Forgiveness Is the Attribute of the Strong:Nonadherence and Regimen-Shortening in Drug-Sensitive TB

RATIONALE: 'Forgiveness' charts the ability of a drug or regimen to withstand non-adherence without negative clinical consequences. OBJECTIVES: We aimed to determine the influence of regimen length, regimen drugs and dosing, and when during treatment non-adherence occurs on the forgiveness of anti-tuberculosis regimens. METHODS: Using data from three randomised controlled trials comparing experimental four-month regimens for drug-sensitive tuberculosis with the standard six-month regimen, we used generalised linear models to examine how the risk of a negative composite outcome changed as dose-taking decreased. The percentage of doses taken and absolute number of doses missed were calculated, during the intensive and continuation phases of treatment, and overall. A mediation analysis was undertaken to determine how much of the association between intensive phase dose-taking and the negative composite outcome was mediated through continuation phase dose-taking. MEASUREMENTS AND MAIN RESULTS: Forgiveness of the four-month and six-month regimens did not differ for any treatment period. Importantly, four-month regimens were no less forgiving of small numbers of absolute missed doses than the six-month regimen (e.g. for 3-7 missed doses versus no missed doses (baseline), six-month regimen adjusted risk ratio 1.65 (95% confidence interval 0.80-3.41) and four-month regimens 1.80 (1.33-2.45)). No four-month regimen was conclusively more forgiving than another. We found evidence of mediation by continuation phase dose-taking on the intensive phase dose-taking and negative composite outcome relationship. CONCLUSIONS: With the current appetite for, and progress towards, shorter drug-sensitive tuberculosis regimens worldwide, we offer reassurance that shorter regimens are not necessarily less forgiving of non-adherence. Given the importance of continuation phase adherence, patient support during this period should not be neglected

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer

BACKGROUND The comparative effectiveness of treatments for prostate cancer that is detected by prostatespecific antigen (PSA) testing remains uncertain. METHODS We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. RESULTS There were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P = 0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P = 0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P = 0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). CONCLUSIONS At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.) a bs tr ac

Reducing intrapartum-related deaths and disability: can the health system deliver?

BACKGROUND: Each year 1.02 million intrapartum stillbirths and 904,000 intrapartum-related neonatal deaths (formerly called "birth asphyxia") occur, closely linked to 536,000 maternal deaths, an estimated 42% of which are intrapartum-related. OBJECTIVE: To summarize the results of a systematic evidence review, and synthesize actions required to strengthen healthcare delivery systems and home care to reduce intrapartum-related deaths. METHODS: For this series, systematic searches were undertaken, data synthesized, and meta-analyses carried out for various aspects of intrapartum care, including: obstetric care, neonatal resuscitation, strategies to link communities with facility-based care, care within communities for 60 million non-facility births, and perinatal audit. We used the Lives Saved Tool (LiST) to estimate neonatal deaths prevented with relevant interventions under 2 scenarios: (1) to address missed opportunities for facility and home births; and (2) assuming full coverage of comprehensive emergency obstetric care and emergency newborn care. Countries were first grouped into 5 Categories according to level of neonatal mortality rate and examined, and then priorities were suggested to reduce intrapartum-related deaths for each Category based on health performance and possible lives saved. RESULTS: There is moderate GRADE evidence of effectiveness for the reduction of intrapartum-related mortality through facility-based neonatal resuscitation, perinatal audit, integrated community health worker packages, and community mobilization. The quality of evidence for obstetric care is low, requiring further evaluation for effect on perinatal outcomes, but is expected to be high impact. Over three-quarters of intrapartum-related deaths occur in settings with weak health systems marked by low coverage of skilled birth attendance (<50%), low density of skilled human resources (<0.9 per 1000 population) and low per capita spending on health (<US $20 per year). By providing comprehensive emergency obstetric care and emergency newborn care for births already occurring in facilities, 327,200 intrapartum-related neonatal deaths could be averted globally, and with full (90%) coverage, 613,000 intrapartum-related neonatal deaths could be saved, primarily in high mortality settings. CONCLUSION: Even in high-performance settings, there is scope to improve intrapartum care and especially reduce impairment and disability. Addressing missed opportunities for births already occurring in facilities could avert 36% of intrapartum-related deaths. Improved quality of care through drills and audit are promising strategies. However, the majority of deaths occur in poorly performing health systems requiring urgent strategic planning and investment to scale up effective care at birth, neonatal resuscitation, and community mobilization as well as to develop, adapt, and introduce tools, technologies, and task shifting to reach the poorest