Treatment Strategy for Rifampin-Susceptible Tuberculosis.

BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. METHODS: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points. RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups. CONCLUSIONS: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).

Drug-resistant tuberculosis treatments, the case for a phase III platform trial.

Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens.

La majorité des essais de phase III relatifs à la tuberculose pharmacorésistante soit n'étaient pas assez puissants pour quantifier les fluctuations au niveau des critères microbiologiques, soit étaient trop longs, se poursuivant parfois pendant dix ans. Les critères primaires composites, dominés par des différences dans l'interruption du traitement et les changements de schéma, pourraient dissimuler d'importantes variations en termes d'échec thérapeutique et de rechute. Bien que les nouveaux traitements contre la tuberculose pharmacorésistante semblent très efficaces, la résistance aux nouveaux médicaments évolue rapidement. Il est donc nécessaire d'opter pour des traitements plus courts, plus sûrs et mieux tolérés, y compris ceux actifs contre la tuberculose résistant à la bédaquiline. Délaisser la multitude d'essais opposant un schéma de traitement A à un schéma de traitement B pour se diriger vers un unique essai plateforme de phase III de grande envergure permettrait d'obtenir plus vite des estimations solides concernant l'innocuité et l'efficacité relative. En outre, adopter des modèles de plateforme modernes et adaptatifs contribuerait à de meilleures performances. Enfin, la collaboration entre investigateurs, représentants des communautés concernées, bailleurs de fonds et organismes de réglementation est essentielle à l'élaboration de ce type d'essai plateforme de phase III sur les traitements contre la tuberculose pharmacorésistante.

La mayoría de los ensayos en fase III sobre tuberculosis resistente a los fármacos no ha tenido la potencia suficiente para cuantificar diferencias en los criterios de valoración microbiológicos o ha tardado hasta una década en completarse. Los criterios de valoración principales compuestos, dominados por las diferencias en la interrupción del tratamiento y los cambios de régimen, pueden ocultar diferencias importantes en el fracaso del tratamiento y la recaída. Aunque los nuevos regímenes de tratamiento para la tuberculosis resistente a los fármacos parecen muy eficaces, la resistencia a los nuevos fármacos está apareciendo rápidamente. Se necesitan regímenes de tratamiento más cortos, seguros y tolerables, incluidos los activos contra la tuberculosis resistente a la bedaquilina. La transición de múltiples ensayos de régimen A frente a régimen B a un único gran ensayo de plataforma en fase III aceleraría la obtención de estimaciones sólidas de la eficacia y seguridad relativas. Podrían lograrse mayores eficiencias si se adoptaran diseños de plataforma adaptativos modernos. La colaboración entre los autores de los ensayos, los representantes de las comunidades afectadas, los financiadores y los reguladores es esencial para desarrollar un ensayo de plataforma en fase III de este tipo para los regímenes de tratamiento de la tuberculosis resistente a los fármacos.

Evaluation of a Novel Emergency General Surgery Handover: A Prospective Feasibility Study.

INTRODUCTION: High-quality health information handovers are critical to optimal patient care and trainee education. The purposes of this study were to assess the feasibility of implementing an emergency general surgery (EGS) morning handover and to explore its impact upon markers of clinical care. METHODS: This prospective feasibility study was conducted at a single academic tertiary-care medical center following implementation of a novel EGS morning handover process. We assessed organizational perspective through a two-part anonymous survey delivered to the EGS service staff (n = 29) and collected feasibility metrics daily at the morning handover meetings. Exploratory clinical metrics of quality improvement were compared between parallel 5-month periods preimplementation and postimplementation of the handover. Data were compared by descriptive statistics. RESULTS: One hundred and seventeen patients from March 1, 2022, to July 31, 2022, and 185 patients from March 1, 2023, to July 31, 2023, were identified prehandover and posthandover implementation, respectively, with an increase in time to operating room posting by 49% (95% confidence interval [CI]: 1.03-2.14) and no statistically significant change in length of stay. The average duration of the formalized EGS morning handover was 14 min (95% CI: 12:18-15:42) having an average of 12 questions asked (95% CI: 9.98-14.02) and an average attendance of 70% from essential personnel. Eighty-four percent of postimplementation survey responses indicated positive regard toward the new EGS handover. CONCLUSIONS: The implementation of an EGS morning handover is feasible, necessitating further studies to define the impact of the EGS morning handover upon clinical outcomes.

Radiographic characteristics of rifampicin-resistant tuberculosis in the STREAM stage 1 trial and their influence on time to culture conversion in the short regimen.

BACKGROUND: Stage 1 of the STREAM trial demonstrated that the 9 month (Short) regimen developed in Bangladesh was non-inferior to the 20 month (Long) 2011 World Health Organization recommended regimen. We assess the association between HIV infection and radiographic manifestations of tuberculosis and factors associated with time to culture conversion in Stage 1 of the STREAM trial. METHODS: Reading of chest radiographs was undertaken independently by two clinicians, and films with discordant reading were read by a third reader. Recording of abnormal opacity of the lung parenchyma included location (right upper, right lower, left upper, and left lower) and extent of disease (minimal, moderately-advanced, and far advanced). Time to culture conversion was defined as the number of days from initiation of treatment to the first of two consecutive negative culture results, and compared using the log-rank test, stratified by country. Cox proportional hazards models, stratified by country and adjusted for HIV status, were used to identify factors associated with culture conversion. RESULTS: Of the 364 participants, all but one had an abnormal chest X-ray: 347 (95%) had opacities over upper lung fields, 318 (87%) had opacities over lower lung fields, 124 (34%) had far advanced pulmonary involvement, and 281 (77%) had cavitation. There was no significant association between HIV and locations of lung parenchymal opacities, extent of opacities, the presence of cavitation, and location of cavitation. Participants infected with HIV were significantly less likely to have the highest positivity grade (3+) of sputum culture (p = 0.035) as compared to participants not infected with HIV. Cavitation was significantly associated with high smear positivity grades (p < 0.001) and high culture positivity grades (p = 0.004) among all participants. Co-infection with HIV was associated with a shorter time to culture conversion (hazard ratio 1.59, 95% CI 1.05-2.40). CONCLUSIONS: Radiographic manifestations of tuberculosis among the HIV-infected in the era of anti-retroviral therapy may not differ from that among those who were not infected with HIV. Radiographic manifestations were not consistently associated with time to culture conversion, perhaps indicating that the Short regimen is sufficiently powerful in achieving sputum conversion across the spectrum of radiographic pulmonary involvements. TRIAL REGISTRATION: ISRCTN ISRCTN78372190. Registered 14/10/2010. The date of first registration 10/02/2016.

Unmet healthcare needs, access to services and experiences with health providers among persons with spinal cord injury in Australia.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: Appropriate and timely lifelong access to healthcare following a spinal cord injury (SCI) is critical, yet unmet healthcare needs in this population are common. Poor experiences with healthcare providers can be a barrier to health-seeking behaviour, and we hypothesised that there would be an association between unmet healthcare needs and care experiences. This study aimed to: (1) describe healthcare provider utilisation in the past year, unmet care needs and satisfaction with healthcare services; (2) explore the association between experiences with healthcare providers and unmet healthcare needs; and (3) explore the association between healthcare provider utilisation and participant characteristics, including unmet healthcare needs. SETTING: Community. METHODS: Analysis of data for 1579 Australians aged ≥ 18, who were ≥ 1-year post-SCI and living in the community. Bayesian penalised regression was used to model six binary outcomes: unmet healthcare needs; the use of general practitioners (GPs), allied health practitioners, rehabilitation specialists; medical specialists; and hospitalisations in the past 12-months. RESULTS: Unmet needs were reported by 17% of participants, with service cost the common deterrent. There was evidence of an effect for provider experiences on unmet healthcare needs, but no evidence that unmet healthcare needs was associated with the use of GPs, allied health practitioners, and rehabilitation or medical specialists. CONCLUSIONS: Unmet healthcare needs were reported in the context of high healthcare use and large proportions of secondary conditions in a cohort with long-term SCI. Improved health access for people with SCI include better primary-secondary care collaboration is needed.

Emigration of post-spawned twaite shad Alosa fallax, an anadromous and iteroparous fish, in a highly fragmented river.

Anthropogenic barriers are widely known to negatively impact the spawning migrations of anadromous fishes, by delaying or preventing passage upstream. Although the impacts of barriers on emigrating post-spawned adults are less well studied, they could potentially impact the fitness and subsequent return rates of iteroparous species. In this study, passive acoustic telemetry was used to track the emigrations of 53 twaite shad Alosa fallax in the River Severn basin in their first spawning migration a year after being tagged, giving insights into their emigration movements and the impacts of anthropogenic weirs on these movements. A. fallax began their emigrations after spending varying amounts of time and migrating various distances within the river, with late-emigrating individuals moving fastest and most directly. Emigrations became faster and more direct the further downstream individuals were from their furthest upstream extent. Downstream passage delays at weirs increased emigration times by a median of 61%, with environmental conditions (i.e., temperature, flow, and tidal influence on river level) having little influence on downstream passage at weirs with no modifications to facilitate fish passage. As weir-induced emigration delays are suggested to deplete energy reserves (when energy levels are already depleted post-spawning), limit spawning opportunities (by preventing access to downstream spawning habitat), and expose individuals to increased predation risk and suboptimal conditions (e.g., high temperatures), these delays can potentially diminish the benefits of iteroparity. The evidence presented here suggests that more consideration should be given to the potential impacts of anthropogenic barriers on the emigrations of iteroparous species when assessing river connectivity or undertaking barrier mitigation.

Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.

BACKGROUND: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. METHODS: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. FINDINGS: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. INTERPRETATION: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. FUNDING: USAID and Janssen Research & Development.

Outcomes following balloon sphincteroplasty as an adjunct to laparoscopic common bile duct exploration.

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) at the time of cholecystectomy is an efficient pathway for management of choledocholithiasis. Performing this safely under one anesthetic offers advantages over a two-step process with cholecystectomy and endoscopic retrograde cholangiopancreatography (ERCP). Despite the proven efficacy of LCBDE, endoscopy continues to be predominantly utilized. Simplifying the intervention may drive LCBDE adoption. To this end, we refined a stepwise intraoperative pathway that utilizes over the wire balloon catheters to dilate the Sphincter of Oddi to facilitate stone passage into the duodenum. To determine the efficacy during the initial adoption phase on a general surgery service, we reviewed our experience with LCBDE balloon sphincteroplasty as part of this pathway. METHODS: We retrospectively reviewed the records of patients who underwent LCBDE with balloon sphincteroplasty at a single tertiary care center over a three-year period. Preoperative demographics, imaging/laboratory results, intra and postoperative outcomes were reviewed. RESULTS: Choledocholithiasis was managed with transcystic balloon sphincteroplasty during LCBDE in 28 cases over a three-year period. The cohort included 16 women and 12 men with a mean age of 47 years (range = 19-89). Operative indications included cholecystitis (n = 11, 39%), choledocholithiasis (n = 13, 47%), cholelithiasis (n = 2, 7%), and gallstone pancreatitis (n = 2, 7%). The stones were successfully cleared by the balloon sphincteroplasty technique in 75% of the cases. The average fluoroscopy time during LCBDE was 338 s (± 214). The average operating room time was 173 min (± 35). Mean length of stay was 58 h (± 46). There were no intra- or postoperative complications. CONCLUSION: Wire ready cholangiography followed by balloon sphincteroplasty with saline/contrast flush is a simple and safe way to clear the common bile duct. This technique is a gateway for further expansion and adoption of LCBDE.

Australian arm of the International Spinal Cord Injury (Aus-InSCI) Community Survey: 3. Drivers of quality of life in people with spinal cord injury.

STUDY DESIGN: Cross-sectional population-based survey for the Australian cohort of the International Spinal Cord Injury (InSCI) Community Survey. OBJECTIVES: To differentiate subgroups of people with spinal cord injury (SCI) who self-report good and poor overall quality of life (QoL) using domains of the International Classification of Functioning (ICF), and to evaluate how these factors contribute to QoL when considered together, while controlling confounders. SETTING: Australian survey data from four state-wide SCI services, one government insurance agency, and three not-for-profit consumer organisations. METHODS: Explanatory factors for QoL were compared between participants reporting poor vs. good QoL. Path models estimated total, direct and mediated contributions from each explanatory factor to QoL ratings after accounting for confounders. RESULTS: Most participants (62%) reported good or very good QoL, 12% reported poor or very poor QoL. When explanatory factors were considered together, the strongest total effects on QoL involved social integration (+0.36 SDs), subjective social position (+0.29), secondary health condition burden (-0.28), activity/participation problem burden (-0.26), day-to-day assistance (-0.26), mental health (+0.18), pain (-0.16), self-efficacy (+0.15), vitality (+0.14) and environmental barriers (-0.11). Effects of social integration, mental health, vitality, self-efficacy, pain and activity/participation problems were partly or wholly direct. CONCLUSION: Opportunities to improve QoL in people with SCI exist at every level of the health system. Virtually all aspects of the ICF framework make a substantive difference to QoL outcomes. Social and psychological factors and ability to complete desired activities have key direct effects and influence effects of secondary health condition burden and environmental barriers.

Australian arm of the International Spinal Cord Injury (Aus-InSCI) community survey: 1. population-based design, methodology and cohort profile.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To describe design and methods of Australian arm of International Spinal Cord Injury (Aus-InSCI) community survey, reporting on participation rates, potential non-response bias and cohort characteristics. SETTING: Survey of community-dwelling people with SCI at least 12 months post-injury, recruited between March 2018 and January 2019, from state-wide SCI services, a government insurance agency and not-for-profit consumer organisations across four Australian states. METHODS: The Aus-InSCI survey combined data for people with SCI from nine custodians, using secure data-linkage processes, to create a population-based, anonymised dataset. The Aus-InSCI questionnaire comprised 193 questions. Eligibility, response status and participation rates were calculated. Descriptive statistics depict participant characteristics. Logistic regression models were developed for probability of participation, and inverse probability weights generated to assess potential non-response bias. RESULTS: 1579 adults with SCI were recruited, a cooperation rate of 29.4%. Participants were predominantly male (73%), with 50% married. Mean age was 57 years (range 19-94) and average time post-injury 17 years (range 1-73). Paraplegia (61%) and incomplete lesions (68%) were most common. Males were more likely than females to have traumatic injuries (p < 0.0001) and complete lesions (p = 0.0002), and younger age-groups were more likely to have traumatic injuries and tetraplegia (p < 0.0001). Potential non-response bias evaluated using selected outcomes was found to be negligible in the Aus-InSCI cohort. CONCLUSIONS: The Aus-InSCI survey made efforts to maximise coverage, avoid recruitment bias and address non-response bias. The distributed, linked and coded (re-identifiable at each custodian level) 'virtual quasi-registry' data model supports systematic cross-sectional and longitudinal research.

Early and intensive motor training to enhance neurological recovery in people with spinal cord injury: trial protocol.

STUDY DESIGN: Protocol for a multi-centre randomised controlled trial (the SCI-MT trial). OBJECTIVES: To determine whether 10 weeks of intensive motor training enhances neurological recovery in people with recent spinal cord injury (SCI). SETTING: Fifteen spinal injury units in Australia, Scotland, England, Italy, Netherlands, Norway, and Belgium. METHODS: A pragmatic randomised controlled trial will be undertaken. Two hundred and twenty people with recent SCI (onset in the preceding 10 weeks, American Spinal Injuries Association Impairment Scale (AIS) A lesion with motor function more than three levels below the motor level on one or both sides, or an AIS C or D lesion) will be randomised to receive either usual care plus intensive motor training (12 h of motor training per week for 10 weeks) or usual care alone. The primary outcome is neurological recovery at 10 weeks, measured with the Total Motor Score from the International Standards for Neurological Classification of SCI. Secondary outcomes include global measures of motor function, ability to walk, quality of life, participants' perceptions about ability to perform self-selected goals, length of hospital stay and participants' impressions of therapeutic benefit at 10 weeks and 6 months. A cost-effectiveness study and process evaluation will be run alongside the trial. The first participant was randomised in June 2021 and the trial is due for completion in 2025. CONCLUSIONS: The findings of the SCI-MT Trial will guide recommendations about the type and dose of inpatient therapy that optimises neurological recovery in people with SCI. TRIAL REGISTRATION: ACTRN12621000091808 (1.2.2021).

A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.

BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011. METHODS: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority. RESULTS: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).

Rethinking intercurrent events in defining estimands for tuberculosis trials.

BACKGROUND/AIMS: Tuberculosis remains one of the leading causes of death from an infectious disease globally. Both choices of outcome definitions and approaches to handling events happening post-randomisation can change the treatment effect being estimated, but these are often inconsistently described, thus inhibiting clear interpretation and comparison across trials. METHODS: Starting from the ICH E9(R1) addendum's definition of an estimand, we use our experience of conducting large Phase III tuberculosis treatment trials and our understanding of the estimand framework to identify the key decisions regarding how different event types are handled in the primary outcome definition, and the important points that should be considered in making such decisions. A key issue is the handling of intercurrent (i.e. post-randomisation) events (ICEs) which affect interpretation of or preclude measurement of the intended final outcome. We consider common ICEs including treatment changes and treatment extension, poor adherence to randomised treatment, re-infection with a new strain of tuberculosis which is different from the original infection, and death. We use two completed tuberculosis trials (REMoxTB and STREAM Stage 1) as illustrative examples. These trials tested non-inferiority of new tuberculosis treatment regimens versus a control regimen. The primary outcome was a binary composite endpoint, 'favourable' or 'unfavourable', which was constructed from several components. RESULTS: We propose the following improvements in handling the above-mentioned ICEs and loss to follow-up (a post-randomisation event that is not in itself an ICE). First, changes to allocated regimens should not necessarily be viewed as an unfavourable outcome; from the patient perspective, the potential harms associated with a change in the regimen should instead be directly quantified. Second, handling poor adherence to randomised treatment using a per-protocol analysis does not necessarily target a clear estimand; instead, it would be desirable to develop ways to estimate the treatment effects more relevant to programmatic settings. Third, re-infection with a new strain of tuberculosis could be handled with different strategies, depending on whether the outcome of interest is the ability to attain culture negativity from infection with any strain of tuberculosis, or specifically the presenting strain of tuberculosis. Fourth, where possible, death could be separated into tuberculosis-related and non-tuberculosis-related and handled using appropriate strategies. Finally, although some losses to follow-up would result in early treatment discontinuation, patients lost to follow-up before the end of the trial should not always be classified as having an unfavourable outcome. Instead, loss to follow-up should be separated from not completing the treatment, which is an ICE and may be considered as an unfavourable outcome. CONCLUSION: The estimand framework clarifies many issues in tuberculosis trials but also challenges trialists to justify and improve their outcome definitions. Future trialists should consider all the above points in defining their outcomes.

Factors Related to Engagement in Employment After Spinal Cord Injury in Australia: A Cross-sectional Study.

OBJECTIVE: To explore the association between sociodemographic, health, functional independence, and environmental variables with engagement in paid work for people with spinal cord injury (SCI). DESIGN: Self-reported, cross-sectional Australian data from a large international SCI survey. SETTING: Community-based. PARTICIPANTS: 1189 working-age people with SCI (18-67 years) or aged >67 years and engaged in paid employment. Respondents were community based and at least 1 year after injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Employment and work integration variables. Bayesian penalized regression was used to determine associations between 23 predictor variables and engagement in paid work. RESULTS: Most participants (87%) were employed pre-injury, with 39% in paid employment at the time of the survey. Participants who attained a master's/doctoral degree (odds ratio [OR]=3.01; 95% credible interval [CrI], 1.63, 5.44) and those married (OR=1.68; 95% CrI, 1.13, 2.49) were more likely to be engaged in paid work. Women (OR=0.55; 95% CrI, 0.37, 0.81), people receiving a disability pension (OR=0.17; 95% CrI, 0.13, 0.24), and older participants (OR=0.75; 95% CrI, 0.63, 0.90) were less likely to be in paid work. Working participants identified hardships including problems completing their work (60%) and accessing the workplace (32%), as well as unmet needs relating to assistive devices required for completing their work (50%). CONCLUSIONS: Findings from the current study can assist in directing resources to subgroups within the SCI population who need greater assistance or intervention related to employment outcomes, including through vocational rehabilitation services/programs. Unmet needs and workplace issues expressed by employed individuals identify gaps in work integration and satisfaction that could affect employment sustainability that need to be addressed.

Australian arm of the International Spinal Cord Injury (Aus-InSCI) Community Survey: 2. Understanding the lived experience in people with spinal cord injury.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To identify common problems across key domains of functioning, health and wellbeing, as well as evaluate self-reported quality of life (QoL) by people with SCI, examining differences by age, gender, injury characteristics and level of mobility. SETTING: Data from four state-wide SCI clinical services, one government insurance agency and three not-for-profit consumer organisations. METHODS: Participants were 18 years or over with SCI and at least 12 months post-injury, recruited between Mar'18 and Jan'19. The Aus-InSCI questionnaire comprised 193 questions, including socio-demographics, SCI characteristics, body functions and structures, activities and participation, environmental and personal factors, and appraisal of health and well-being. General linear model was used to examine differences in functioning and QoL. RESULTS: Participants (mean age 57 years, range 19-94 years) with tetraplegia and/or complete injuries had more health problems, activity/participation problems and environmental barriers. However, self-rated overall QoL did not differ for injury level or completeness. Participants with more recent injuries exhibited lower independence levels, more mental health problems and poorer satisfaction with self and their living conditions. Major activity/participation problems related to intimate relationships and accessing public transportation. Less than half of the working age population were engaged in paid work. The top two environmental barriers frequently related to accessing public places or homes and unfavourable climatic conditions. CONCLUSIONS: This large, comprehensive community survey draws a detailed picture of the lived experience of people with SCI in Australia, identifying priority needs, gaps in services and barriers to achieving a full and satisfying life.

Employment outcomes following spinal cord injury: a population-based cross-sectional study in Australia.

STUDY DESIGN: Self-reported cross-sectional data for the Australian cohort participating in the International Spinal Cord Injury Community survey. OBJECTIVES: To contextualise post-injury employment for people with spinal cord injury (SCI) in Australia, including work participation rates, time to resuming work, underemployment and pre- and post-SCI employment changes. SETTING: Australian survey data from four state-wide SCI services, one government insurance agency and three not-for-profit consumer organisations across New South Wales, Queensland, South Australia and Victoria. METHODS: Data were analysed from 1579 participants with SCI who are at least 1-year post discharge from an inpatient facility. Survey measures included 16-items dedicated to employment. Pre- and post-injury job titles were based on the International Standard Classification of Occupations (ISCO-08) major classification. A mix of chi-squared, t-test and negative binomial regression were used to analyse data. RESULTS: The absolute post-injury employment rate was 49.9%, with one-third of the sample currently working. Pre-injury employment and engagement with vocational rehabilitation resulted in higher employment rates. Individuals who were unable to return immediately following inpatient rehabilitation took mean 28 months (SD, 35.9) to return. Time to employment was significantly lengthier for those without pre-injury jobs, at 59.7 months [SD, 43.8] (p < 0.001). Engagement in less manual roles increased post-injury, accounting for three quarters of post-SCI jobs. Underemployment was identified by 16.6% of those currently working. CONCLUSIONS: While there are current services and programmes in place in Australia that support post-injury employment, findings indicate a need for more comprehensive early intervention focused services targeted towards employers and individuals.

Advances in clinical trial design: Weaving tomorrow's TB treatments.

Christian Lienhardt and co-authors discuss the conclusions of the PLOS Medicine Collection on advances in clinical trial design for development of new tuberculosis treatments.

Economic evaluation of short treatment for multidrug-resistant tuberculosis, Ethiopia and South Africa: the STREAM trial.

OBJECTIVE: To investigate cost changes for health systems and participants, resulting from switching to short treatment regimens for multidrug-resistant (MDR) tuberculosis. METHODS: We compared the costs to health systems and participants of long (20 to 22 months) and short (9 to 11 months) MDR tuberculosis regimens in Ethiopia and South Africa. Cost data were collected from participants in the STREAM phase-III randomized controlled trial and we estimated health-system costs using bottom-up and top-down approaches. A cost-effectiveness analysis was performed by calculating the incremental cost per unfavourable outcome avoided. FINDINGS: Health-care costs per participant in South Africa were 8340.7 United States dollars (US$) with the long and US$ 6618.0 with the short regimen; in Ethiopia, they were US$ 6096.6 and US$ 4552.3, respectively. The largest component of the saving was medication costs in South Africa (67%; US$ 1157.0 of total US$ 1722.8) and social support costs in Ethiopia (35%, US$ 545.2 of total US$ 1544.3). In Ethiopia, trial participants on the short regimen reported lower expenditure for supplementary food (mean reduction per participant: US$ 225.5) and increased working hours (i.e. 667 additional hours over 132 weeks). The probability that the short regimen was cost-effective was greater than 95% when the value placed on avoiding an unfavourable outcome was less than US$ 19 000 in Ethiopia and less than US$ 14 500 in South Africa. CONCLUSION: The short MDR tuberculosis treatment regimen was associated with a substantial reduction in health-system costs and a lower financial burden for participants.

Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape.

In a Collection Review, Patrick Phillips and colleagues discuss developments in clinical trial design for the evaluation of TB therapeutics.

Patterns and Predictors of Return to Work After Major Trauma: A Prospective, Population-based Registry Study.

OBJECTIVE: To characterize patterns of engagement in work during the 4-year period after major traumatic injury, and to identify factors associated with those patterns. BACKGROUND: Employment is an important marker of functional recovery from injury. There are few population-based studies of long-term employment outcomes, and limited data on the patterns of return to work (RTW) after injury. METHODS: A population-based, prospective cohort study using the Victorian State Trauma Registry. A total of 1086 working age individuals, in paid employment or full-time education before injury, were followed-up through telephone interview at 6, 12, 24, 36, and 48 months post-injury. Responses to RTW questions were used to define 4 discrete patterns: early and sustained; delayed; failed; no RTW. Predictors of RTW patterns were assessed using multivariate multinomial logistic regression. RESULTS: Slightly more than half of respondents (51.6%) recorded early sustained RTW. A further 15.5% had delayed and 13.3% failed RTW. One in 5 (19.7%) did not RTW. Compared with early sustained RTW, predictors of delayed and no RTW included being in a manual occupation and injury in a motor vehicle accident. Older age and receiving compensation predicted both failed and no RTW patterns. Preinjury disability was an additional predictor of failed RTW. Presence of comorbidity was an additional predictor of no RTW. CONCLUSIONS: A range of personal, occupational, injury, health, and compensation system factors influence RTW patterns after serious injury. Early identification of people at risk for delayed, failed, or no RTW is needed so that targeted interventions can be delivered.