Nyt fra tidsskrifterne

An integrated-care intervention conducted in primary care practices reduced all-cause mortality among elderly patients with atrial fibrillation (AF), a noninferiority trial in the European Heart Journal demonstrated.

Daily low-dose aspirin does not reduce the risk of dementia, mild cognitive impairment (MCI), or cognitive decline, according to a secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, published in Neurology.

Treatment with the HIV combination drug lopinavir-ritonavir did not accelerate recovery or improve mortality rates among hospitalized patients with severe coronavirus disease 2019 (COVID-19), a trial in the New England Journal of Medicine reported.

In Reply Ms Saban and colleagues raise questions about treatment with intravenous ondansetron in our cohort study of congenital malformations. We reported an adjusted relative risk (RR) of oral clefts of 0.95 (95% CI, 0.63-1.43) for intravenous ondansetron and 1.24 (95% CI, 1.03-1.48) for oral ondansetron in an earlier publication. Although the point estimate is lower for intravenous ondansetron compared with oral ondansetron, the 95% CI was wide, with an upper limit similar to that for oral ondansetron. Although the increase in risk was statistically significant for oral ondansetron and was not for intravenous ondansetron, interpretation of risk estimates from epidemiological studies should focus on the magnitude of the observed increase in risk and the precision of the estimate and not on statistical significance alone. Based on our analyses, given the width of the 95% CIs, there is insufficient evidence to conclude that the observed risks are different for intravenous vs oral ondansetron.

In Reply As pointed out by Dr Cramer, the cohorts in our pooled analysis assessed powder use with less detail compared with prior case-control studies. He is also correct that most participants were postmenopausal at enrollment, although ever use included premenopausal time and we considered menopausal status and hormone use as effect modifiers. We noted that genital powder exposure was likely misclassified for some individuals, especially with regard to frequency and duration, and we did not have data on changes in use over time, use during specific exposure windows, or use of different types of powder. This lack of detail may have biased our effect estimates toward the null.

To the Editor Dr Huybrechts and colleagues conducted a population-based cohort study of intravenous ondansetron use during pregnancy and congenital malformations and found no association.

To the Editor We disagree with the analysis and interpretation of the findings presented by Dr O’Brien and colleagues. The increased risk of ovarian cancer in women with intact genital tracts exposed to powder (HR, 1.13) is actually greater than the estimated 10% increased incidence of ovarian cancer attributable to cumulative talc exposure with 10 000 or more applications previously reported in women with intact genital tracts. The lack of association in women without an intact genital tract is consistent with their curtailed exposure. O’Brien and colleagues discounted the results because their statistical test for heterogeneity was not statistically significant. No statistical test is needed to know that women without an intact genital tract face a different risk of ovarian cancer than women whose genital tract is intact.

This survey study describes surgical trainees’ self-reported experiences of bullying and symptoms of burnout and suicidality assessed at the time of their board certification examination.

The etiology of pellagra has attracted the consideration of a number of investigators who have been able to study it on an unusually large scale and with exceptional facilities. In this country the zeist theory, which related pellagra in some way to the dietary use of maize and maize products, has been finally abandoned. An exclusive diet of corn is unquestionably inadequate; and corn damaged by microbiotic changes may well be harmful at times to persons ingesting it. But no adequate review of the actual incidence of pellagra, as it has occurred in different places and among different peoples, will any longer justify the assumption that the pathogenesis of the disease is concerned primarily with a corn factor. Pellagra may occur without the use of corn.

In a little more than 1 month, US society and its hospitals were transformed by coronavirus disease 2019 (COVID-19). The once-boisterous streets of New York City became quiet, while the hospital wards reverberated with the swooshes and beeps usually heard in intensive care units (ICUs). COVID-19 echoed that duality. There are so many outside the hospital who were silently infected, while so many fought for their lives in the hospital, struggling just to breathe.

Traumatic brain injury (TBI) was diagnosed in more than 1 million US inpatient stays and emergency department (ED) visits in 2017, a recent Agency for Healthcare Research and Quality (AHRQ) report estimated.

Patients who die while receiving hospice care at home often leave behind unused controlled substances that aren’t disposed of properly and could be diverted or misused, according to a recent US Government Accountability Office (GAO) report.

Consuming a Mediterranean diet, particularly with lots of fish, was associated with higher cognitive function, National Eye Institute (NEI) researchers and colleagues reported recently.

This JAMA Guide to Statistics and Methods reviews common types of nonparametric statistics, which make no assumptions about underlying population distribution, and explains when they are appropriate to use.

The treatment of hypertension in older adults is a major public health concern. Among the nearly 13 million persons in the United States aged 80 years or older, approximately 80% have high blood pressure (BP). Hypertension is the most potent modifiable risk factor for cardiovascular disease in older adults and has been strongly associated with stroke, myocardial infarction, heart failure, peripheral artery disease, kidney failure, and dementia. Thus, defining optimal strategies for managing elevated BP in older individuals is a high priority.

On February 12, 2020, the Federation of State Medical Boards and the National Board of Medical Examiners announced a change in score reporting of Step 1 of the United States Medical Licensing Examination (USMLE) from a 3-digit numerical score to pass/fail. As explained in the Viewpoint by Chaudhry et al, 3-digit numerical scoring is perceived to have had deleterious effects on student well-being and the medical education learning environment.

This Arts and Medicine feature presents a neurology-themed crossword puzzle with clinical clues and other brain teasers.

This Viewpoint discusses the shifting landscape of health care financing, regulation, and delivery as a result of the coronavirus pandemic, and discusses regulatory and other changes that need to be in place if telehealth and physician practice and hospital mergers become the “new normal” once the pandemic is controlled.

This Viewpoint discusses the likely effects of the COVID-19 pandemic on US health care spending and on estimates of its share of gross domestic product (GDP).

In this narrative medicine essay, an internist considers the effects of the coronavirus disease 2019 pandemic on noninfected patients whose access to care may be blocked by fear, economic loss, or an overwhelmed health care system.

This study uses an atomizer and fluorescent markers to simulate contamination of uncovered skin and hair of health care workers wearing personal protective equipment after intubating patient manikins under emergency conditions.

Health care personnel who care for critically ill patients with suspected or confirmed novel coronavirus disease 2019 (COVID-19) routinely participate in procedures, such as endotracheal intubation, that may create infectious aerosols. Among persons infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, approximately 8% will require endotracheal intubation and mechanical ventilation.

In the Original Investigation titled “Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area” published online April 22, 2020, in JAMA, clarification and correction of data were required. In the Abstract, Results paragraph, the sentence reporting mortality for patients receiving mechanical ventilation should read, “As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital.” This same sentence was added to the second paragraph of the Results section in the text. In the first paragraph of the text Results, the sentence about test results should read, “The first test for COVID-19 was positive in 5517 patients (96.8%), while 183 patients (3.2%) had a negative first test and positive repeat test.” In the Discussion, a paragraph was added to clarify the calculation of mortality rates. In Table 2, the number (%) of patients with concurrent entero/rhinovirus infection should be “22 (52.4).” This article has been corrected online.

This JAMA Insights Clinical Update reviews current approaches to screening for and managing opioid use disorder, summarizing available screening instruments, diagnostic criteria, and appropriate use of medication-assisted treatment (MAT), including methadone, buprenorphine, and naltrexone.

This case series describes clinical characteristics, health services use, and outcomes of patients with confirmed coronavirus disease 2019 (COVID-19) cared for at 12 hospitals of a single health system in the New York City (NYC) area.

This study reports on the prevalence, intensity, and timing of an altered sense of smell or taste in patients with SARS-CoV-2 infections.

The COVID-19 pandemic has accounted for tens of thousands of deaths and ultimately will affect millions more people who will survive. There will be time to mourn the victims and care for the survivors. But it is also time to recognize and thank some of the heroes who have emerged so far.

This JAMA Patient Page describes who should wear face masks during the COVID-19 pandemic and provides suggestions for making masks at home and wearing them properly.

This study assessed the spectrum of initial symptoms at the onset of polymerase chain reaction–confirmed coronavirus disease 2019 (COVID-19) among health care personnel in King County, Washington.

This Medical News Feature examines what hemodialysis centers are doing to protect their high-risk patients from COVID-19.

This study describes the prevalence of SARS-CoV-2 co-infection with noncoronavirus respiratory pathogens in a sample of symptomatic patients undergoing PCR testing in March 2020.

This Viewpoint proposes a framework for modifying cancer care in the midst of the COVID-19 pandemic that balances considerations about the time-sensitivity of patient need for visits and treatment, risk of infectious exposure, and hospital and staff capacity and stress.

This Viewpoint discusses the second surge of COVID-19 patients on postacute care facilities and offers suggestions on how the medical community and policy makers should prepare by ensuring adequate infrastructure, staff training, and protective equipment.

This Viewpoint discusses the ways social media can be used as a critical tool in managing the COVID-19 outbreak, such as by directing users to trusted sources and counteracting misinformation, and how it can transform aspects of preparedness and response for the future.

This Viewpoint reviews options legally available to state Medicaid programs to respond to the COVID-19 pandemic, including increasing coverage of the uninsured, expanding telehealth capabilities, removing financial barriers to testing and treatment, and easing limits on drug prescriptions.

This Viewpoint discusses the rationale for the announced 2022 change in USMLE Step 1 examination scoring from a 3-digit score to a pass/fail designation, addressing concerns that the change might lead to a shift in the importance of Step 2 Clinical Knowledge scores and emphasizing it as one part of a process to improve students’ transition into graduate medical education (GME) training programs.

This Viewpoint reviews the roles international medical graduates (IMGs) play in US health care systems and discusses the potential challenges that the announced 2022 change in USMLE Step 1 examination scoring from a 3-digit score to a pass/fail designation will pose for this workforce segment.

This Viewpoint discusses possible unforeseen consequences of the announced 2022 change to USMLE Step 1 licensure examination results reporting from a 3-digit score to a pass/fail designation, including increased emphasis by programs on the scored Step 2 Clinical Knowledge examination and increased reliance on institutional reputations as criteria to recruit trainees.

AbstractBackgroundInfection-induced preterm birth is a major cause of neonatal mortality and morbidity and leads to preterm premature rupture of the placental chorioamniotic membranes. The loss of amniotic epithelial cells and tensile strength preceding membrane rupture is poorly understood. We hypothesized that intrauterine bacterial infection induces changes in microRNA (miRNA) expression, leading to amniotic epithelial cell loss and membrane weakening.MethodsTen pregnant pigtail macaques received choriodecidual inoculation of either Group B Streptococcus (GBS) or saline (N=5/group). Placental chorioamniotic membranes were studied using RNA microarray and immunohistochemistry. Chorioamniotic membranes from women with preterm premature rupture of membranes (pPROM) and normal term pregnancies was studied using transmission electron microscopy.ResultsIn our model, an experimental GBS infection was associated with changes in the miRNA profile in the chorioamniotic membranes consistent with epithelial to mesenchymal transition (EMT) along with loss of epithelial (E-cadherin) and gain of mesenchymal (vimentin) markers. Similarly, loss of desmosomes (intercellular junctions) was seen in placental tissues from women with pPROM.

AbstractBackgroundIn tissue infections, adenosine triphosphate (ATP) is released into extracellular space and contributes to purinergic chemotaxis. Neutrophils are important players in bacterial clearance and recruited to the site of tissue infections. Pneumococcal infections can lead to uncontrolled hyper-inflammation of the tissue along with substantial tissue damage through excessive neutrophil activation and uncontrolled granule release. We aimed to investigate the role of ATP in neutrophil response to pneumococcal infections.MethodsPrimary human neutrophils were exposed to the pneumococcal strain TIGR4 and its pneumolysin deficient mutant or directly to different concentrations of recombinant pneumolysin. Neutrophil activation was assessed by measurement of secreted azurophilic granule protein resistin and profiling of the secretome, using mass spectrometry.ResultsPneumococci are potent inducers of neutrophil degranulation. Pneumolysin was identified as a major trigger of neutrophil activation. This process is partially lysis independent and inhibited by ATP. Pneumolysin and ATP interact with each other in the extracellular space leading to reduced neutrophil activation. Proteome analyses of the neutrophil secretome confirmed that ATP inhibits pneumolysin-dependent neutrophil activation.ConclusionsOur findings suggest that despite its cytolytic activity, pneumolysin serves as a potent neutrophil activating factor. Extracellular ATP mitigates pneumolysin induced neutrophil activation.

AbstractGlobally, tuberculosis is the leading infectious cause of death; discovering biomarkers that predict a high mortality-risk may improve treatment outcomes. We prospectively enrolled 252 pulmonary tuberculosis patients who were not co-infected with human immunodeficiency virus and initiated anti-tuberculosis treatment, measured serum procalcitonin levels, and assessed mortality. Procalcitonin serum levels higher than 0.13 ng/ml (day 0), 0.05 ng/ml (day 7), 0.12 ng/ml (day 14), and 0.06 ng/ml (day 28) predicted non-survivors with odds ratios 7.9, 14.3, 20.0, and 7.3 (P ≤ 0.005, for all), respectively. Therefore, serum procalcitonin levels are a promising mortality-risk indicator for pulmonary tuberculosis patients.

The coronavirus disease 2019 (COVID-19) broke out throughout the world now. The total number of deaths has been Over 88900 up to now. The patients with confirmed COVID-19 progressed to acute respiratory distress syndrome (ARDS) rapidly in an incident rate as high as 41.8%(Wu et al., 2020), and many of them require mechanic ventilation. In a cohort of an intensive care unit (ICU) from Italy, 1287 cases need respiratory support, and among them, 88% of patients (1150 cases) had to be supported with mechanical ventilation(Grasselli et al., 2020).

The human intestinal anaerobic commensal and opportunistic pathogen Bacteroides fragilis does not synthesize the tetrapyrrole protoporphyrin IX in order to form heme which is required for growth stimulation and survival in vivo. Consequently, B. fragilis acquires essential heme from host tissues during extra-intestinal infection. The absence of several genes necessary for de novo heme biosynthesis is a common characteristic in many anaerobic bacteria; however, the uroS gene, encoding a uroporphyrinogen-III synthase for an early step of heme biosynthesis, is conserved among the heme-requiring Bacteroidales that inhabit the mammalian gastrointestinal tract. In this study we show that the ability of B. fragilis to utilize heme or protoporphyrin IX for growth was greatly reduced in a uroS mutant. This growth defect appears to be linked to the suppression of the reverse chelatase and the ferrochelatase activities in the absence of uroS. In addition, this uroS suppressive effect was enhanced by deletion of the yifB gene which encodes for a Mg2+-chelatase protein belonging to the ATPases associated with various cellular activities (AAA+) superfamily of proteins. Furthermore, the uroS and the uroS yifB double-mutant had a severe survival defect when compared to the parent strain in competitive infection assays using animal models of intra-abdominal infection and intestinal colonization. This shows that the presence of uroS and yifB genes in B. fragilis seems to be linked to pathophysiological and nutritional competitive fitness for survival in host tissues. Genetic complementation studies and enzyme kinetics assays indicate that B. fragilis UroS is functionally different from canonical bacterial UroS. Taken together, these findings show that heme assimilation and metabolism in the anaerobe B. fragilis has diverged from aerobic and facultative anaerobic pathogenic bacteria.…

W. Zhang et al.

Colistin resistance in Klebsiella pneumoniae is predominantly caused by mutations that increase expression of the arn (also known as pbg or pmrF) operon. Expression is activated by the PhoPQ and PmrAB two-component systems. Constitutive PhoPQ activation occurs directly by mutation or following loss of MgrB. PhoPQ may also cross-activate PmrAB via the linker protein PmrD. Using proteomics, we show that MgrB loss causes a wider proteomic effect than direct PhoPQ activation, suggesting additional targets for MgrB. Different mgrB mutations cause different amounts of Arn protein production, which correlated with colistin MIC. Disruption of phoP in an mgrB mutant had a reciprocal effect to direct activation of PhoQ in a wild-type background, but the regulated proteins showed almost total overlap. Disruption of pmrD or pmrA slightly reduced Arn protein production in an mgrB mutant, but production was still high enough to confer colistin resistance; disruption of phoP conferred wild-type Arn production and colistin MIC. Activation of PhoPQ directly, or through mgrB mutation did not significantly activate PmrAB or PmrC production but direct activation of PmrAB by mutation did, and also activated Arn production and conferred colistin resistance. There was little overlap between the PmrAB and PhoPQ regulons. We conclude that under the conditions used for colistin susceptibility testing, PhoPQ-PmrD-PmrAB cross-regulation is not significant and that independent activation of PhoPQ or PmrAB is the main reason that Arn protein production increases above the threshold required for colistin resistance.…

In response to the recent discussion on xdr typhoid in Pakistan1, we would like to bring attention towards critical genotypic evolution in Salmonella Typhi strains from Pakistan which would be of interest to healthcare community....…

T-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins like actin and tubulin. In Leishmania donovani, subunit of TCP1 (LdTCP1) has been cloned and characterized. It forms high molecular weight, homo-oligomeric complex that performs ATP dependent protein folding. In the present study, we evaluated the essentiality of LdTCP1 gene. Gene replacement studies indicate that LdTCP1 is essential for parasite survival. The LdTCP1 single-allele replacement mutants exhibited slowed growth and decreased infectivity in mouse macrophages compared to the wild-type parasites. Modulation of LdTCP1 expression in promastigotes, also modulate cell cycle progression. Suramin, an anti-trypanosomal drug, not only inhibited the luciferase refolding activity of recombinant LdTCP1 homo-oligomeric complex but also exhibited potential antileishmanial efficacy both in vitro and in vivo. The interaction of suramin and LdTCP1 was further validated by isothermal titration calorimetry. The study suggests LdTCP1 as potential drug target and also provides a framework for the development of a new class of drugs.…

Bacterial plasmids harboring antibiotic resistance genes are critical in the spread of antibiotic resistance. It is known that plasmids differ in their kinetic values i.e. conjugation rate, segregation rate by copy-number incompatibility with related plasmids, and rate of stochastic loss during replication. They also differ in cost to the cell in terms of reducing fitness and in the frequency of compensatory mutations compensating plasmid cost. However, we do not know how variation in these values influences the success of a plasmid and their resistance genes in complex ecosystems, as the microbiota. Genes are in plasmids, plasmids in cells, cells in bacterial populations and microbiotas, which are inside hosts, hosts in human communities at the hospital or the community, under various levels of cross-colonization and antibiotic exposure. Differences in plasmid kinetics might have consequences on the global spread of antibiotic resistance. New membrane computing methods help to predict these consequences. In our simulation, conjugation frequency of at least 10-3 influences the dominance of a strain with a resistance plasmid. Coexistence of different antibiotic resistances occur if host strains can maintain two copies of similar plasmids. Plasmid loss rates of 10-4 or 10-5 or plasmid fitness costs ≥0.06 favor plasmids located in the most abundant species. The beneficial effect of compensatory mutations for plasmid fitness cost is proportional to this cost at high mutation frequencies (10-3-10-5). The results of this computational model clearly show how changes in plasmid kinetics can modify the entire population ecology of antibiotic resistance in the hospital setting.…

Resistance-nodulation-division (RND) efflux pumps are important contributors to bacterial antibiotic resistance. Here, we combine evolutionary sequence analyses, computational structural modeling and ligand docking to develop a framework that can explain the known antibiotic substrate selectivity differences between two Pseudomonas aeruginosa RND transporters, MexY and MexB. For efficient efflux, antibiotic substrates must possess a "Goldilocks affinity": binding strong enough to allow interaction with transporter, but not too tight as to impede movement through the pump.…

Chromosomal resistance to metronidazole has emerged in clinical Clostridioides difficile, but the genetic mechanisms remain unclear. This is further hindered by the inability to generate spontaneous metronidazole-resistant mutants in the lab to interpret genetic variations in clinical isolates. We therefore constructed a mismatch repair mutator, in non-toxigenic ATCC 700057, to survey the mutational landscape for de novo resistance mechanisms. In separate experimental evolutions, the mutator adopted a deterministic path to resistance, with truncation of ferrous iron transporter FeoB1 as a first-step mechanism of low-level resistance. Deletion of feoB1 in ATCC 700057 reduced intracellular iron content, appearing to shift cells toward flavodoxin-mediated oxidoreductase reactions, which are less favorable for metronidazole's cellular action. Higher level resistance evolved from sequential acquisition of mutations to catalytic domains of pyruvate-ferredoxin/flavodoxin oxidoreductase (PFOR encoded by nifJ); a synonymous codon change to putative xdh (xanthine dehydrogenase encoded by CD630_31770), likely affecting mRNA stability; and lastly, frameshift and point mutations that inactivated the iron-sulfur cluster regulator (IscR). Gene silencing of nifJ, xdh or iscR with catalytically dead Cas9 revealed that resistance involving these genes only occurred when feoB1 was inactivated i.e. resistance was only seen in the feoB1-deletion mutant and not the isogenic WT parent. Interestingly, metronidazole resistance in CDI-associated strains, carrying mutations in nifJ, was reduced upon gene complementation. This supports that mutations to PFOR is one mechanism of metronidazole resistance in clinical strains. Our findings indicate that metronidazole resistance in C. difficile is complex, involving multi-genetic mechanisms that could intersect with iron-dependent and oxidoreductive metabolic pathways.…