Proton Pump Inhibitors Versus Histamine-2 Receptor Antagonists Likely Increase Mortality in Critical Care: An Updated Meta-Analysis

BackgroundUpper gastrointestinal bleeding is common among the critically ill. Recently, the Proton Pump Inhibitors (PPIs) vs. Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) trial suggested PPIs might increase mortality. We performed an updated meta-analysis to further inform discussion.MethodsWe leveraged 2 recent systematic reviews to identify randomized controlled trials directly comparing PPIs and H-2 Receptor Antagonists (H2RAs) for stress ulcer prophylaxis in critically ill patients and reporting mortality. We extracted mortality data from each study and meta-analyzed them with the PEPTIC trial using a random effects model.ResultsOf 28,559 total patients, 14,436 (50.5%) were allocated to PPI and 14,123 to H2RAs (49.5%). Compared to H2RAs, the pooled relative risk for mortality was 1.05 (95% confidence interval 1.00-1.10) with an estimated risk difference for mortality of 9 additional deaths per 1000 patients exposed to PPI (95% confidence interval 0-18); heterogeneity was low (I² = 0%; P = 0.826).ConclusionsStress ulcer prophylaxis with PPIs likely increases mortality compared to H2RAs. Whether stress ulcer prophylaxis is beneficial in critical care remains open to further study.     

Iron status and anemia in the elderly: new findings and a review of previous studies

Iron status was determined in 280 free-living and healthy elderly men (n = 131) and women (n = 149) by assessing dietary and supplemental iron intake as well as ten biochemical measures of iron nutriture (erythrocyte count, hemoglobin level, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, plasma iron level, total iron-binding capacity, per cent transferrin saturation, and ferritin level). Subject ages ranged from 60 to 93 years with a median age of 72 years for both women and men. For comparison purposes, iron status measures in an unselected group of younger men (n = 107) and women (n = 164) between the ages of 20 and 39 years were also obtained. None of the elderly women and only two (1.2 per cent) of the younger women had low hemoglobin levels (less than 12.0 g/dl). Three (2.3 per cent) of the elderly men and none of the younger men had low hemoglobin levels (less than 14 g/dl). Other iron status measures revealed that anemia or iron deficiency was no more prevalent in the healthy elderly population than in the younger adult population when identical criteria were used to assess iron nutriture. The genesis of anemia often seen in the elderly is not completely understood. Reported evidence suggests the presence of anemia in the elderly is a result of overall reduction of hematopoietic reserves. Because of the potentially serious consequences of this assumption about anemia to the treatment of the elderly, the authors critically review some of the studies that have been designed in the past to determine the prevalence and etiology of anemia in the aged. They suggest that health status, race, socioeconomic status, diet, and region are more important than age as explanations for the high prevalence of anemia seen in many previous studies.     

Altered muscle metabolism in rats after thermal injury

Burn injury is associated with an elevation in total body oxygen consumption, increased hepatic alanine uptake and conversion to glucose, and a negative nitrogen balance. The primary source of the alanine used for gluconeogenesis by the liver and of the nitrogen lost as urea is believed to be from skeletal muscle. Selected muscle regulatory enzymes and pyruvate and oleate oxidation rates were assayed for maximal activity during the postburn period. Male Sprague-Dawley rats that received 50% total body surface scald burns on the dorsum and abdomen were examined for citrate synthase (CS), phosphofructokinase (PFK), and glutamate-pyruvate transaminase (GPT) activity in uninjured muscle at 3, 7, 13, and 20 days postburn, and the ability of muscle to oxidize pyruvate and oleate was measured at 3 and 13 days after injury. CS, PFK, and GPT activities increased significantly (p < 0.05) by 13–20 days after injury in the soleus and diaphragm. The epitrochlearis showed no change in CS, but PFK and GPT were elevated within this time frame. The gastrocnemius muscle showed an elevated oleate oxidation rate at 13 days after injury, but no change at 3 days postburn. Pyruvate oxidation rates were unaltered.The results of this study indicate that during the postburn period several metabolic alterations occur in muscle. These adaptations include: (1) elevated CS activity which may be associated with increased oxidative capactiy, (2) increased PFK activity which implies that more substrate is being shuttled through the glycolytic pathway, (3) increased GPT activity which may reflect increased pyruvate conversion to alanine, and (4) increased oleate oxidation rates which demonstrate that muscle is utilizing more fatty acid substrates during the postburn period.     

Thyroid storm in a child following radioactive iodine (RAI) therapy: a consequence of RAI versus withdrawal of antithyroid medication

A 7.5-yr-old boy with Graves' disease, difficult to control with antithyroid medication and radioactive iodine (RAI) therapy, developed thyroid storm encephalopathy on day 13 after withdrawal of methimazole therapy, 4 days after iodine-131 treatment. We attributed his thyroid storm to withdrawal of antithyroid medication as opposed to RAI therapy. We interpret this case as indicating that there may be a need to reevaluate the duration of antithyroid medication withdrawal before RAI therapy for hyperthyroid children at increased risk for thyroid storm.     

Directional genomic hybridization for chromosomal inversion discovery and detection

Chromosomal rearrangements are a source of structural variation within the genome that figure prominently in human disease, where the importance of translocations and deletions is well recognized. In principle, inversions—reversals in the orientation of DNA sequences within a chromosome—should have similar detrimental potential. However, the study of inversions has been hampered by traditional approaches used for their detection, which are not particularly robust. Even with significant advances in whole genome approaches, changes in the absolute orientation of DNA remain difficult to detect routinely. Consequently, our understanding of inversions is still surprisingly limited, as is our appreciation for their frequency and involvement in human disease. Here, we introduce the directional genomic hybridization methodology of chromatid painting—a whole new way of looking at structural features of the genome—that can be employed with high resolution on a cell-by-cell basis, and demonstrate its basic capabilities for genome-wide discovery and targeted detection of inversions. Bioinformatics enabled development of sequence- and strand-specific directional probe sets, which when coupled with single-stranded hybridization, greatly improved the resolution and ease of inversion detection. We highlight examples of the far-ranging applicability of this cytogenomics-based approach, which include confirmation of the alignment of the human genome database and evidence that individuals themselves share similar sequence directionality, as well as use in comparative and evolutionary studies for any species whose genome has been sequenced. In addition to applications related to basic mechanistic studies, the information obtainable with strand-specific hybridization strategies may ultimately enable novel gene discovery, thereby benefitting the diagnosis and treatment of a variety of human disease states and disorders including cancer, autism, and idiopathic infertility.     

Proton pump inhibitor use and risk for recurrent Clostridioides difficile infection: a systematic review and meta-analysis

ObjectivesProton pump inhibitor (PPI) therapy is a potentially modifiable risk factor for recurrent Clostridioides difficile infection (CDI). Citing an absence of clinical trials, many guidelines do not provide recommendations for addressing PPI management. Our aim was to perform an updated systematic review and meta-analysis evaluating the association between PPI use and recurrent CDI addressing prior methodological limitations.MethodsData sources were MEDLINE and EMBASE. Eligible studies were cohort and case–control studies; there were no restrictions on study setting or duration of follow-up. Participants were adults with prior CDI who did or did not receive PPI therapy and were assessed for recurrent CDI. Summary (unadjusted) odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Prespecified subgroup analyses were performed to explore heterogeneity including study design, study quality, duration of follow-up, adjustment for confounders, and outcome definition.ResultsSixteen studies were included in the meta-analysis, comprising 57 477 patients with CDI, of whom 6870 (12%) received PPIs. The rate of recurrent CDI was 24% in patients treated with PPIs versus 18% in those who were not. A meta-analysis that pooled unadjusted odds ratios demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.69, 95%CI 1.46–1.96) versus those who did not. There was moderate heterogeneity between studies (I² 56%); however, a sensitivity analysis restricted to studies with 56 days of follow-up substantially reduced the heterogeneity (OR 1.59, 95%CI 1.36–1.85; I² 12%). An analysis restricted to multivariate studies that combined adjusted ORs also demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.49, 95%CI 1.12–2.00). No publication bias was identified.ConclusionsWe found significantly higher odds of recurrent CDI among users of PPIs that persisted across multiple sensitivity analyses. These results support stronger recommendations for PPI stewardship at CDI diagnosis.     

Exceptional record of mid-Pleistocene vertebrates helps differentiate climatic from anthropogenic ecosystem perturbations

Mid-Pleistocene vertebrates in North America are scarce but important for recognizing the ecological effects of climatic change in the absence of humans. We report on a uniquely rich mid-Pleistocene vertebrate sequence from Porcupine Cave, Colorado, which records at least 127 species and the earliest appearances of 30 mammals and birds. By analyzing >20,000 mammal fossils in relation to modern species and independent climatic proxies, we determined how mammal communities reacted to presumed glacial-interglacial transitions between 1,000,000 and 600,000 years ago. We conclude that climatic warming primarily affected mammals of lower trophic and size categories, in contrast to documented human impacts on higher trophic and size categories historically. Despite changes in species composition and minor changes in small-mammal species richness evident at times of climatic change, overall structural stability of mammal communities persisted >600,000 years before human impacts.