Weak evidence, supplemented with common sense for reduction in postoperative pulmonary complications

A clinical decision report appraising: Kaminski PN, Forgiarini LA, Jr., Andrade CF. Early respiratory therapy reduces postoperative atelectasis in children undergoing lung resection. Respir Care. 2013;58(5):805-809. https://doi.org/10.4187/respcare.01870 for prevention of postoperative pulmonary complications following thoracic surgery for a patient who is not able to participate in incentive spirometry

Campylobacter jejuni bacteremia in the setting of pancytopenia

Introduction: Campylobacter species are a common infectious cause of acute diarrhea worldwide. Small gram-negative bacteria, Campylobacter species are commonly transmitted fecal-orally and frequently found nonpathogenically in the guts of animals including chickens, creating a risk for frequent animal-human transmission. Campylobacter jejuni, one of the most important Campylobacter species for human health, typically produces a watery or inflammatory diarrhea. It is common in developing countries and outbreaks are often linked to contaminated water, unpasteurized milk, undercooked poultry, and contact with animals or infected persons. C. jejuni is a fastidious, gram-negative spiral-shaped rod which is best detected by culture but can also be seen on microscopic examination of a stool sample of a symptomatic patient with enteritis. Microscopy typically also reveals red blood cells or neutrophils. Culture is usually performed using a selective agar with sheep blood, vancomycin, amphotericin B, cephalothin, polymyxin B, and trimethoprim, incubated at 42 degrees with 5-10% oxygen, 1-10% carbon dioxide, and some hydrogen. C. jejuni typically presents in adults with diarrhea, commonly associated with abdominal pain and a high fever. The diarrhea is usually watery but frequently becomes bloody. Symptoms usually peak for 24-48 hours before gradually resolving, but some cases can last up to a week. While antibiotics are not typically necessary, as the course is short, they are commonly used in more severe or prolonged cases or in cases where the patient has immunosuppression or immunodeficiency. Infection can spread to contiguous organs, including the pancreas or gallbladder, and bacteremia can lead to seeding of distant organs, though bacteremia is rare and usually occurs only in immunocompromised patients. Complications of infection can include Guillain-Barre syndrome, reactive arthritis, and spontaneous abortion. Case description: Our patient is a 57-year-old woman with a past medical history of decompensated NASH cirrhosis and type II diabetes mellitus currently undergoing workup for a pancytopenia who presented to our emergency department with low-grade fever two days after bone marrow biopsy. She was found to have a two-day history of explosive watery yellow stool without any nausea, vomiting, or abdominal discomfort. Her temperature was 38.1 degrees Celsius with an increase in white blood cells to 4,000 from her baseline of 3,000, with minor increases in creatinine and liver enzymes stable as per her baseline. On CT, she had mild duodenitis. Influenza and Clostridium difficile workup were negative. Stool and blood cultures were taken and she was started on IV vancomycin and cefepime for her neutropenic fever. Stool culture came back positive for C. jejuni and blood cultures later came back positive for the same, demonstrating curved gram-negative bacteria. Due to her neutropenia and her existing once-weekly ciprofloxacin dosing for spontaneous bacterial peritonitis prophylaxis, she was treated azithromycin for a total of 7 days. During her inpatient stay, her bone marrow biopsy also came back and appeared normal. She was discharged to follow up on the pancytopenia with her usual doctors, continuing her SBP prophylaxis and counseled on common complications of C. jejuni. Discussion: Bacteremia is an uncommon consequence of C. jejuni enteritis, though it is also likely underreported due to difficulty in culturing and lack of indication in many patients. Risk of bacteremia increases with immunocompromise, but patients who are not immunocompromised may also be affected. C. jejuni can evade host defenses with several virulence factors, including flagella, cytotoxin, and serum resistance. Risk is also increased with old age and male gender, as well. While most cases may go unnoticed due to the short, self-limiting course of the diarrheal illness, an increased suspicion in patients with immunocompromise may be warranted.https://scholarlycommons.henryford.com/merf2020caserpt/1128/thumbnail.jp

Hepatitis B Therapy in Pregnancy

All decisions about initiating, continuing, or stopping therapy of the hepatitis B virus (HBV) during pregnancy must include an analysis of the risks and benefits for mother and fetus. The trimester of the pregnancy and the stage of the mother’s liver disease are important factors. Treatment in the third trimester may be initiated to aid in preventing perinatal transmission, which appears to be most pronounced in mothers with high viral loads. Consideration of initiating treatment in the third trimester should occur after a high viral load is documented in the latter part of the second trimester, to allow adequate time for initiation of antiviral therapy with significant viral suppression before delivery. This discussion should include the topic of breastfeeding, because it is generally not recommended while receiving antiviral therapy. Currently, lamivudine and tenofovir appear to be the therapeutic options with the most reasonable safety data in pregnancy

Differential Regulation of Adhesion Complex Turnover by ROCK1 and ROCK2

ROCK1 and ROCK2 are serine/threonine kinases that function downstream of the small GTP-binding protein RhoA. Rho signalling via ROCK regulates a number of cellular functions including organisation of the actin cytoskeleton, cell adhesion and cell migration.In this study we use RNAi to specifically knockdown ROCK1 and ROCK2 and analyse their role in assembly of adhesion complexes in human epidermal keratinocytes. We observe that loss of ROCK1 inhibits signalling via focal adhesion kinase resulting in a failure of immature adhesion complexes to form mature stable focal adhesions. In contrast, loss of ROCK2 expression results in a significant reduction in adhesion complex turnover leading to formation of large, stable focal adhesions. Interestingly, loss of either ROCK1 or ROCK2 expression significantly impairs cell migration indicating both ROCK isoforms are required for normal keratinocyte migration.ROCK1 and ROCK2 have distinct and separate roles in adhesion complex assembly and turnover in human epidermal keratinocytes

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

The connectivity domain: Analyzing resting state fMRI data using feature-based data-driven and model-based methods

AbstractSpontaneous fluctuations of resting state functional MRI (rsfMRI) have been widely used to understand the macro-connectome of the human brain. However, these fluctuations are not synchronized among subjects, which leads to limitations and makes utilization of first-level model-based methods challenging. Considering this limitation of rsfMRI data in the time domain, we propose to transfer the spatiotemporal information of the rsfMRI data to another domain, the connectivity domain, in which each value represents the same effect across subjects. Using a set of seed networks and a connectivity index to calculate the functional connectivity for each seed network, we transform data into the connectivity domain by generating connectivity weights for each subject. Comparison of the two domains using a data-driven method suggests several advantages in analyzing data using data-driven methods in the connectivity domain over the time domain. We also demonstrate the feasibility of applying model-based methods in the connectivity domain, which offers a new pathway for the use of first-level model-based methods on rsfMRI data. The connectivity domain, furthermore, demonstrates a unique opportunity to perform first-level feature-based data-driven and model-based analyses. The connectivity domain can be constructed from any technique that identifies sets of features that are similar across subjects and can greatly help researchers in the study of macro-connectome brain function by enabling us to perform a wide range of model-based and data-driven approaches on rsfMRI data, decreasing susceptibility of analysis techniques to parameters that are not related to brain connectivity information, and evaluating both static and dynamic functional connectivity of the brain from a new perspective

Circulating Inflammatory Markers Are Associated With Magnetic Resonance Imaging-Visible Perivascular Spaces But Not Directly With White Matter Hyperintensities

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) and perivascular spaces (PVS) are features of small vessel disease (SVD), found jointly on magnetic resonance imaging (MRI) of older people. Inflammation is a prominent pathological feature of SVD. We examined the association between inflammation, PVS and WMH in the Lothian Birth Cohort 1936 (N=634). METHODS: We measured plasma fibrinogen, C-reactive protein (CRP) and interleukin-6 (IL-6) and rated PVS in three brain regions. We measured WMH volumetrically and visually using the Fazekas scale. We derived latent variables for ‘PVS’, ‘WMH’ and ‘Inflammation’ from measured PVS, WMH and inflammation markers, and modelled associations using structural equation modelling. RESULTS: After accounting for age, sex, stroke and vascular risk factors, ‘PVS’ were significantly associated with ‘WMH’ (β=0.47, p<0.0001); ‘Inflammation’ was weakly but significantly associated with ‘PVS’ (β=0.12, p=0.048); but not with ‘WMH’ (β=0.02, p=NS). CONCLUSIONS: Circulating inflammatory markers are weakly associated with MR-visible PVS but not directly with WMH. Longitudinal studies should examine whether visible PVS predate WMH progression and whether inflammation-modulators can prevent SVD

Cognitive abilities, brain white matter hyperintensity volume and structural network connectivity in older age

Objective: To assess brain structural connectivity in relation to cognitive abilities in healthy ageing, and the mediating effects of white matter hyper‐intensity (WMH) volume. Methods: MRI data were analysed in 558 members of the Lothian Birth Cohort 1936. Brains were segmented into 85 regions and combined with tractography to generate structural connectomes. WMH volume was quantified. Relationships between whole‐brain connectivity, assessed using graph theory metrics, and four major domains of cognitive ability (visuospatial reasoning, verbal memory, information processing speed and crystallized ability) were investigated, as was the mediating effects of WMH volume on these relationships. Results: Visuospatial reasoning was associated with network strength, mean shortest path length, and global efficiency. Memory was not associated with any network connectivity metric. Information processing speed and crystallized ability were associated with all network measures. Some relationships were lost when adjusted for mean network FA. WMH volume mediated 11%–15% of the relationships between most network measures and information processing speed, even after adjusting for mean network FA. Conclusion: Brain structural connectivity relates to visuospatial reasoning, information processing speed and crystallized ability, but not memory, in this relatively healthy age‐homogeneous cohort of 73 year olds. When adjusted for mean FA across the network, most relationships are lost, except with information processing speed suggesting that the underlying topological network structure is related to this cognitive domain. Moreover, the connectome‐processing speed relationship is partly mediated by WMH volume in this cohort