Quantifying infection risks in incompatible living donor kidney transplant recipients.

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0-4 plasmaphereses, n = 47), moderate (5-9, n = 74), and high (≥10, n = 94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high-intensity desensitization (P < .001). The most common infections were UTI (33.5% of ILDKT vs. 21.5% compatible), opportunistic (21.9% vs. 10.8%), and bloodstream (19.1% vs. 5.4%) (P < .001). In weighted models, a trend toward increased risk was seen in low (wIRR = 0.77 1.402.56 ,P = .3) and moderately (wIRR = 0.88 1.352.06 ,P = .2) desensitized recipients, with a statistically significant 2.22-fold (wIRR = 1.33 2.223.72 ,P = .002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR = 2.62 3.574.88 , P < .001) and death-censored graft loss (wHR = 1.15 4.0113.95 ,P = .03). Post-KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients.

Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis.

Gulf War illness (GWI) is a chronic disease of unknown etiology characterized by persistent symptoms such as cognitive impairment, unexplained fatigue, pervasive pain, headaches, and gastrointestinal abnormalities. Current reports suggest that as many as 200,000 veterans who served in the 1990-1991 Persian Gulf War were afflicted. Several potential triggers of GWI have been proposed including chemical exposure, toxins, vaccines, and unknown infectious agents. However, a definitive cause of GWI has not been identified and a specific biological marker that can consistently delineate the disease has not been defined. Myalgic encephalomyelitis (ME) is a disease with similar and overlapping symptomology, and subjects diagnosed with GWI typically fit the diagnostic criteria for ME. For these reasons, GWI is often considered a subgroup of ME. To explore this possibility and identify immune parameters that may help to understand GWI pathophysiology, we measured 77 serum cytokines in subjects with GWI and compared these data to that of subjects with ME as well as healthy controls. Our analysis identified a group of cytokines that identified ME and GWI cases with sensitivities of 92.5% and 64.9%, respectively. The five most significant cytokines in decreasing order of importance were IL-7, IL-4, TNF-α, IL-13, and IL-17F. When delineating GWI and ME cases from healthy controls, the observed specificity was only 33.3%, suggesting that with respect to cytokine expression, GWI cases resemble control subjects to a greater extent than ME cases across a number of parameters. These results imply that serum cytokines are representative of ME pathology to a greater extent than GWI and further suggest that the two diseases have distinct immune profiles despite their overlapping symptomology.

A systematic review and meta-analysis to compare the efficacy of acyclovir 3% ophthalmic ointment to idoxuridine in curing herpetic keratitis by Day 7 of treatment.

BACKGROUND: This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis (HK) presenting as dendritic and geographic ulcer sub-types. DATA SOURCES: Publications in human subjects were identified by searching the Ovid MEDLINE database through April 2011, combining medical subject headings (MESH) "Keratitis, Herpetic/" AND "Acyclovir/" limiting by the key words "topical" OR "ointment" and also restricted to MESH "Administration, Topical/" OR "Ointments/". The results were cross checked with the references used in the Cochrane Database Syst Rev. 1:1-134, 2009 and GlaxoSmithKline clinical documents related to acyclovir. STUDY SELECTION: Randomized, double-masked studies in subjects diagnosed with HK with head to head comparator arms of ACV ophthalmic ointment and topical IDU that had actual or calculable healing rates at Day seven. DATA EXTRACTION: Data independently extracted from identified articles by two authors of this manuscript. DATA SYNTHESIS: Data from seven randomized, controlled trials (RCT) evaluating 432 subjects that met inclusion criteria (214 were treated with ACV and 218 were treated with IDU) and had Day seven healing rates calculable. All sub-classified lesions were identified as either dendritic ulcers (n = 185) or geographic ulcers (n = 35). The Cochran-Mantel-Haenszel (CMH) method in Biometrics 10:417-51, 1954 and JNCI 22:719-48, 1959, controlling for study, was performed as the primary analysis using SAS v9. Homogeneity was assessed using Breslow-Day-Tarone (BDT) test in IARC 1:1-32, 1980 and Biometrika 72:91-5, 1985. The analysis was performed with outliers removed to assess their impact. RESULTS: ACV showed statistically significant greater odds of healing HK at Day seven in all subjects (Odds Ratio 3.95, 95% CI2.60, 6.00, p < 0.0001), in dendritic ulcers (Odds Ratio 4.22, 95% CI: 2.14, 8.32; p < 0.0001) and geographic ulcers (Odds Ratio 5.31, 95% CI: 1.09, 25.93; p = 0.0244). CONCLUSION: ACV 3% ophthalmic ointment is a valuable intervention for dendritic and geographic corneal ulcers. ACV and IDU were generally well tolerated in the studies reviewed.

Guideline for referral of patients with suspected prostate cancer by family physicians and other primary care providers.

OBJECTIVE: The aim of this guideline is to assist FPs and other primary care providers with recognizing features that should raise their suspicion about the presence of prostate cancer in their patients. COMPOSITION OF THE COMMITTEE: Committee members were selected from among the regional primary care leads from the Cancer Care Ontario Provincial Primary Care and Cancer Network and from among the members of the Cancer Care Ontario Genitourinary Cancer Disease Site Group. METHODS: This guideline was developed through systematic review of the evidence base, synthesis of the evidence, and formal external review involving Canadian stakeholders to validate the relevance of recommendations. REPORT: Evidence-based guidelines were developed to improve the management of patients presenting with clinical features of prostate cancer within the Canadian context. CONCLUSION: These guidelines might lead to more timely and appropriate referrals and might also be of value for informing the development of prostate cancer diagnostic programs and for helping policy makers to ensure appropriate resources are in place.

Systematic review of clinical features of suspected prostate cancer in primary care.

OBJECTIVE: To systematically review the literature and provide an update and integration of existing peer-reviewed guidelines with recent systematic reviews and with primary studies related to the early recognition and management of prostate cancer in primary care. DATA SOURCES: We searched MEDLINE and EMBASE for relevant articles. The quality of the evidence to support existing guideline recommendations and the consistency of recommendations with updated evidence were assessed. Applicability in a Canadian primary care setting was also evaluated. STUDY SELECTION: All studies conducted in the primary care setting that provided information on clinical features predictive of prostate cancer were included. Also, studies that assessed the accuracy of nomograms to predict prostate cancer were reviewed. SYNTHESIS: The findings suggest that lower urinary tract symptoms are not highly predictive of prostate cancer. However, evidence suggests that FPs might be good at discriminating between patients with and without prostate cancer using digital rectal examination and prostate-specific antigen testing. Nomograms might also be useful in assessing patients for aggressive prostate cancers. CONCLUSION: The results of this review can be used to inform recommendations for referral for suspected prostate cancer in the primary care setting. They could also inform development of prostate cancer diagnostic assessment programs.

Guideline for referral of patients with suspected lung cancer by family physicians and other primary care providers.

OBJECTIVE: The aim of this guideline is to assist FPs and other primary care providers with recognizing features that should raise their suspicions about the presence of lung cancer in their patients. COMPOSITION OF THE COMMITTEE: Committee members were selected from among the regional primary care leads from the Cancer Care Ontario Provincial Primary Care and Cancer Network and from among the members of the Cancer Care Ontario Lung Cancer Disease Site Group. METHODS: This guideline was developed through systematic review of the evidence base, synthesis of the evidence, and formal external review involving Canadian stakeholders to validate the relevance of recommendations. REPORT: Evidence-based guidelines were developed to improve the management of patients presenting with clinical features of lung cancer within the Canadian context. CONCLUSION: Earlier identification and referral of patients with lung cancer might ultimately help improve lung cancer morbidity and mortality. These guidelines might also be of value for informing the development of lung cancer diagnostic programs and for helping policy makers to ensure appropriate resources are in place.

Systematic review of guidelines for the management of suspected lung cancer in primary care.

OBJECTIVE: To systematically review the literature and provide an update and integration of existing peer-reviewed guidelines with recent systematic reviews and with primary studies related to the early recognition and management of lung cancer in primary care. DATA SOURCES: MEDLINE and EMBASE were searched for relevant articles. The quality of the evidence to support existing guideline recommendations, and the consistency of recommendations with updated evidence, were assessed. Applicability in a Canadian primary care setting was also evaluated. STUDY SELECTION: All studies that explored signs or symptoms of or risk factors for lung cancer in the primary care setting were included. All diagnostic studies in which symptomatic primary care patients underwent 1 or more investigations were also searched. SYNTHESIS: Recommendations were consistent among guidelines despite a paucity of supporting evidence. Updated evidence provided further support for the recommendations. Recommendations for identifying signs and symptoms of lung cancer presenting in primary care and for initial management can be adopted and applied within a Canadian primary care setting. CONCLUSION: This updated review of recommendations might help promote evidence-based practice and, ultimately, more timely management and improved prognosis for lung cancer patients. It might also assist in the development of lung cancer diagnostic assessment programs.

Clinical Characteristics and Outcomes of COVID-19 Acute Respiratory Distress Syndrome (ARDS) Survivors in Early Pandemic: A Single Healthcare System Retrospective Study.

INTRODUCTION:  Acute respiratory distress syndrome (ARDS) management in the intensive care unit (ICU) has attracted strong interest since the start of the COVID-19 pandemic. Our retrospective study aims to describe the outcomes and predictors of mortality of ARDS associated with COVID-19 within one university-based healthcare system. METHODS:  We identified 165 patients within our healthcare system during the months of April 2020 through July 2020, who were admitted to our medical ICUs and eligible for our study. Baseline patient characteristics, ICU and hospital course information, ICU interventions, ventilator settings, and hospital complications were collected and analyzed using descriptive statistical techniques. RESULTS:  Our cohort had an average age of 64. No significant difference in mortality was identified with male vs. female gender or BMI. Most of the patient cohort was identified as black (68.2%). The overall mortality of our cohort was 38.2%. Hyperlipidemia, coronary artery disease, and chronic obstructive pulmonary disease were all associated with higher mortality. There was a significant difference in mortality between those with higher observed ventilator plateau pressures at 24 hours and higher driving pressures at 24 hours. CONCLUSION:  COVID-19-associated ARDS is associated with significant mortality. Physicians should be aware of pre-existing conditions potentially related to worse outcomes so that they receive an appropriate level of care in a timely manner. Ventilator management should focus on maintaining low intra-thoracic pressure changes. Prospective studies are needed to guide COVID-19-associated ARDS management.

A novel FK506-like binding protein interacts with the glucocorticoid receptor and regulates steroid receptor signaling.

FKBP-like (FKBPL) protein is a novel immunophilin-like protein that plays a role in the cellular stress response. Its three tetratricopeptide repeat motifs are homologous to the heat shock protein 90 interaction sites of other immunophilins that have roles in steroid hormone receptor signaling. In this study, using biomolecular complementation and coimmunoprecipitation techniques, we show that FKBPL also colocalizes and interacts with the components of the heat shock protein 90-glucocorticoid receptor (GR) complex and demonstrate that the PPIase domain of FKBPL is important for the interaction between this complex and the dynein motor protein, dynamitin. Treatment of DU145 cells with the GR ligand, dexamethasone, induced a rapid and coordinated translocation of both GR and FKBPL to the nucleus; this response was perturbed when FKBPL was knocked down with a targeted small interfering RNA. Furthermore, overexpression of FKBPL increased GR protein levels and transactivation of a luciferase reporter gene in response to dexamethasone in DU145 cells. However, these responses were cell line dependent. In summary, these data suggest that FKBPL can be classed as a new member of the FKBP protein family with a role in steroid receptor complexes and signaling.

Hydrolysis of glucosinolates to isothiocyanates after ingestion of raw or microwaved cabbage by human volunteers.

Cabbage contains the glucosinolate sinigrin, which is hydrolyzed by myrosinase to allyl isothiocyanate. Isothiocyanates are thought to inhibit the development of cancer cells by a number of mechanisms. The effect of cooking cabbage on isothiocyanate production from glucosinolates during and after their ingestion was examined in human subjects. Each of 12 healthy human volunteers consumed three meals, at 48-h intervals, containing either raw cabbage, cooked cabbage, or mustard according to a cross-over design. At each meal, watercress juice, which is rich in phenethyl isothiocyanate, was also consumed to allow individual and temporal variation in postabsorptive isothiocyanate recovery to be measured. Volunteers recorded the time and volume of each urination for 24 h after each meal. Samples of each urination were analyzed for N-acetyl cysteine conjugates of isothiocyanates as a measure of entry of isothiocyanates into the peripheral circulation. Excretion of isothiocyanates was rapid and substantial after ingestion of mustard, a source of preformed allyl isothiocyanate. After raw cabbage consumption, allyl isothiocyanate was again rapidly excreted, although to a lesser extent than when mustard was consumed. On the cooked cabbage treatment, excretion of allyl isothiocyanate was considerably less than for raw cabbage, and the excretion was delayed. The results indicate that isothiocyanate production is more extensive after consumption of raw vegetables but that isothiocyanates still arise, albeit to a lesser degree, when cooked vegetables are consumed. The lag in excretion on the cooked cabbage treatment suggests that the colon microflora catalyze glucosinolate hydrolysis in this case.