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Abstract In children's chronic pain services, healthcare decisions involve a three‐way interaction between the child, their parent or guardian, and the health professional. Parents have unique needs, and it is unknown how they visualize their child's recovery and which outcomes they perceive to be an indication of their child's progress. This qualitative study explored the outcomes parents considered important, when their child was undergoing treatment for chronic pain. A purposive sample of twenty‐one parents of children receiving treatment for chronic musculoskeletal pain, completed a one‐off semi‐structured interview that involved drawing a timeline of their child's treatment. The interview and timeline content were analyzed using thematic analysis. Four themes are evident at different points of the child's treatment course. The “perfect storm” that described their child's pain starting, “fighting in the dark” was a stage when parents focused on finding a service or health professional that could solve their child's pain. The third stage, “drawing a line under it,” changed the outcomes parents considered important, parents changed how they approached their child's pain and worked alongside professionals, focusing on their child's happiness and engagement with life. They watched their child make positive change and moved toward the final theme “free.” The outcomes parents considered important changed over their child's treatment course. The shift described by parents during treatment appeared pivotal to the recovery of young people, demonstrating the importance of the role of parents within chronic pain treatment.

Abstract Aim The aim of this study is to assess effect of hospital walking programs on outcomes for older inpatients and to characterize hospital walking dose reported across studies. Design A systematic review and meta‐analysis examining impact of hospital walking and/or reported walking dose among medical‐surgical inpatients. For inclusion, studies were observational or experimental, published in English, enrolled inpatients aged ≥ 65 yrs hospitalized for medical or surgical reasons. Methods Searches of PubMed, CINAHL, Embase, Scopus, NICHSR, OneSearch, ClinicalTrials.gov, and PsycINFO were completed in December 2020. Two reviewers screened sources, extracted data, and performed quality bias appraisal. Results Hospital walking dose was reported in 6 studies and commonly as steps/24 hr. Length of stay (LOS) was a common outcome reported. Difference in combined mean LOS between walking and control groups was −5.89 days. Heterogeneity across studies was considerable (I2 = 96%) suggesting poor precision of estimates. Additional, high‐quality trials examining hospital walking and patient outcomes of older patients is needed.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

International Registered Report Identifier (IRRID)RR2-10.3928/19404921-20210825-02

Introduction: The purpose is to report on the fourth set of recommendations developed by SPINE20 to advocate for evidence-based spine care globally under the theme of “One Earth, One Family, One Future WITHOUT Spine DISABILITY”. Research question: Not applicable. Material and methods: Recommendations were developed and refined through two modified Delphi processes with international, multi-professional panels. Results: Seven recommendations were delivered to the G20 countries calling them to: - establish, prioritize and implement accessible National Spine Care Programs to improve spine care and health outcomes. - eliminate structural barriers to accessing timely rehabilitation for spinal disorders to reduce poverty. - implement cost-effective, evidence-based practice for digital transformation in spine care, to deliver self-management and prevention, evaluate practice and measure outcomes. - monitor and reduce safety lapses in primary care including missed diagnoses of serious spine pathologies and risk factors for spinal disability and chronicity. - develop, implement and evaluate standardization processes for spine care delivery systems tailored to individual and population health needs. - ensure accessible and affordable quality care to persons with spine disorders, injuries and related disabilities throughout the lifespan. - promote and facilitate healthy lifestyle choices (including physical activity, nutrition, smoking cessation) to improve spine wellness and health. Discussion and conclusion: SPINE20 proposes that focusing on the recommendations would facilitate equitable access to health systems, affordable spine care delivered by a competent healthcare workforce, and education of persons with spine disorders, which will contribute to reducing spine disability, associated poverty, and increase productivity of the G20 nations.

Abstract Background There is a need to improve consultations between patients with persistent musculoskeletal low back pain and orthopaedic spine clinicians when surgery is not indicated. Poor communication and lack of education about self- management in these consultations have been shown to be associated with increased distress and higher subsequent health care seeking. Aim To develop a standardised intervention to improve spine care consultations for patients for whom surgery is not beneficial. Method The intervention was developed in six stages. The first three stages included: interviews with patients, an interactive workshop with clinicians from a mix of disciplines, and interviews with spine clinicians about their perspective of the recommendations, their perceived difficulties and potential improvements. Information from these stages was synthesised by an expert panel, creating a draft intervention structure and content. The main features of the intervention and the materials developed were then reviewed by patients and spine clinicians. Finally, the research team incorporated the recommended amendments to produce the intervention. Results In total, 36 patients and 79 clinicians contributed to the development of the intervention. The final intervention includes three components: a pre-consultation letter with information suggesting that surgery is one possible intervention amongst many, introducing the staff, and alerting patients to bring with them a potted history of interventions tried previously. The intervention includes short online training sessions to improve clinicians’ communication skills, during the consultation, in reference to listening skills, validation of patients’ pain, and use of appropriate language. Clinicians are also supplied with a list of evidence-based sources for advice and further information to share with patients. Finally, post consultation, a follow up letter includes a short summary of the patients’ clinical journey, the results of their examination and tests, and a reminder of recommendations for self-management. Conclusion The intervention includes aspects around patient education and enhanced clinician skills. It was developed with input from a multitude of stakeholders and is based on patients’ perceptions of what they would find reassuring and empowering when surgery is excluded. The intervention has the potential to improve the patients care journey and might lead to changes in practice in spine clinicians.

Functional neurological disorders remain common presentations to both outpatient and inpatient NHS services, but little consensus exists with respect to how such services and clinical pathways for patients should be structured and should function. This article sets out a model for an integrated multidisciplinary approach that takes full account of the number specialties involved, constraint on resources and time involved, and that has functioned well in the NHS despite a pandemic.

Abstract Background India has the highest number of stillbirths and the highest neonatal death rate in the world. In the context of its pronatalist society, women who experience perinatal loss often encounter significant social repercussions on top of grief. Furthermore, even when pregnancy outcomes were favorable, adverse life circumstances put some women at risk for postnatal depression. Therefore, perinatal loss and postnatal depression take a heavy toll on women’s mental health. The purpose of this study is to assess mental health among a sample of Mumbai slum-dwelling women with a history of recent childbirth, stillbirth, or infant death, who are at risk for perinatal grief, postnatal depression, or mental health sequelae. Methods We conducted a mixed method, cross-sectional study. A focus group discussion informed the development of a comprehensive survey using mainly internationally validated scales. After rigorous forward and back-translation, surveys were administered as face-to-face structured interviews due to low literacy and research naiveté among our respondents. Interviews were conducted by culturally, linguistically, gender-matched, trained research assistants. Results Of our reproductive age (N = 260) participants, 105 had experienced stillbirth, 69 had a history of infant death, and 25 had experienced both types of loss. Nearly half of the sample met criteria for postnatal depression, and 20% of these women also met criteria for perinatal grief. Anxiety and depression varied by subgroup, and was highest among women desiring an intervention. Conclusions Understanding factors contributing to women’s suffering related to reproductive challenges in this pronatalist context is critically important for women’s wellbeing.

Objective This study aimed to explore the perceptions of orthopaedic clinicians about consultations for people with persistent musculoskeletal low back pain (PMLBP) in which surgery is not recommended. Surgery is not recommended for the majority of PMLBP consulting in secondary care settings.Setting Secondary care sector in the UK.Participants Semi-structured qualitative interviews were conducted with 24 orthopaedic team clinicians from 17 different hospitals in the UK and Ireland. Interviews explored clinicians’ perceptions of the challenges in consultations where surgery is not indicated. Interviews were transcribed verbatim and analysed using thematic analysis.Results Two meta-themes, Difficulties and Enablers, each consisting of several subthemes were identified. Difficulties included challenges around the choice of appropriate terminology and labels for PMLBP, managing patients’ expectations, working with mentally vulnerable patients and explaining imaging findings. Enablers included early management of expectations, use of routine imaging, triaging, access to direct referral elsewhere, including other non-surgical practitioners in the team, training to improve communication skills and understanding of psychological issues.Conclusion The findings highlight clinicians’ perceived need for concordance in messages delivered across the care pathway and training of orthopaedic clinicians to deliver effective reassurance and address patients’ needs in circumstances where surgery is not indicated.

Healthcare workers (HCWs) from minoritized communities are a critical partner in moving vaccine-hesitant populations toward vaccination, yet a significant number of these HCWs are delaying or deciding against their own COVID-19 vaccinations. Our study aims to provide a more nuanced understanding of vaccine hesitancy among racially and ethnically minoritized HCWs and to describe factors associated with vaccine non-acceptance. Analysis of a sub-sample of racially and ethnically minoritized HCWs (N = 1131), who participated in a cross-sectional study at two large Southern California medical centers, was conducted. Participants completed an online survey consisting of demographics, work setting and clinical role, influenza vaccination history, COVID-19 knowledge, beliefs, personal COVID-19 exposure, diagnosis, and impact on those closest to them. While overall most HCWs were vaccinated (84%), 28% of Black, 19% of Hispanic, and 8% of Asian American HCWs were vaccine-hesitant. Age, education level, occupation, history of COVID-19, and COVID-19 related knowledge were predictive of vaccine hesitancy. We found significant variations in COVID-19 related knowledge and reasons for vaccine hesitancy among Black (governmental mistrust), Hispanic (preference for physiological immunity), and Asian-American HCWs (concern about side effects) who were vaccine-hesitant or not. Our findings highlight racial and ethnic differences in vaccine-hesitancy and barriers to vaccination among HCWs of color. This study indicates the necessity of targeted interventions to reduce vaccine hesitancy that are mindful of the disparities in knowledge and access and differences between and among racial and ethnic groups.

This paper provides a perspective on how art and cross-cultural conversations can facilitate understanding of important scientific processes, outcomes and conclusions, using the Marine Ecosystem Assessment for the Southern Ocean (MEASO) as a case study. First, we reflect on our rationale and approach, describing the importance of deeper communication, such as through the arts, to the policy process; more enduring decisions are possible by engaging and obtaining perspectives through more than just a utilitarian lens. Second, we draw on the LivingData Website [http://www.livingdata.net.au] where art in all its forms is made to bridge differences in knowledge systems and their values, provide examples of how Indigenous knowledge and Western science can be complementary, and how Indigenous knowledge can show the difference between historical natural environmental phenomena and current unnatural phenomena, including how the Anthropocene is disrupting cultural connections with the environment that ultimately impact everyone. Lastly, we document the non-linear process of our experience and draw lessons from it that can guide deeper communication between disciples and cultures, to potentially benefit decision-making. Our perspective is derived as a collective from diverse backgrounds, histories, knowledge systems and values.

Objectives Contextual components of treatment previously associated with patient outcomes include the environment, therapeutic relationship and expectancies. Questions remain about which components are most important, how they influence outcomes and comparative effects across treatment approaches. We aimed to identify significant and strong contextual predictors of patient outcomes, test for psychological mediators and compare effects across three treatment approaches.Design Prospective cohort study with patient-reported and practitioner-reported questionnaire data (online or paper) collected at first consultation, 2 weeks and 3 months.Setting Physiotherapy, osteopathy and acupuncture clinics throughout the UK.Participants 166 practitioners (65 physiotherapists, 46 osteopaths, 55 acupuncturists) were recruited via their professional organisations. Practitioners recruited 960 adult patients seeking treatment for low back pain (LBP).Primary and secondary outcomes The primary outcome was back-related disability. Secondary outcomes were pain and well-being. Contextual components measured were: therapeutic alliance; patient satisfaction with appointment systems, access, facilities; patients’ treatment beliefs including outcome expectancies; practitioners’ attitudes to LBP and practitioners’ patient-specific outcome expectancies. The hypothesised mediators measured were: patient self-efficacy for pain management; patient perceptions of LBP and psychosocial distress.Results After controlling for baseline and potential confounders, statistically significant predictors of reduced back-related disability were: all three dimensions of stronger therapeutic alliance (goal, task and bond); higher patient satisfaction with appointment systems; reduced patient-perceived treatment credibility and increased practitioner-rated outcome expectancies. Therapeutic alliance over task (ηp2=0.10, 95% CI 0.07 to 0.14) and practitioner-rated outcome expectancies (ηp2=0.08, 95% CI 0.05 to 0.11) demonstrated the largest effect sizes. Patients’ self-efficacy, LBP perceptions and psychosocial distress partially mediated these relationships. There were no interactions with treatment approach.Conclusions Enhancing contextual components in musculoskeletal healthcare could improve patient outcomes. Interventions should focus on helping practitioners and patients forge effective therapeutic alliances with strong affective bonds and agreement on treatment goals and how to achieve them.

Introduction Self-management and remaining physically active are first-line recommendations for the care of patients with low back pain (LBP). With a lifetime prevalence of up to 85%, novel approaches to support behavioural self-management are needed. Internet interventions may provide accessible support for self-management of LBP in primary care. The aim of this randomised controlled trial is to determine the clinical and cost-effectiveness of the ‘SupportBack’ internet intervention, with or without physiotherapist telephone support in reducing LBP-related disability in primary care patients.Methods and analysis A three-parallel arm, multicentre randomised controlled trial will compare three arms: (1) usual primary care for LBP; (2) usual primary care for LBP and an internet intervention; (3) usual primary care for LBP and an internet intervention with additional physiotherapist telephone support. Patients with current LBP and no indicators of serious spinal pathology are identified and invited via general practice list searches and mailouts or opportunistic recruitment following LBP consultations. Participants undergo a secondary screen for possible serious spinal pathology and are then asked to complete baseline measures online after which they are randomised to an intervention arm. Follow-ups occur at 6 weeks, 3, 6 and 12 months. The primary outcome is physical function (using the Roland and Morris Disability Questionnaire) over 12 months (repeated measures design). Secondary outcomes include pain intensity, troublesome days in pain over the last month, pain self-efficacy, catastrophising, kinesophobia, health-related quality of life and cost-related measures for a full health economic analysis. A full mixed-methods process evaluation will be conducted.Ethics and dissemination This trial has been approved by a National Health Service Research Ethics Committee (REC Ref: 18/SC/0388). Results will be disseminated through peer-reviewed journals, conferences, communication with practices and patient groups. Patient representatives will support the implementation of our full dissemination strategy.Trial registration number ISRCTN14736486.

Prostate cancer (PCa) is the second leading cause of cancer-related death among Black men who present with higher incidence, mortality, and survival compared to other racial groups. African immigrant men, however, are underrepresented in PCa research and thus this research sought to address that gap. This study applied a social determinants of health framework to understand the knowledge, perceptions, and behavioral tendencies regarding PCa in African immigrants. African immigrant men and women residing in different parts of the country (California, Texas, Colorado, Oklahoma, and Florida) from various faith-based organizations, African community groups, and social groups were recruited to participate in key informant interviews ( n = 10) and two focus groups ( n = 23). Four themes were identified in this study: (a) PCa knowledge and attitudes—while knowledge is very limited, perceptions about prostate health are very strong; (b) culture and gender identity strongly influence African health beliefs; (c) preservation of manhood; and (d) psychosocial stressors (e.g., financial, racial, immigration, lack of community, and negative perceptions of invasiveness of screening) are factors that play a major role in the overall health of African immigrant men. The results of this qualitative study unveiled perceptions, attitudes, beliefs, and knowledge of PCa among African immigrants that should inform the planning, development, and implementation of preventive programs to promote men’s health and PCa awareness.

Objectives Amid a political agenda for integrated, high-value care, the UK is implementing its Low Back and Radicular Pain Pathway. To align care with need, it is imperative to understand the patients’ perspective. The purpose of this study was, therefore, to explore how people experience being managed for sciatica within an National Health Service (NHS) pathway.Design Qualitative interpretative study.Setting Musculoskeletal Service in an NHS, Primary Care Trust, UK.Participants The sample comprised 14 people aged ≥18 years with a clinical presentation of sciatica, who were currently under the care of a specialist physiotherapist (the specialist spinal triage practitioner), had undergone investigations (MRI) and received the results within the past 6 weeks. People were excluded if they had previously undergone spinal surgery or if the suspected cause of symptoms was cauda equina syndrome or sinister pathology. Participants were sampled purposively for variation in age and gender. Data were collected using individual semi-structured interviews (duration: 38–117 min; median: 82.6 min), which were audio-recorded and transcribed verbatim. Data were analysed thematically.Results A series of problems with the local pathway (insufficient transparency and information; clinician-led decisions; standardised management; restricted access to specialist care; and a lack of collaboration between services) made it difficult for patients to access the management they perceived necessary. Patients were therefore required to be independent and proactive or have agency. This was, however, difficult to achieve (due to the impact of sciatica and because patients lacked the necessary skills, funds and support) and together with the pathway issues, this negated patients’ capability to manage sciatica.Conclusions This novel paper explores how patients experience the process of being managed within a sciatica pathway. While highlighting the need to align with recommended best practice, it shows the need to be more person-centred and to support and empower patient agency.Trial registration number ClinicalTrials.gov reference (UOS-2307-CR); Pre-results.

Acute interstitial nephritis is a well-known cause of acute kidney injury, but its association with cocaine use is extremely rare. In this article, we chronicle the case of a patient who developed acute interstitial nephritis secondary to cocaine insufflation. Furthermore, we conducted a systematic literature search of MEDLINE, Cochrane, Embase, and Scopus databases regarding cocaine-induced acute interstitial nephritis. A comprehensive review of the search results yielded a total of 7 case reports only. The data on patient characteristics, clinical features, biochemical profiles, treatment, and outcomes were collected and analyzed. This paper illustrates that acute interstitial nephritis may be added to the list of differentials in patients with acute kidney injury and a history of cocaine use. The therapeutic approach for cocaine-related kidney disease may be different than other etiologies responsible for acute renal insult. Prompt recognition of this entity is crucial because such patients may ultimately develop severe deterioration in renal function.

Global and national policies state that all children and young people should be part of decision making and that outcomes that matter to them should take priority, yet patient-centred outcomes have been identified as a gap in the paediatric chronic pain literature. This study gave youths experiencing chronic pain a platform to have their views heard. Using novel methods, twenty-one young people, aged 11 to 18 years old, completed a semi-structured interview in which they constructed a timeline drawing to symbolise their treatment. They identified when aspects of their life changed (outcomes) and described the importance of these changes. Thematic analysis identified four themes that emerged at different stages of the treatment: “perfect storm”; “turning points”; “disconnect”; and; “free”. “Turning points” were points in time when the narrative of the young person took a turn in a different direction. At these points, the outcomes important to them also changed. Youths initially prioritised outcomes related to pain, then during treatment the focus became their emotional functioning, with role functioning and “going out” becoming the focus at the end. The stage of treatment as perceived by the young person impacted which outcomes mattered most.

Abstract Background Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges. Methods In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines. Results Gene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance. Conclusions Overall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance.

Mountain biking is an increasingly popular outdoor activity on the extreme sport continuum. Extreme and high-risk sports have been investigated using a variety of motivational theories with sensation seeking a dominant theme; however, behavioral and motivational homogeneity within these types of populations should not be assumed. Recent studies have highlighted the therapeutic potential of extreme sports and similar outdoor activities. The aim of this study was to describe the characteristics of mountain biking participants, their engagement methods, and perceived benefits to mental health and well-being. This was a cross-sectional survey and participants were recruited via social media. An online questionnaire specific to the domain of mountain biking was developed. Analysis of the full sample (n = 1,484) and of three independent paired sub-samples was conducted using SPSS. The sub-samples compared the results of males and females; younger and older riders; and those who have recently engaged in downhill mountain biking and those who have not. The results have succeeded in identifying some disparities in mountain biker characteristics and engagement methods. The results suggest that some riders found pleasure in higher risk engagement. The study proposes various explanations for the disproportion of women in mountain biking. Irrespective of the confounding factors related to rider characteristics or engagement methods, mountain bikers reported copious benefits to mental health and well-being related to their engagement. There was a high reported usage of mountain biking as a coping strategy. As such, this study provides insights that could inform the development of outdoor activities as interventions for mental health.

Background: Developmental dysplasia of the hip (DDH) is a very common congenital disorder, and late-presenting cases often require surgical treatment. Surgical reduction of the hip may be complicated by avascular necrosis (AVN), which occurs as a result of interruption to the femoral head blood supply during treatment and can result in long-term problems. Some surgeons delay surgical treatment until the ossific nucleus (ON) has developed, whereas others believe that the earlier the reduction is performed, the better the result. Currently there is no definitive evidence to support either strategy. Objectives: To determine, in children aged 12 weeks to 13 months, whether or not delayed surgical treatment of a congenitally dislocated hip reduces the incidence of AVN at 5 years of age. The main clinical outcome measures were incidence of AVN and the need for a secondary surgical procedure during 5 years’ follow-up. In addition, to perform (1) a qualitative evaluation of the adopted strategy and (2) a health economic analysis based on NHS and societal costs. Design: Phase III, unmasked, randomised controlled trial with qualitative and health economics analyses. Participants were randomised 1 : 1 to undergo either early or delayed surgery. Setting: Paediatric orthopaedic surgical centres in the UK. Participants: Children aged 12 weeks to 13 months with DDH, either newly diagnosed or following failed splintage, and who required surgery. We had a target recruitment of 636 children. Interventions: Surgical reduction of the hip performed as per the timing allocated at randomisation. Main outcome measures: Primary outcome – incidence of AVN at 5 years of age (according to the Kalamchi and MacEwen classification). Secondary outcomes – need for secondary surgery, presence or absence of the ON at the time of primary treatment, quality of life for the main carer and child, and a health economics and qualitative analysis. Results: The trial closed early after reaching

Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.

Background: The Alexander technique probably helps back pain but it is unclear whether or not it can be combined with physiotherapy exercise classes, how many lessons are needed and what mechanisms might be involved. Objectives: To undertake a feasibility trial of the Alexander technique and supervised exercise classes and perform exploratory biomechanical and neuromuscular physiological marker analyses to better understand mediators of recovery. Design: Feasibility parallel-group randomised controlled trial. Setting: General practices in southern England. Participants: Patients with recurrent back pain (at least 3 weeks’ duration of a current episode). Interventions: Participants were allocated by an external randomisation line to four groups: (1) normal care, (2) 10 Alexander technique lessons, (3) 12 physiotherapy exercise classes, (4) Alexander technique lessons plus exercise classes. Main outcome measures: The feasibility outcomes were recruitment, acceptability and follow-up. The clinical outcomes were the Roland–Morris Disability Questionnaire (RMDQ), days in pain, the Von Korff pain and disability scale, overall improvement, fear of activity, enablement, the Oswestry Disability Index and the Aberdeen pain and function scale. Laboratory-based markers were axial muscle tone and flexibility, electrical activity, muscle tone and mechanical properties of elasticity and stiffness, trunk strength, and proprioception. Results: In total, 83 patients consented, 69 were randomised and 56 (81%) were followed up at 6 months. Most patients had long-standing pain (median > 300 days of pain). The RMDQ and other instruments were sensitive to change and the preliminary evidence suggests that the Aberdeen scale could be a useful measure. Study procedures were feasible and three methods of recruitment were successfully piloted. At 6 months the control group had changed little (RMDQ 1 point lower than at baseline) and, compared with the control group, clinically important improvements in RMDQ were seen in all groups, albeit not significant [Alexander technique −3.0, 95% confidence interval (CI) −6.7 to 0.8]; exercise classes −2.9, 95% CI −6.5 to 0.8; combined Alexander technique + exercise classes −2.50, 9% CI −6.20 to 1.19]. Novel biomechanical variables strongly associated with RMDQ score at 6 months were muscle tone (0.94 increase in RMDQ per unit increase in Hz, 95% CI 0.48 to 1.40; p