Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.

BACKGROUND: Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. METHODS: Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures. RESULTS: Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. CONCLUSIONS: Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome. CLINICAL TRIALS REGISTRATION: NCT03559582.

Patient preferences for breast cancer screening: a systematic review update to inform recommendations by the Canadian Task Force on Preventive Health Care.

BACKGROUND: Different guideline panels, and individuals, may make different decisions based in part on their preferences. Preferences for or against an intervention are viewed as a consequence of the relative importance people place on the expected or experienced health outcomes it incurs. These findings can then be considered as patient input when balancing effect estimates on benefits and harms reported by empirical evidence on the clinical effectiveness of screening programs. This systematic review update examined the relative importance placed by patients on the potential benefits and harms of mammography-based breast cancer screening to inform an update to the 2018 Canadian Task Force on Preventive Health Care's guideline on screening. METHODS: We screened all articles from our previous review (search December 2017) and updated our searches to June 19, 2023 in MEDLINE, PsycINFO, and CINAHL. We also screened grey literature, submissions by stakeholders, and reference lists. The target population was cisgender women and other adults assigned female at birth (including transgender men and nonbinary persons) aged ≥ 35 years and at average or moderately increased risk for breast cancer. Studies of patients with breast cancer were eligible for health-state utility data for relevant outcomes. We sought three types of data, directly through (i) disutilities of screening and curative treatment health states (measuring the impact of the outcome on one's health-related quality of life; utilities measured on a scale of 0 [death] to 1 [perfect health]), and (ii) other preference-based data, such as outcome trade-offs, and indirectly through (iii) the relative importance of benefits versus harms inferred from attitudes, intentions, and behaviors towards screening among patients provided with estimates of the magnitudes of benefit(s) and harms(s). For screening, we used machine learning as one of the reviewers after at least 50% of studies had been reviewed in duplicate by humans; full-text selection used independent review by two humans. Data extraction and risk of bias assessments used a single reviewer with verification. Our main analysis for utilities used data from utility-based health-related quality of life tools (e.g., EQ-5D) in patients; a disutility value of about 0.04 can be considered a minimally important value for the Canadian public. When suitable, we pooled utilities and explored heterogeneity. Disutilities were calculated for screening health states and between different treatment states. Non-utility data were grouped into categories, based on outcomes compared (e.g. for trade-off data), participant age, and our judgements of the net benefit of screening portrayed by the studies. Thereafter, we compared and contrasted findings while considering sample sizes, risk of bias, subgroup findings and data on knowledge scores, and created summary statements for each data set. Certainty assessments followed GRADE guidance for patient preferences and used consensus among at least two reviewers. FINDINGS: Eighty-two studies (38 on utilities) were included. The estimated disutilities were 0.07 for a positive screening result (moderate certainty), 0.03-0.04 for a false positive (FP; "additional testing" resolved as negative for cancer) (low certainty), and 0.08 for untreated screen-detected cancer (moderate certainty) or (low certainty) an interval cancer. At ≤12 months, disutilities of mastectomy (vs. breast-conserving therapy), chemotherapy (vs. none) (low certainty), and radiation therapy (vs. none) (moderate certainty) were 0.02-0.03, 0.02-0.04, and little-to-none, respectively, though in each case findings were somewhat limited in their applicability. Over the longer term, there was moderate certainty for little-to-no disutility from mastectomy versus breast-conserving surgery/lumpectomy with radiation and from radiation. There was moderate certainty that a majority (>50%) and possibly a large majority (>75%) of women probably accept up to six cases of overdiagnosis to prevent one breast-cancer death; there was some uncertainty because of an indication that overdiagnosis was not fully understood by participants in some cases. Low certainty evidence suggested that a large majority may accept that screening may reduce breast-cancer but not all-cause mortality, at least when presented with relatively high rates of breast-cancer mortality reductions (n = 2; 2 and 5 fewer per 1000 screened), and at least a majority accept that to prevent one breast-cancer death at least a few hundred patients will receive a FP result and 10-15 will have a FP resolved through biopsy. An upper limit for an acceptable number of FPs was not evaluated. When using data from studies assessing attitudes, intentions, and screening behaviors, across all age groups but most evident for women in their 40s, preferences reduced as the net benefit presented by study authors decreased in magnitude. In a relatively low net-benefit scenario, a majority of patients in their 40s may not weigh the benefits as greater than the harms from screening whereas for women in their 50s a large majority may prefer screening (low certainty evidence for both ages). There was moderate certainty that a large majority of women 50 years of age and 50 to 69 years of age, who have usually experienced screening, weigh the benefits as greater than the harms from screening in a high net-benefit scenario. A large majority of patients aged 70-71 years who have recently screened probably think the benefits outweigh the harms of continuing to screen. A majority of women in their mid-70s to early 80s may prefer to continue screening. CONCLUSIONS: Evidence across a range of data sources on how informed patients value the potential outcomes from breast-cancer screening will be useful during decision-making for recommendations. The evidence suggests that all of the outcomes examined have importance to women of any age, that there is at least some and possibly substantial (among those in their 40s) variability across and within age groups about the acceptable magnitude of effects across outcomes, and that provision of easily understandable information on the likelihood of the outcomes may be necessary to enable informed decision making. Although studies came from a wide range of countries, there were limited data from Canada and about whether findings applied well across an ethnographically and socioeconomically diverse population. SYSTEMATIC REVIEW REGISTRATION: Protocol available at Open Science Framework https://osf.io/xngsu/ .

Associations between SARS-CoV-2 infection and incidence of new chronic condition diagnoses: a systematic review.

Because of the large number of infected individuals, an estimate of the future burdens of the long-term consequences of SARS-CoV-2 infection is needed. This systematic review examined associations between SARS-CoV-2 infection and incidence of categories of and selected chronic conditions, by age and severity of infection (inpatient vs. outpatient/mixed care). MEDLINE and EMBASE were searched (1 January 2020 to 4 October 2022) and reference lists scanned. We included observational studies from high-income OECD countries with a control group adjusting for sex and comorbidities. Identified records underwent a two-stage screening process. Two reviewers screened 50% of titles/abstracts, after which DistillerAI acted as second reviewer. Two reviewers then screened the full texts of stage one selections. One reviewer extracted data and assessed risk of bias; results were verified by another. Random-effects meta-analysis estimated pooled hazard ratios (HR). GRADE assessed certainty of the evidence. Twenty-five studies were included. Among the outpatient/mixed SARS-CoV-2 care group, there is high certainty of a small-to-moderate increase (i.e. HR 1.26-1.99) among adults ≥65 years of any cardiovascular condition, and of little-to-no difference (i.e. HR 0.75-1.25) in anxiety disorders for individuals <18, 18-64, and ≥65 years old. Among 18-64 and ≥65 year-olds receiving outpatient/mixed care there are probably (moderate certainty) large increases (i.e. HR ≥2.0) in encephalopathy, interstitial lung disease, and respiratory failure. After SARS-CoV-2 infection, there is probably an increased risk of diagnoses for some chronic conditions; whether the magnitude of risk will remain stable into the future is uncertain.

Quantifying unused opioids following emergency and ambulatory care: A systematic review and meta-analysis.

Objective: To quantify unused opioids among adult and pediatric patients discharged from the emergency department (ED) or ambulatory care settings with a prescription for acute pain. Methods: We searched MEDLINE, Embase, CINHAL, PsycINFO, the Cochrane Library, and the gray literature from inception to April 29, 2021. We included observational studies in which any patient with an acutely painful condition received a prescription for an opioid on discharge from an outpatient care setting, and unused opioids were quantified. Two reviewers screened records for eligibility, extracted data, and conducted the quality assessment. Where possible, we pooled data and otherwise described the results of studies narratively. Total unused prescriptions were synthesized using a weighted average. Random effects models were used, and heterogeneity was measured by the I2 statistic. Our primary outcome was the quantity of unused opioid medication available after receiving a prescription for acute pain. Secondary outcomes were the proportion of patients with unused opioids following a prescription, the proportion of patients using no opioids, morphine equivalents of unused opioids, and factors associated with leftover opioids. Results: In this systematic review and meta-analysis of 9 studies in emergency and ambulatory care settings, 59.6% of prescribed opioids remained unused; pediatric patients had 69.3% of their prescriptions remaining, compared to 54.6% among adult patients. The highest proportion of unused opioids was found following dental extractions (82.6%). Conclusions and Relevance: More than 50% of opioids remain unused following prescriptions for acute pain. Responsible prescribing must be accompanied by education on safer use, storage, and disposal.

Mental health difficulties of adults with COVID-19-like symptoms in Bangladesh: A cross-sectional correlational study.

BACKGROUND: The rapid spread of novel corona virus disease (COVID-19) coupled with inefficient testing capacities in Bangladesh has resulted in a number of deaths from COVID-19-like symptoms that have no official test results. This study was the first study that explored the mental health of adults with the most common COVID-19-like symptoms in Bangladesh. METHODS: This cross-sectional correlational study gathered data via an online survey to explore the mental health of Bangladeshi adults with symptoms akin to COVID-19. Level of stress, anxiety symptoms, and depressive symptoms were measured with the DASS-21. Chi-square tests and multivariate logistic regression was performed to examine the association of variables. RESULTS: The prevalence rates of anxiety symptoms and depressive symptoms of the overall population were 26.9% and 52.0% respectively and 55.6% reported mild to extremely severe levels of stress. Multivariate logistic regression determined that respondents with COVID-19-like symptoms reported higher odds for stress level (AOR = 2.043, CI = 1.51 to 2.76), anxiety symptoms (AOR = 2.770, CI = 2.04 to 3.77) and depressive symptoms (AOR = 1.482, CI = 1.12 to 1.96) than asymptomatic respondents. LIMITATIONS: There was a chance of recall bias as it was not possible to validate the information due to the retrospective design of the study. Recruitment methods only captured internet users, which reduces the generalizability of findings. CONCLUSIONS: Patients with symptoms like those of COVID-19 should be prioritized in the healthcare setting in order to reduce mental health difficulties throughout the pandemic .