1 RCT); 2) exercise and education vs. neck massage or watchful waiting (1 RCT); 3) exercise, education, and in-hospital usual care vs. in-hospital usual care (1 RCT); 4) functional or staged exercise vs. usual post-surgical care including exercise (2 RCTs); and 5) supervised exercise with education vs. education (1 RCT). No studies assessed adverse events. Discussion and conclusion: Evidence on effective and safe post-surgical rehabilitation interventions is sparse. This review identified two interventions with potential short-term benefits (Pilates exercises, whole-body magnetic therapy) but safety is unclear, and one with an iatrogenic effect (pregabalin).

Association of back pain with all-cause and cause-specific mortality among older men: a cohort study.

OBJECTIVE: We evaluated whether more severe back pain phenotypes-persistent, frequent or disabling back pain-are associated with higher mortality among older men. METHODS: In this secondary analysis of a prospective cohort, the Osteoporotic Fractures in Men (MrOS) study, we evaluated mortality rates by back pain phenotype among 5215 older community-dwelling men (mean age, 73 years, SD = 5.6) from six U.S. sites. The primary back pain measure used baseline and year five back pain questionnaire data to characterize participants as having: no back pain; non-persistent back pain; infrequent persistent back pain; or frequent persistent back pain. Secondary measures of back pain from year five questionnaire included disabling back pain phenotypes. The main outcomes measured were all-cause and cause-specific mortality. RESULTS: After the year five exam, during up to 18 years of follow-up (mean follow-up=10.3 years), there were 3513 deaths (1218 cardiovascular, 764 cancer, 1531 other). A higher proportion of men with frequent persistent back pain versus no back pain died (78% versus 69%; sociodemographic-adjusted HR = 1.27, 95%CI=1.11-1.45). No association was evident after further adjusting for health-related factors such as self-reported general health and comorbid chronic health conditions (fully-adjusted HR = 1.00; 95%CI=0.86-1.15). Results were similar for cardiovascular mortality and other mortality, but we observed no association of back pain with cancer mortality. Secondary back pain measures including back-related disability were associated with increased mortality risk that remained statistically significant in fully-adjusted models. CONCLUSION: While frequent persistent back pain was not independently associated with mortality in older men, additional secondary disabling back pain phenotypes were independently associated with increased mortality. Future investigations should evaluate whether improvements in disabling back pain effect general health and well-being or mortality.

Intermittent tourniquet compared to throughout tourniquet use during Total Knee Arthroplasty in patients with Body Mass Index of 30 or more: A retrospective cohort study.

Background: Tourniquet use during total knee arthroplasty (TKA) reduces bleeding which optimises bone-cement interface for prosthesis stability and improves surgical field visualisation. However, prolonged usage can lead to complications and poorer outcomes. Some surgeons advocate for intermittent tourniquet application. Limited literature exists for patients with high body mass index (BMI). This study aims to compare the outcomes of intermittent tourniquet (IT) to throughout tourniquet (TT) use among obese patients undergoing primary TKA for knee osteoarthritis. Methods: This was a retrospective cohort study. In the TT group, tourniquet was inflated from the beginning and released once the bone cement has hardened. In the IT group, tourniquet was inflated at the beginning, released after initial incision and haemostasis, then inflated again during cementation. Tourniquet was released once the bone cement had set. Categorical outcome measures were analysed using Chi-squared or Fisher's exact test. T-test or Kruskal-Wallis test were used for continuous data. Results: When comparing IT to TT among patients with BMI≥30 (IT n = 48, TT n = 47), the mean duration of surgery was shorter in the TT group (p < 0.05). The difference in haemoglobin drop between the two groups was not statistically significant from post-operative day three onwards. There was no difference in transfusion rate (p > 0.05). ROM was greater in the IT group up to three weeks post-operatively (p < 0.05). When comparing patients with BMI <30 (n = 71) and BMI≥30 (n = 48) with IT use, there was no statistically significant difference in ROM and LOS. Conclusion: Patients with BMI≥30 in the IT group had greater ROM in the initial post-operative period. Although operative time and blood loss were greater among the IT group, there was no difference in transfusion rate. Outcomes of TKA performed with IT were similar for patients with BMI≥30 and BMI <30. The authors recommend intermittent tourniquet use during TKA for patients with BMI≥30. Level of evidence: 3.

Responsive Neurostimulation for People With Drug-Resistant Epilepsy and Autism Spectrum Disorder.

PURPOSE: Individuals with autism spectrum disorder (ASD) have comorbid epilepsy at much higher rates than the general population, and about 30% will be refractory to medication. Patients with drug-resistant epilepsy (DRE) should be referred for surgical evaluation, yet many with ASD and DRE are not resective surgical candidates. The aim of this study was to examine the response of this population to the responsive neurostimulator (RNS) System. METHODS: This multicenter study evaluated patients with ASD and DRE who underwent RNS System placement. Patients were included if they had the RNS System placed for 1 year or more. Seizure reduction and behavioral outcomes were reported. Descriptive statistics were used for analysis. RESULTS: Nineteen patients with ASD and DRE had the RNS System placed at 5 centers. Patients were between the ages of 11 and 29 (median 20) years. Fourteen patients were male, whereas five were female. The device was implanted from 1 to 5 years. Sixty-three percent of all patients experienced a >50% seizure reduction, with 21% of those patients being classified as super responders (seizure reduction >90%). For the super responders, two of the four patients had the device implanted for >2 years. The response rate was 70% for those in whom the device was implanted for >2 years. Improvements in behaviors as measured by the Clinical Global Impression Scale-Improvement scale were noted in 79%. No complications from the surgery were reported. CONCLUSIONS: Based on the authors' experience in this small cohort of patients, the RNS System seems to be a promising surgical option in people with ASD-DRE.

Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration.

BACKGROUND: A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events. METHODS: We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates. FINDINGS: The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15-45) and 52 in non-initiators (39 months; 18-47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (-0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9-29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15-37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference -0·068% (-0·60 to 0·52). INTERPRETATION: We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV. FUNDING: National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.

Similar improvements in patient-reported outcomes for non-specific low back pain patients with and without lumbar spinal stenosis symptoms following a structured education and exercise therapy program.

BACKGROUND: People with nonspecific low back pain (NSLBP) can also experience overlapping symptoms of lumbar spinal stenosis (LSS), but the impact on treatment outcomes is unknown. This study investigated differences in treatment outcomes for disability, back pain intensity, and leg pain intensity following an education and exercise therapy program for NSLBP patients with and without comorbid LSS symptoms. METHODS: This was a longitudinal analysis of 655 Danish participants in the GLA:D® Back program; an education and exercise therapy program for people with persistent NSLBP. Participants were classified as having comorbid LSS symptoms based on self-report. Linear mixed models were used to assess differences in change in disability (Oswestry Disability Index [0-100]) and back and leg pain intensity (Numeric Rating Scale [0-10]) at 3-, 6-, and 12-months between those with and without LSS symptoms. RESULTS: 28% of participants reported LSS symptoms. No certain differences in change in disability or back pain intensity improvement were observed at any time-point between those with and without LSS symptoms. Participants with LSS symptoms had slightly greater improvement in leg pain intensity at 6- (-0.7, 95% CI -1.2 to -0.2) and 12-months (-0.6, 95% CI -1.2 to -0.1). CONCLUSION: Compared to those without LSS symptoms, patients with persistent NSLBP and LSS symptoms can expect similar improvements in disability and back pain intensity, and slightly greater improvements in leg pain intensity with treatment. Therefore, education and exercise therapy programs designed for NSLBP are likely helpful for those also experiencing LSS symptoms.

The GLA:D® Canada program for knee and hip osteoarthritis: A comprehensive profile of program participants from 2017 to 2022.

BACKGROUND: The Good Life with osteoArthritis in Denmark (GLA:D®) program was implemented in Canada in 2017 with the aim of making treatment guideline-recommended care available to the 4 million Canadians with knee and hip osteoarthritis (OA). This report describes the GLA:D® Canada program, registry and data collection procedures, and summarizes the sociodemographic and clinical profile of participants with knee and hip OA to inform the scientific research community of the availability of these data for future investigations and collaborations. METHODS: The GLA:D® program consists of three standardized components: a training course for health care providers, a group-based patient education and exercise therapy program, and a participant data registry. Patients seeking care for knee or hip OA symptoms and enrolling in GLA:D® are given the option to provide data to the GLA:D® Canada registry. Participants agreeing to provide data complete a pre-program survey and are followed up after 3-, and 12-months. Data collected on the pre-program and follow-up surveys include sociodemographic factors, clinical characteristics, health status measures, and objective physical function tests. These variables were selected to capture information across relevant health constructs and for future research investigations. RESULTS: At 2022 year-end, a total of 15,193 (11,228 knee; 3,965 hip) participants were included in the GLA:D® Canada registry with 7,527 (knee; 67.0%) and 2,798 (hip; 70.6%) providing pre-program data. Participants were 66 years of age on average, predominately female, and overweight or obese. Typically, participants had knee or hip problems for multiple years prior to initiating GLA:D®, multiple symptomatic knee and hip joints, and at least one medical comorbidity. Before starting the program, the average pain intensity was 5 out of 10, with approximately 2 out of 3 participants using pain medication and 1 in 3 participants reporting a desire to have joint surgery. Likewise, 9 out 10 participants report having previously been given a diagnosis of OA, with 9 out 10 also reporting having had a radiograph, of which approximately 87% reported the radiograph showed signs of OA. CONCLUSION: We have described the GLA:D® Canada program, registry and data collection procedures, and provided a detailed summary to date of the profiles of participants with knee and hip OA. These individual participant data have the potential to be linked with local health administrative data registries and comparatively assessed with other international GLA:D® registries. Researchers are invited to make use of these rich datasets and participate in collaborative endeavours to tackle questions of Canadian and global importance for a large and growing clinical population of individuals with hip and knee OA.

The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation.

Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0-1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning.

From Local Action to Global Policy: A Comparative Policy Content Analysis of National Policies to Address Musculoskeletal Health to Inform Global Policy Development.

BACKGROUND: Global policy to guide action on musculoskeletal (MSK) health is in a nascent phase. Lagging behind other non-communicable diseases (NCDs) there is currently little global policy to assist governments to develop national approaches to MSK health. Considering the importance of comparison and learning for global policy development, we aimed to perform a comparative analysis of national MSK policies to identify areas of innovation and draw common themes and principles that could guide MSK health policy. METHODS: Multi-modal search strategy incorporating a systematic online search targeted at the 30 most populated nations; a call to networked experts; a specified question in a related eDelphi questionnaire; and snowballing methods. Extracted data were organised using an a priori framework adapted from the World Health Organization (WHO) Building Blocks and further inductive coding. Subsequently, texts were open coded and thematically analysed to derive specific sub-themes and principles underlying texts within each theme, serving as abstracted, transferable concepts for future global policy. RESULTS: The search yielded 165 documents with 41 retained after removal of duplicates and exclusions. Only three documents were comprehensive national strategies addressing MSK health. The most common conditions addressed in the documents were pain (non-cancer), low back pain, occupational health, inflammatory conditions, and osteoarthritis. Across eight categories, we derived 47 sub-themes with transferable principles that could guide global policy for: service delivery; workforce; medicines and technologies; financing; data and information systems; leadership and governance; citizens, consumers and communities; and research and innovation. CONCLUSION: There are few examples of national strategic policy to address MSK health; however, many countries are moving towards this by documenting the burden of disease and developing policies for MSK services. This review found a breadth of principles that can add to this existing work and may be adopted to develop comprehensive system-wide MSK health approaches at national and global levels.

Randomized Phase II Trial of Dendritic Cell/Myeloma Fusion Vaccine with Lenalidomide Maintenance after Upfront Autologous Hematopoietic Cell Transplantation for Multiple Myeloma: BMT CTN 1401.

PURPOSE: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating multiple myeloma-reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (auto-HCT). PATIENTS AND METHODS: In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared with control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of multiple myeloma-specific immunity at 1-year posttransplant. RESULTS: The study enrolled 203 patients, with 140 randomized posttransplantation. Vaccine production was successful in 63 of 68 patients. At 1 year, rates of CR were 52.9% (vaccine) and 50% (control; P = 0.37, 80% CI 44.5%, 61.3%, and 41.6%, 58.4%, respectively), and rates of VGPR or better were 85.3% (vaccine) and 77.8% (control; P = 0.2). Conversion to CR at 1 year was 34.8% (vaccine) and 27.3% (control; P = 0.4). Vaccination induced a statistically significant expansion of multiple myeloma-reactive T cells at 1 year compared with before vaccination (P = 0.024) and in contrast to the nonvaccine arm (P = 0.026). Single-cell transcriptomics revealed clonotypic expansion of activated CD8 cells and shared dominant clonotypes between patients at 1-year posttransplant. CONCLUSIONS: DC/MM fusion vaccination with lenalidomide did not result in a statistically significant increase in CR rates at 1 year posttransplant but was associated with a significant increase in circulating multiple myeloma-reactive lymphocytes indicative of tumor-specific immunity. Site-specific production of a personalized cell therapy with centralized product characterization was effectively accomplished in the context of a multicenter cooperative group study. See related commentary by Qazilbash and Kwak, p. 4703.

Reduction of Collision Risk in Multi-ligament Knee Injury KD-III-M and KD-IV Surgery-Superficial Medial Collateral Ligament Reconstruction with Suture Anchors.

Surgical reconstruction of the medial collateral ligament (MCL) can be challenging during multi-ligament knee injury surgery due to the limited working space. There is risk of collision between the guide pin, pulling sutures, reamer, tunnel, implant, and graft of the different ligament reconstructions. In this Technical Note, we detail our senior author's technique for superficial MCL reconstruction using suture anchors and cruciate ligament reconstruction with all-inside techniques. The technique mitigates the risk of collision by confining the reconstruction process and implants for MCL fixation on the medial femoral condyle and medial proximal tibia.

Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant.

BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: This study was conducted to elucidate the safety of roxadustat, an oral medication, in patients with non-dialysis-dependent (NDD) or incident dialysis dialysis-dependent (ID-DD) chronic kidney disease (CKD). METHODS: Safety results from four phase 3, randomized, open-label studies comparing roxadustat to an erythropoiesis-stimulating agent (ESA) in men and women with NDD or ID-DD CKD with anemia were pooled and evaluated. Endpoints were time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), all-cause mortality, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8- and 1.3-margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS: In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA). Roxadustat was comparable to ESA for risk of MACE (HR 0.79, 95% CI 0.61-1.02), MACE+ (HR 0.78, 95% CI 0.62-0.98), and all-cause mortality (HR 0.78, 95% CI 0.57-1.05). TEAEs were comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 (IR/100) patient-exposure years 56.1 vs. 53.5], TEAEs leading to study drug discontinuation (IR/100 patient-exposure years 6.7 vs. 5.1), and TEAEs leading to death (IR/100 patient-exposure years 6.9 vs. 7.4). CONCLUSION: There was no evidence of increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAEs occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued the study drug because of an adverse event. CLINICAL TRIAL REGISTRATION NUMBERS: DOLOMITES, 1517-CL-0610 [NCT02021318]; HIMALAYAS, FGCL-4592-063 [NCT02052310]; SIERRAS, FGCL-4592-064 [NCT02273726]; and ROCKIES, D5740C00002 [NCT02174731].

Analysis of disparities in time to allogeneic transplantation in adults with acute myelogenous leukemia.

Although alternative donors extend transplant access, whether recipient ancestry affects the time to allogeneic transplant is not established. We analyzed the likelihood of clinically significant delays to allograft by patient ancestry in 313 adult patients with acute myelogenous leukemia (AML) who underwent transplantation. Non-European ancestry patients (n = 99) were more likely than Europeans (n = 214) to receive HLA-mismatched donor allografts (45% vs 24%). Overall, the median time from transplant indication to allograft was 127 days (range, 57-1683). In multivariable analysis, non-Europeans had an increased risk of prolonged indication to transplant time >180 days owing to significant delays in indication to consult >90 days and consult to transplant >120 days. Compared with recipients of HLA-matched unrelated donors (URDs), HLA-mismatched adult donor recipients were at an increased risk of delayed indication to transplant, whereas HLA-identical sibling and cord blood recipients were at a lower risk. Subanalysis showed more indication to transplant delays >180 days in non-European (44%) vs European (19%) 8/8 URD recipients. Finally, the pandemic further exacerbated delays for non-Europeans. In summary, although non-European patients with AML are less likely to receive 8/8 URDs as expected, if they do, their transplants are delayed. HLA-identical siblings and cord blood facilitate the fastest transplants regardless of patient ancestry, whereas other adult donor transplants are delayed. Strategies to mitigate referral barriers, hasten donor evaluation, and use all alternative donor sources are critical to ensure timely transplantation for patients with AML.

Context and priorities for health systems strengthening for pain and disability in low- and middle-income countries: a secondary qualitative study and content analysis of health policies.

Musculoskeletal (MSK) health impairments contribute substantially to the pain and disability burden in low- and middle-income countries (LMICs), yet health systems strengthening (HSS) responses are nascent in these settings. We aimed to explore the contemporary context, framed as challenges and opportunities, for improving population-level prevention and management of MSK health in LMICs using secondary qualitative data from a previous study exploring HSS priorities for MSK health globally and (2) to contextualize these findings through a primary analysis of health policies for integrated management of non-communicable diseases (NCDs) in select LMICs. Part 1: 12 transcripts of interviews with LMIC-based key informants (KIs) were inductively analysed. Part 2: systematic content analysis of health policies for integrated care of NCDs where KIs were resident (Argentina, Bangladesh, Brazil, Ethiopia, India, Kenya, Malaysia, Philippines and South Africa). A thematic framework of LMIC-relevant challenges and opportunities was empirically derived and organized around five meta-themes: (1) MSK health is a low priority; (2) social determinants adversely affect MSK health; (3) healthcare system issues de-prioritize MSK health; (4) economic constraints restrict system capacity to direct and mobilize resources to MSK health; and (5) build research capacity. Twelve policy documents were included, describing explicit foci on cardiovascular disease (100%), diabetes (100%), respiratory conditions (100%) and cancer (89%); none explicitly focused on MSK health. Policy strategies were coded into three categories: (1) general principles for people-centred NCD care, (2) service delivery and (3) system strengthening. Four policies described strategies to address MSK health in some way, mostly related to injury care. Priorities and opportunities for HSS for MSK health identified by KIs aligned with broader strategies targeting NCDs identified in the policies. MSK health is not currently prioritized in NCD health policies among selected LMICs. However, opportunities to address the MSK-attributed disability burden exist through integrating MSK-specific HSS initiatives with initiatives targeting NCDs generally and injury and trauma care.

Loss of G0/G1 switch gene 2 (G0S2) promotes disease progression and drug resistance in chronic myeloid leukaemia (CML) by disrupting glycerophospholipid metabolism.

Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have turned chronic myeloid leukaemia (CML) from a fatal disease into a manageable condition for most patients. Despite improved survival, targeting drug-resistant leukaemia stem cells (LSCs) remains a challenge for curative CML therapy. Aberrant lipid metabolism can have a large impact on membrane dynamics, cell survival and therapeutic responses in cancer. While ceramide and sphingolipid levels were previously correlated with TKI response in CML, the role of lipid metabolism in TKI resistance is not well understood. We have identified downregulation of a critical regulator of lipid metabolism, G0/G1 switch gene 2 (G0S2), in multiple scenarios of TKI resistance, including (1) BCR::ABL1 kinase-independent TKI resistance, (2) progression of CML from the chronic to the blast phase of the disease, and (3) in CML versus normal myeloid progenitors. Accordingly, CML patients with low G0S2 expression levels had a worse overall survival. G0S2 downregulation in CML was not a result of promoter hypermethylation or BCR::ABL1 kinase activity, but was rather due to transcriptional repression by MYC. Using CML cell lines, patient samples and G0s2 knockout (G0s2-/- ) mice, we demonstrate a tumour suppressor role for G0S2 in CML and TKI resistance. Our data suggest that reduced G0S2 protein expression in CML disrupts glycerophospholipid metabolism, correlating with a block of differentiation that renders CML cells resistant to therapy. Altogether, our data unravel a new role for G0S2 in regulating myeloid differentiation and TKI response in CML, and suggest that restoring G0S2 may have clinical utility.

19S Proteasome Subunits as Oncogenes and Prognostic Biomarkers in FLT3-Mutated Acute Myeloid Leukemia (AML).

26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3) were recently identified as prognostic biomarkers and potential therapeutic targets in chronic myeloid leukemia (CML) and multiple solid tumors. In the present study, we analyzed the expression of 19S proteasome subunits in acute myeloid leukemia (AML) patients with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene and assessed their impact on overall survival (OS). High levels of PSMD3 but not PSMD1 expression correlated with a worse OS in FLT3-mutated AML. Consistent with an oncogenic role for PSMD3 in AML, shRNA-mediated PSMD3 knockdown impaired colony formation of FLT3+ AML cell lines, which correlated with increased OS in xenograft models. While PSMD3 regulated nuclear factor-kappa B (NF-κB) transcriptional activity in CML, we did not observe similar effects in FLT3+ AML cells. Rather, proteomics analyses suggested a role for PSMD3 in neutrophil degranulation and energy metabolism. Finally, we identified additional PSMD subunits that are upregulated in AML patients with mutated versus wild-type FLT3, which correlated with worse outcomes. These findings suggest that different components of the 19S regulatory complex of the 26S proteasome can have indications for OS and may serve as prognostic biomarkers in AML and other types of cancers.

Low-dose unfractionated heparin prophylaxis is a safe strategy for the prevention of hepatic sinusoidal obstruction syndrome after myeloablative adult allogenic stem cell transplant.

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication after allogeneic stem cell transplantation (allo-HCT). However, there is no uniform consensus on the optimal strategy for SOS prevention. Ursodeoxycholic acid is the most used regimen, even though its administration is challenging in recipients unable to tolerate oral medication. Defibrotide was recently studied in a phase 3 trial, but enrollment was stopped early due to futility. Low-dose unfractionated heparin (UFH) is an alternative strategy. However, its efficacy is reputed but unproven increased risk of bleeding has not been fully established. We evaluated 514 adult allo-HCT recipients who received SOS prophylaxis with low-dose UFH. Bleeding complications occurred in 12 patients 2.3% of patients of which only 2 (0.4%) had significant grade 3 bleeding. Only 14 patients were diagnosed with hepatic SOS. Univariate analysis showed that day 100 SOS was higher in recipients of unmodified grafts when compared to CD34+ selected ex vivo T-cell depleted grafts (p ≤ 0.001), and patients with hepatitis B and/or C exposure pre-HCT (p = 0.028). Overall, UFH was well tolerated and associated with a low incidence of subsequent hepatic SOS. Low-dose UFH prophylaxis can be considered in select patients who cannot tolerate oral ursodiol.

Non-operative treatment for lumbar spinal stenosis with neurogenic claudication: an updated systematic review.

OBJECTIVES: Neurogenic claudication due to lumbar spinal stenosis (LSS) is a growing health problem in older adults. We updated our previous Cochrane review (2013) to determine the effectiveness of non-operative treatment of LSS with neurogenic claudication. DESIGN: A systematic review. DATA SOURCES: CENTRAL, MEDLINE, EMBASE, CINAHL and Index to Chiropractic Literature databases were searched and updated up to 22 July 2020. ELIGIBILITY CRITERIA: We only included randomised controlled trials published in English where at least one arm provided data on non-operative treatment and included participants diagnosed with neurogenic claudication with imaging confirmed LSS. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias using the Cochrane Risk of Bias Tool 1. Grading of Recommendations Assessment, Development and Evaluation was used for evidence synthesis. RESULTS: Of 15 200 citations screened, 156 were assessed and 23 new trials were identified. There is moderate-quality evidence from three trials that: Manual therapy and exercise provides superior and clinically important short-term improvement in symptoms and function compared with medical care or community-based group exercise; manual therapy, education and exercise delivered using a cognitive-behavioural approach demonstrates superior and clinically important improvements in walking distance in the immediate to long term compared with self-directed home exercises and glucocorticoid plus lidocaine injection is more effective than lidocaine alone in improving statistical, but not clinically important improvements in pain and function in the short term. The remaining 20 new trials demonstrated low-quality or very low-quality evidence for all comparisons and outcomes, like the findings of our original review. CONCLUSIONS: There is moderate-quality evidence that a multimodal approach which includes manual therapy and exercise, with or without education, is an effective treatment and that epidural steroids are not effective for the management of LSS with neurogenic claudication. All other non-operative interventions provided insufficient quality evidence to make conclusions on their effectiveness. PROSPERO REGISTRATION NUMBER: CRD42020191860.