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Meta-analysis is of critical importance to decision makers to assess the comparative efficacy and safety of interventions and is integral to health technology assessment. A major problem for the meta-analysis of continuous outcomes is that associated variance data are not consistently reported in trial publications. The omission of studies from a meta-analysis due to incomplete reporting may introduce bias. The objectives of this study are to summarise and describe the methods used for handling missing variance data in meta-analyses in populations with type 2 diabetes mellitus (T2DM). Electronic databases, Embase, MEDLINE, and the Cochrane Library (accessed June 2015), were systematically searched to identify meta-analyses of interventions in patients with T2DM. Eligible studies included those which analysed the change in HbA1c from baseline. Sixty-seven publications reporting on meta-analyses of change in HbA1c from baseline in T2DM were identified. Approaches for dealing with missing variance data were reported in 41% of publications and included algebraic calculation, trial-level imputation, and no imputation. Meta-analysis publications typically fail to report standardised approaches for dealing with missing variance data. While no particular imputation method is favoured, authors are discouraged from using a no-imputation approach. Instead, authors are encouraged to explore different approaches using sensitivity analyses and to improve the quality of reporting by documenting the methods used to deal with missing variance data.

Background and Objective Clostridium difficile infection (CDI) is associated with high management costs, particularly in recurrent cases. Fidaxomicin treatment results in lower recurrence rates than vancomycin and metronidazole, but has higher acquisition costs in Europe and the USA. This systematic literature review summarises economic evaluations (EEs) of fidaxomicin, vancomycin and metronidazole for treatment of CDI. Methods Electronic databases (MEDLINE ® , Embase, Cochrane Library) and conference proceedings (ISPOR, ECCMID, ICAAC and IDWeek) were searched for publications reporting EEs of fidaxomicin, vancomycin and/or metronidazole in the treatment of CDI. Reference bibliographies of identified manuscripts were also reviewed. Cost-effectiveness was evaluated according to the overall population of patients with CDI, as well as in subgroups with severe CDI or recurrent CDI, or those at higher risk of recurrence or mortality. Results Overall, 27 relevant EEs, conducted from the perspective of 12 different countries, were identified. Fidaxomicin was cost-effective versus vancomycin and/or metronidazole in 14 of 24 EEs (58.3%), vancomycin was cost-effective versus fidaxomicin and/or metronidazole in five of 27 EEs (18.5%) and metronidazole was cost-effective versus fidaxomicin and/or vancomycin in two of 13 EEs (15.4%). Fidaxomicin was cost-effective versus vancomycin in most of the EEs evaluating specific patient subgroups. Key cost-effectiveness drivers were cure rate, recurrence rate, time horizon, drug costs and length and cost of hospitalisation. Conclusions In most EEs, fidaxomicin was demonstrated to be cost-effective versus metronidazole and vancomycin in patients with CDI. These results have relevance to clinical practice, given the high budgetary impact of managing CDI and increasing restrictions on healthcare budgets. Other This analysis was initiated and funded by Astellas Pharma Inc.

Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.

Anti-PD-1 agents are recommended in adjuvant or perioperative settings in some early-stage cancers. The health and productivity benefits of anti-PD-1 use on a population level, however, are unknown. A decision model was developed to quantify the health and productivity outcomes of adding anti-PD-1 agents to traditional management strategies in the adjuvant or perioperative setting for melanoma stage IIB/IIC/III, triple negative breast cancer, and renal cell carcinoma in the United Kingdom. The model consisted of four separate Markov models and compared outcomes in two scenarios: one where anti-PD-1 agents are restricted to advanced/metastatic disease, against one where anti-PD-1 agents are used as adjuvant or perioperative therapy for early-stage cancers. Population and incidence inputs were obtained from nation-specific sources, while efficacy and quality of life data were informed by the individual trials. Productivity outcomes were estimated using a human capital approach. Between 2023 and 2032, 57,075 (60.4%) of 94,426 patients with early-stage cancers eligible for adjuvant or perioperative treatment are estimated to receive anti-PD-1 agents. This was associated with an increase in total life years (8,878, 2.4%), quality-adjusted life-years (9,029, 3.1%), and event-/disease-/recurrence-free life years (25,149, 9.0%), and a reduction in progression events or recurrences (6,839, 16.8%), active metastatic treatments (4,845, 14.0%), and deaths (3,013, 16.2%). The clinical benefits also resulted in a gain in productive years (20,717, 17.6%). The use of anti-PD-1 agents in adjuvant or perioperative settings can lead to substantial health and productivity gains. Effective planning and investment are needed for timely access to these agents for patients.

RituxiCAN-C4 combined an open-labeled randomized controlled trial (RCT) in 7 UK centers to assess whether rituximab could stabilize kidney function in patients with chronic rejection, with an exploratory analysis of how B cell-depletion influenced T cell anti-donor responses relative to outcome. Between January 2007 and March 2015, 59 recruits were enrolled after screening, 23 of whom consented to the embedded RCT. Recruitment was halted when in a pre-specified per protocol interim analysis, the RCT was discovered to be significantly underpowered. This report therefore focuses on the exploratory analysis, in which we confirmed that when B cells promoted CD4+ anti-donor IFNγ production assessed by ELISPOT, this associated with inferior clinical outcome; these patterns were inhibited by optimized immunosuppression but not rituximab. B cell suppression of IFNγ production, which associated with number of transitional B cells and correlated with slower declines in kidney function was abolished by rituximab, which depleted transitional B cells for prolonged periods. We conclude that in this patient population, optimized immunosuppression but not rituximab promotes anti-donor alloresponses associated with favorable outcomes. Registered with EudraCT (2006-002330-38) and www.ClinicalTrials.gov, identifier: NCT00476164.

Background Measurement-based care (MBC) is an evidence-based practice for depression, but its use by clinicians remains low. Enhanced MBC (eMBC), which uses digital technologies, can help to facilitate the use of MBC by clinicians and patients. Understanding factors that act as barriers and drivers to the implementation of MBC and eMBC is important to support the design of implementation strategies, promoting uptake by clinicians and patients. Objective This situational analysis identifies barriers and facilitators to the implementation of standard and eMBC at mental health centers in Shanghai, China. Methods We used mixed methods to develop a comprehensive understanding of the factors influencing MBC and eMBC implementation in Shanghai. This study took place across three mental health centers in Shanghai. We used situational analysis tools to collect contextual information about the three centers, conducted surveys with n  = 116 clinicians and n  = 301 patients, conducted semi-structured interviews with n = 30 clinicians and six focus groups with a total of n  = 19 patients. Surveys were analysed using descriptive statistics, and semi-structured interviews and focus groups were analysed using framework analysis. Results Several potential barriers and facilitators to MBC and eMBC implementation were identified. Infrastructure, cost, attitudes and beliefs, and perceptions about feasibility and efficacy emerged as both challenges and drivers to MBC and eMBC implementation in Shanghai. Conclusions The results of this study will directly inform the design of an implementation strategy for MBC and eMBC in Shanghai, that will be tested via a randomized controlled trial. This study contributes to the emerging body of literature on MBC implementation and, to the best of our knowledge, is the first such study to take place in Asia. This study identifies several factors that are relevant to the equitable delivery of MBC, recognizing the need to explicitly address equity concerns in global mental health implementation research.

Background and objective Orthopaedic services have reorganised their delivery of care in response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. In this study, we aimed to share our operating experience during the coronavirus disease 2019 (COVID-19) pandemic and analyse its effect on urgent hip and knee arthroplasty. Our study involved a comparative analysis between a cohort of patients from 2019 (pre-COVID) and another from 2020. Methods Tha data relating to patients undergoing urgent operations requiring arthroplasty interventions such as for infection, periprosthetic fracture (PPF) and neck of femur fracture (NOF) between April and July of 2020 and 2019 were reviewed prospectively and retrospectively. Patients were categorised according to the Royal College of Surgeons (RCS) case prioritisation and the COVID-19 risk assessment. Data were collected on 30-day mortality, readmissions, reoperations, complications, length of hospital stay and theatre efficiency. This was analysed, matched and compared. Statistical analysis was performed on categorical variables including the time to the theatre as well as dual consultant operating. Results A total of 46 consecutive patients were included in the 2020 cohort with a mean age of 78 years (range: 58-108 years). The median length of stay was 6.5 days (range: 3-35 days) and the median time to theatre for NOF patients was 23.8 hours (range: 16.2-87.7 hours). There were six complications and two deaths; one of the deaths was COVID-19-related. A total of 56 patients were included from 2019 with a mean age of 74.6 years (range: 45-88 years). The median length of stay was five days (range: 1-18 days) and the median time to theatre for NOF patients was 40.8 hours (range: 18.9-167 hours). There were four complications and one death. Conclusion Based on our findings, it is safe to perform complex surgery in a region of low community prevalence of COVID-19, and the outcomes were comparable to those from a pre-COVID-19 cohort.

Introduction Multiligament knee injuries are uncommon but serious injuries. There is ongoing debate on the optimal treatment of these injuries. We designed a study to establish the effects of repair or reconstruction on proprioceptive outcomes following multiligament injury to the knee. Materials and Methods A total of 34 patients were analysed by independent researchers who had no conflict of interest in the cases (23 in the repair group and 11 in the reconstruction group). Proprioception of the knee was measured using a previously validated tool to assess the reproduction of passive positioning. Functional outcome was measured using the Lysholm score. Sub-group analysis was performed. The mean time from injury to review was 83 months (range: 25-193 months). Results There were no significant differences in proprioceptive acuity between the injured (5.9±4.2°; range: 1.0-18.3°) and uninjured contralateral (control) knees (5.2±3.8°; range: 1.0-15.0°; p=0.35). Similarly, there was no significant difference in proprioceptive acuity identified between the injured knees that underwent repair (6.0±4.3°; range: 1.0-18.3°) or reconstruction (5.0±3.6°; range: 1.3-14°; p=0.53). Overall knee outcomes were good; the mean Lysholm score at final follow-up was 75.5±16.8 (range: 36-100). No significant differences were identified in any of the sub-groups. Conclusions We were unable to identify any differences in knee proprioceptive acuity between injured knees and controls nor between the types of surgical treatment, demonstrating equivocal recovery for both methods of treatment.Introduction Multiligament knee injuries are uncommon but serious injuries. There is ongoing debate on the optimal treatment of these injuries. We designed a study to establish the effects of repair or reconstruction on proprioceptive outcomes following multiligament injury to the knee. Materials and Methods A total of 34 patients were analysed by independent researchers who had no conflict of interest in the cases (23 in the repair group and 11 in the reconstruction group). Proprioception of the knee was measured using a previously validated tool to assess the reproduction of passive positioning. Functional outcome was measured using the Lysholm score. Sub-group analysis was performed. The mean time from injury to review was 83 months (range: 25-193 months). Results There were no significant differences in proprioceptive acuity between the injured (5.9±4.2°; range: 1.0-18.3°) and uninjured contralateral (control) knees (5.2±3.8°; range: 1.0-15.0°; p=0.35). Similarly, there was no significant difference in proprioceptive acuity identified between the injured knees that underwent repair (6.0±4.3°; range: 1.0-18.3°) or reconstruction (5.0±3.6°; range: 1.3-14°; p=0.53). Overall knee outcomes were good; the mean Lysholm score at final follow-up was 75.5±16.8 (range: 36-100). No significant differences were identified in any of the sub-groups. Conclusions We were unable to identify any differences in knee proprioceptive acuity between injured knees and controls nor between the types of surgical treatment, demonstrating equivocal recovery for both methods of treatment.

Abstract Purpose Increasing physical activity could reduce the mortality gap experienced by people with serious mental illness (SMI). To be beneficial, physical activity needs to be undertaken regularly over an extended period. This study provides insights into how best to support continued activity for people with SMI by uncovering the underpinning causal mechanisms. Methods An international sample of stakeholders (n = 19) were consulted. In-depth, semi-structured interviews were undertaken with i) peer physical activity practitioners (n = 5) who were involved in the design and delivery of physical activity programmes for people with SMI, ii) physical activity leaders (n = 3) and iii) people with SMI who participated in these physical activity programmes (n = 25). Data were analysed using Framework analysis. Results Activity that is designed specifically for people with SMI and incorporates structured socialisation opportunities facilitates adherence. Gradual exposure to the group is needed, along with 1-to-1 support incorporating personalised goals. Socialisation opportunities require meticulous planning by the practitioners to carefully curate social interactions that encourage bonding between participants. Adherence is supported when programmes are scheduled, regular and have no end date. Programmes must address accessibility needs of participants, for example, ensuring that people are supported to get to and from physical activity venues and help them overcome social anxiety. Tailoring support to the fluctuating symptoms of SMI is also imperative. Qualities of practitioners deemed essential for adherence include soft skills such as the ability to foster warm connections, be accepting and non-judgemental, cultivate mutual respect, not put pressure on participants and encourage autonomous motivation. Mutual compatibility between the participant and practitioner is important and therefore having a choice of practitioners is critical. Adherence is supported when programmes are (co)delivered by practitioners who have lived experience of SMI and who are genuine and vulnerable (they share personal mental health experiences). Conclusions A combination of soft skills in practitioners and resource-intensive intervention components determine adherence to physical activity programmes among people with SMI. Ensuring that programmes are adequately planned, supported and resourced with consideration to these mechanisms will be critical for their ability to foster prolonged participation. Funding This study was supported by the NIHR Clinical Research Network.