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In observational causal inference, exact covariate matching plays two statistical roles: (i) it effectively controls for bias due to measured confounding; (ii) it justifies assumption-free inference based on randomization tests. In this paper we show that inexact covariate matching does not always play these same roles. We find that inexact matching often leaves behind statistically meaningful bias, and that this bias renders standard randomization tests asymptotically invalid. We therefore recommend additional model-based covariate adjustment after inexact matching. In the framework of local misspecification, we prove that matching makes subsequent parametric analyses less sensitive to model selection or misspecification. We argue that gaining such robustness is the primary statistical role of inexact matching. [ABSTRACT FROM AUTHOR]

In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care. [ABSTRACT FROM AUTHOR]

Background Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time. Methods We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths. Results Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%–89%) at 1 month and 62% (IQR, 58%–75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies. Conclusions The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality. Clinical Trials Registration PROSPERO CRD42021253891. [ABSTRACT FROM AUTHOR]

Mitochondria play a central role in aerobic performance. Studies aimed at elucidating how evolved variation in mitochondrial physiology contributes to adaptive variation in aerobic performance can therefore provide a unique and powerful lens to understanding the evolution of complex physiological traits. Here, we review our ongoing work on the importance of changes in mitochondrial quantity and quality to adaptive variation in aerobic performance in high-altitude deer mice. Whole-organism aerobic capacity in hypoxia (VO2max) increases in response to hypoxia acclimation in this species, but high-altitude populations have evolved consistently greater VO2max than populations from low altitude. The evolved increase in VO2max in highlanders is associated with an evolved increase in the respiratory capacity of the gastrocnemius muscle. This appears to result from highlanders having more mitochondria in this tissue, attributed to a higher proportional abundance of oxidative fiber-types and a greater mitochondrial volume density within oxidative fibers. The latter is primarily caused by an over-abundance of subsarcolemmal mitochondria in high-altitude mice, which is likely advantageous for mitochondrial O2 supply because more mitochondria are situated adjacent to the cell membrane and close to capillaries. Evolved changes in gastrocnemius phenotype appear to be underpinned by population differences in the expression of genes involved in energy metabolism, muscle development, and vascular development. Hypoxia acclimation has relatively little effect on respiratory capacity of the gastrocnemius, but it increases respiratory capacity of the diaphragm. However, the mechanisms responsible for this increase differ between populations: lowlanders appear to adjust mitochondrial quantity and quality (i.e. increases in citrate synthase [CS] activity, and mitochondrial respiration relative to CS activity) and they exhibit higher rates of mitochondrial release of reactive oxygen species, whereas highlanders only increase mitochondrial quantity in response to hypoxia acclimation. In contrast to the variation in skeletal muscles, the respiratory capacity of cardiac muscle does not appear to be affected by hypoxia acclimation and varies little between populations. Therefore, evolved changes in mitochondrial quantity and quality make important tissue-specific contributions to adaptive variation in aerobic performance in high-altitude deer mice. [ABSTRACT FROM AUTHOR]