Wnt signaling regulates chemokine production and cell migration of circulating human monocytes.

The ß-catenin dependent canonical Wnt signaling pathway plays a crucial role in maintaining normal homeostasis. However, when dysregulated, Wnt signaling is closely associated with various pathological conditions, including inflammation and different types of cancer.Here, we show a new connection between the leukocyte inflammatory response and the Wnt signaling pathway. Specifically, we demonstrate that circulating human primary monocytes express distinct Wnt signaling components and are susceptible to stimulation by the classical Wnt ligand-Wnt-3a. Although this stimulation increased the levels of ß-catenin protein, the expression of the classical Wnt-target genes was not affected. Intriguingly, treating circulating human monocytes with Wnt-3a induces the secretion of cytokines and chemokines, enhancing monocyte migration. Mechanistically, the enhanced monocyte migration in response to Wnt stimuli is mediated through CCL2, a strong monocyte-chemoattractant.To further explore the physiological relevance of these findings, we conducted ex-vivo experiments using blood samples of patients with rheumatic joint diseases (RJD) - conditions where monocytes are known to be dysfunctional. Wnt-3a generated a unique cytokine expression profile, which was significantly distinct from that observed in monocytes obtained from healthy donors.Thus, our results provide the first evidence that Wnt-3a may serve as a potent stimulator of monocyte-driven immune processes. These findings contribute to our understanding of inflammatory diseases and, more importantly, shed light on the role of a core signaling pathway in the circulation.

The real-world safety of sacubitril / valsartan among older adults (≥75): A pharmacovigilance study from the FDA data.

BACKGROUND: Heart failure is a major cause of morbidity and mortality among older adults. Sacubitril-Valsartan (Sac/Val) has been shown to improve patients' outcomes; however, its safety profile among older adults has not been adequately examined. We therefore aimed to examine its safety profile among this population. METHODS: We conducted a retrospective pharmacovigilance study utilizing the FDA's database of safety reports (FAERS). We employed disproportionality analysis comparing Sac/Val to angiotensin receptor blockers (ARBs). We aim to evaluate the reporting of pre-defined adverse events associated with Sac/Val (hypotension, acute kidney injury (AKI), hyperkalemia and angioedema) in two age groups: adults (< 75 years) and older adults (≥ 75). For each subgroup, we calculated reporting odds ratio (ROR) and compared them by calculating P for interaction. RESULTS: The FAERS database encompassed 18,432 unique reports of Sac/Val. Of them, 12,630 (68.5%) subjects were adults (< 75 years), and 5802 (31.5%) were older adults (≥ 75 years), with a median age (IQR) of 68 (59-77). When compared to ARBs, Sac/Val was associated with higher reporting of hypotension, lower reporting of acute kidney injury (AKI) and hyperkalemia, and similar reporting of angioedema. Notably, we did not observe a significant interaction between the age subgroups and the risk estimates (AKI: Pinteraction = 0.72, hyperkalemia: Pinteraction = 0.94, hypotension: Pinteraction = 0.31, and angioedema: Pinteraction = 0.61). CONCLUSIONS: In this postmarking study, none of the prespecified adverse events was reported more frequently in older adults. These findings provide reassurance for safety use of Sac/Val in older adults.

A Longitudinal Assessment of the Natural Change in Haemoglobin, Haematocrit, and Mean Corpuscular Volume with Age.

INTRODUCTION: We aimed to assess the natural annual trends in the levels of haemoglobin, haematocrit, and mean corpuscular volume (MCV) in a population of adults, together with the influence of different clinical parameters on these trends. METHODS: A retrospective analysis was carried out on data from a large cohort of subjects attending a screening centre in Israel. For each subject, the yearly average change of haemoglobin, haematocrit, and MCV was calculated. Statistical analysis was performed for the whole cohort and for different subgroups. RESULTS: The study included 3,551 subjects. The average annual rates of decline were found to be -0.0550 g/dL (95% confidence interval [CI] -0.0590 g/dL to -0.0503 g/dL) and -0.097% (95% CI -0.112% to -0.083%) for haemoglobin and haematocrit, respectively. An average annual increase in the MCV level by 0.184 fL (95% CI 0.168 fL-0.200 fL) was found. Among men, the rate of decline in haemoglobin was found to be twice as high compared with women -0.06 g/dL versus -0.03 g/dL, respectively (p = 0.0063). In a multivariate analysis, gender remained the only parameter significantly associated with the annual decline of haemoglobin (p = 0.0001). CONCLUSION: An annual average decrease in the levels of haemoglobin and haematocrit together with an annual increase in MCV was found. These changes were more prominent in men.

External Validity of a Randomized Controlled Trial on Duration of Antibiotics for the Treatment of Gram-Negative Bacteremia.

INTRODUCTION: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial. METHODS: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017. In a concomitant observational study, RCT participants were compared with patients who fulfilled the inclusion criteria but were not included in the trial due to participation in other trials, discharge before approached by researchers, refusal to participate, or unwillingness of the treating physician to allow participants' recruitment. RESULTS: Six hundred and four RCT patients were compared with 613 nonincluded patients. Almost 50% of nonincluded patients (288/613) were dependent on others for activities of daily living at baseline compared to 37.7% of RCT participants (228/604). Dementia was nearly 2-fold more frequent in nonincluded patients than those included (5.9% [36/613] versus 3.6% [22/604], p = 0.07). Patients who were not included in the RCT were more likely to acquire their infection in the hospital (53.3% [327/613] versus 29.1% [176/604], p < 0.001). The primary composite outcome of mortality, clinical failure, readmissions, or extended hospitalization at 90 days occurred in 353 of 613 nonincluded patients (57.6%) compared to 299 of 604 RCT participants (49.6%), p = 0.005. However, on multivariate analysis noninclusion in the RCT was not an independent risk factor for clinical failure and mortality. CONCLUSIONS: RCTs, even with broad eligibility criteria, do not represent the whole spectrum of patients and leave out a population with more severe illness for whom the evidence is lacking.

Elevated Serum Amyloid A Levels Contribute to Increased Platelet Adhesion in COVID-19 Patients.

Coronavirus disease-19 (COVID-19) patients are prone to thrombotic complications that may increase morbidity and mortality. These complications are thought to be driven by endothelial activation and tissue damage promoted by the systemic hyperinflammation associated with COVID-19. However, the exact mechanisms contributing to these complications are still unknown. To identify additional mechanisms contributing to the aberrant clotting observed in COVID-19 patients, we analyzed platelets from COVID-19 patients compared to those from controls using mass spectrometry. We identified increased serum amyloid A (SAA) levels, an acute-phase protein, on COVID-19 patients' platelets. In addition, using an in vitro adhesion assay, we showed that healthy platelets adhered more strongly to wells coated with COVID-19 patient serum than to wells coated with control serum. Furthermore, inhibitors of integrin aIIbß3 receptors, a mediator of platelet-SAA binding, reduced platelet adhesion to recombinant SAA and to wells coated with COVID-19 patient serum. Our results suggest that SAA may contribute to the increased platelet adhesion observed in serum from COVID-19 patients. Thus, reducing SAA levels by decreasing inflammation or inhibiting SAA platelet-binding activity might be a valid approach to abrogate COVID-19-associated thrombotic complications.

Proton pump inhibitor use and its effect on vitamin B12 and homocysteine levels among men and women: A large cross-sectional study.

BACKGROUND: Previous studies have demonstrated an association between proton pump inhibitors (PPI) use and vitamin B12 deficiency. However, data regarding PPI use and elevated serum homocysteine level, an important marker of vitamin B12 deficiency, are scant. METHODS: Data were collected from medical records of subjects examined at a screening center in Israel. Cross sectional analysis was conducted on 25,953 subjects. Levels of vitamin B12 and homocysteine were compared between subjects who consumed PPI medications and those who did not. RESULTS: The mean age of the study population was 45 years and 33% were females. Subjects who received PPI medications had a minor higher vitamin B12 levels (320 pmol/L vs 300 pmol/L, p=0.024). Levels of vitamin B12 remained higher in females receiving PPI medications after performing a stratified analysis according to subjects' gender. Homocysteine levels were higher in subjects receiving PPI medications as compared to those who did not (12.0 µmol/L vs 11.6 0 µmol/L, p<0.001). Levels remained higher in female subjects after performing a stratified analysis according to subjects' sex. There was no statistically significant difference in the prevalence of vitamin B12 deficiency (according to two cutoffs: vitamin B12≤200 or ≤140 pmol/L) as well as the prevalence of hyperhomocysteinemia (defined as homocysteine >15.0 µmol/L) between the two groups. CONCLUSIONS: According to our study, no association was found between PPI medication use and vitamin B12 deficiency or hyperhomocysteinemia. Patients receiving PPI medications had slightly higher levels of vitamin B12 and homocysteine, however these differences were too small to have any clinical relevance.

Risk factors for functional decline among survivors of Gram-negative bloodstream infection: A prospective cohort study.

OBJECTIVE: To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia. PATIENTS AND METHODS: A prospective cohort study based on a randomized controlled trial conducted between January 1, 2013 and August 31, 2017 in Israel and Italy. Hospitalized patients with Gram-negative bacteremia who survived until day 90 and were not bedridden at baseline were included. The primary end point was functional decline at 90 days. RESULTS: Five hundred and nine patients were included. The median age of the cohort was 71 years (interquartile range [IQR], 60-80 years), 46.4% (236/509) were male and 352 of 509 (69%) patients were independent at baseline. Functional decline at 90 days occurred in 24.4% of patients (124/509). In multivariable analysis; older age (odds ratio [OR], 1.03; for an one-year increment, 95% confidence interval [CI] 1.01-1.05), functional dependence in instrumental activities of daily living at baseline (OR, 4.64; 95% CI 2.5-8.6), low Norton score (OR, 0.87; 95% CI 0.79-0.96) and underlying comorbidities: cancer (OR, 2.01; 95% CI 1.14-3.55) and chronic pulmonary disease (OR, 2.23 95% CI 1.12-4.42) and longer length of hospital stay (OR 1.09; for one-day increment, 95% CI 1.04-1.15) were associated with functional decline. Appropriate empirical antibiotic treatment was associated with lower rates of functional decline within 90 days (OR, 0.4; 95% CI 0.21-0.78). CONCLUSIONS: Patients surviving bloodstream infections have poor long term trajectories after clinical recovery and hospital discharge. This has vast implications for patients, their family members and health policy makers.

Streptococcus gallolyticus endocarditis on a prosthetic tricuspid valve: a case report and review of the literature.

BACKGROUND: Streptococcus gallolyticus subspecies gallolyticus is a known pathogen that causes infective endocarditis, and most cases involve the left heart valves. We present the first reported case of prosthetic tricuspid valve endocarditis caused by this microorganism. Relevant literature is reviewed. CASE PRESENTATION: A 67-year-old Jewish female with a history of a prosthetic tricuspid valve replacement was admitted to the emergency department because of nonspecific complaints including effort dyspnea, fatigue, and a single episode of transient visual loss and fever. No significant physical findings were observed. Laboratory examinations revealed microangiopathic hemolytic anemia and a few nonspecific abnormalities. Transesophageal echocardiogram demonstrated a vegetation attached to the prosthetic tricuspid valve. The involved tricuspid valve was replaced by a new tissue valve, and Streptococcus gallolyticus subspecies gallolyticus was grown from its culture. Prolonged antibiotic treatment was initiated. CONCLUSIONS: Based on this report and the reviewed literature, Streptococcus gallolyticus should be considered as a rare but potential causative microorganism in prosthetic right-sided valves endocarditis. The patient's atypical presentation emphasizes the need for a high index of suspicion for the diagnosis of infective endocarditis.

Risk of stroke and other thromboembolic complications after interruption of DOAC therapy compared with warfarin therapy in patients with atrial fibrillation: a retrospective cohort analysis.

Direct oral anticoagulants (DOACs) have become the treatment of choice in thromboembolism prophylaxis for non-valvular atrial fibrillation, surpassing warfarin. While interruption of DOAC therapy for various reasons is a common eventuality, the body of data from real-world clinical practice on the implications of such interruptions in different clinical settings is still limited. We assessed complication rates from DOAC (apixaban, rivaroxaban, dabigatran) interruption compared with warfarin in hospitalized patients. We performed a retrospective cohort analysis of electronic records of patients hospitalized in Rabin Medical Center between 2010 and 2017. Incidents of anticoagulation interruptions for various reasons (including unintended interruptions) were collected. DOAC-treated patients were excluded if they reported non-compliance, and warfarin-treated patients were excluded if their international normalized ratio measurement on admission was subtherapeutic. Outcomes included ischemic stroke, systemic thromboembolism, myocardial infarction, and all-cause mortality within 90 days of anticoagulation interruption. The median CHA2DS2-VASc score was 5.0 (IQR 4.0-6.0) in both treatment groups. The associated risk of stroke, thromboembolic complications, myocardial infarction, and all-cause mortality after interruption of anticoagulation was not significantly different between the 2 treatment groups. Selective comparison of patients who were well balanced on warfarin before treatment interruption to DOAC-treated patients did not significantly influence the outcomes. This study did not find a significant difference in the complication rate after interruption of DOAC therapy compared with interruption of warfarin therapy in hospitalized patients with a high risk of thromboembolism.

The Role of 18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) in Management of Nocardiosis: A Retrospective Study and Review of the Literature.

INTRODUCTION: 18-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is a well-established tool for managing metastatic infections. Nocardiosis, a primarily pulmonary infection, disseminates at high rates. Routine imaging includes chest CT and brain imaging. We examined the use of FDG-PET/CT in nocardiosis and assessed its contribution to diagnosis and management. METHODS: A retrospective study in two tertiary medical centers during 2011-2020. Individuals with nocardiosis for whom FDG-PET/CT was implemented for any reason were included and their medical records were reviewed. A board-certified nuclear medicine physician independently reviewed all scans. Additionally, a systematic review was conducted according to the PRISMA guidelines, to extract data from publications reporting FDG-PET/CT use for the management of nocardiosis. RESULTS: FDG-PET/CT contributed to the management of all seven patients who met inclusion criteria. It assisted in ruling out an underlying malignancy (29%, 2/7); establishing a wide infection extent (57%, 4/7); and affecting decisions regarding treatment (57%, 4/7), including drug regimen, oral step-down, and duration of therapy. We identified 20 published case reports on this topic. In 80% (16/20), FDG-PET/CT contributed to the management of nocardiosis similar to our study. In addition, in most of the literature cases, FDG-PET/CT guided the diagnostic biopsy. CONCLUSION: FDG-PET/CT is valuable in the diagnosis and management of individuals with nocardiosis. The contribution of incorporating FDG-PET/CT to the management of individuals with nocardiosis and its role in monitoring treatment response and shortening treatment duration should be evaluated in prospective studies.

Secondary bacterial infection in COVID-19 patients is a stronger predictor for death compared to influenza patients.

Secondary bacterial infections are a potentially fatal complication of influenza infection. We aimed to define the impact of secondary bacterial infections on the clinical course and mortality in coronavirus disease 2019 (COVID-19) patients by comparison with influenza patients. COVID-19 (n = 642) and influenza (n = 742) patients, admitted to a large tertiary center in Israel and for whom blood or sputum culture had been taken were selected for this study. Bacterial culture results, clinical parameters, and death rates were compared. COVID-19 patients had higher rates of bacterial infections than influenza patients (12.6% vs. 8.7%). Notably, the time from admission to bacterial growth was longer in COVID-19 compared to influenza patients (4 (1-8) vs. 1 (1-3) days). Late infections (> 48 h after admission) with gram-positive bacteria were more common in COVID-19 patients (28% vs. 9.5%). Secondary infection was associated with a higher risk of death in both patient groups 2.7-fold (1.22-5.83) for COVID-19, and 3.09-fold (1.11-7.38) for Influenza). The association with death remained significant upon adjustment to age and clinical parameters in COVID-19 but not in influenza infection. Secondary bacterial infection is a notable complication associated with worse outcomes in COVID-19 than influenza patients. Careful surveillance and prompt antibiotic treatment may benefit selected patients.

Global Academic Productivity in the Field of Internal Medicine and Its Correlation to National Economic Indicators: A Bibliometric Analysis of 24 Years.

BACKGROUND: Previous studies have demonstrated a correlation between national economic indicators and academic productivity. However, such a relationship has not been studied in the field of internal medicine (IM). METHODS: The number of documents published, number of citable documents, number of citations, citations per document and the h index between 1996 and 2019 in the field of IM among the Organisation for Economic Co-operation and Development (OECD) countries were analysed. Data were derived from the The Scimago Journal and Country rank source. We analysed the correlation between these indicators to the gross domestic product (GDP) per capita, health spending as percent of GDP and gross domestic expenditure on research and development as percent of GDP (GERD). Economic data were collected from the OECD websites. RESULTS: A significant correlation was found between health expenditure and h index (r = 0.75, P < 0.001), number of citations (r = 0.72, P < 0.001), number of documents (r = 0.62, P < 0.001) and number of citable documents (r = 0.61, P < 0.001); between GERD and number of citations (r = 0.6, P < 0.001), h index (r = 0.6, P < 0.001), number of documents published (r = 0.53, P = 0.001) and citable documents (r = 0.51, P = 0.001); between the GDP per capita and number of citations (r = 0.46, P = 0.005), citations per document (r = 0.54, P = 0.001) and h index (r = 0.5, P = 0.002). CONCLUSIONS: This study demonstrated a positive correlation between academic productivity in the field of IM and economic indicators of the OECD countries, mainly health expenditure, implying the advantage of domestic investment in health.

Temporary Trends in Fever following Transcatheter Aortic Valve Implantation.

OBJECTIVES: Fever following transcatheter aortic valve implantation (TAVI) is a common phenomenon, attributed mostly to inflammatory response which may impact outcome. Systemic inflammatory response may be triggered by multiple factors, most associated with the TAVI procedure itself. However, there are no data regarding the incidence of fever following TAVI in contemporary era with newer generation devices. Our primary objective was to measure temporal trends in fever incidence and features following TAVI. METHODS: We analyzed a retrospective cohort of 802 consecutive patients who underwent TAVI at our institution between November 2008 and February 2018. We identified and characterized all patients who developed fever (>38.0°C from any cause) within the first 72 h following the procedure and analyzed incidence and characteristics stratified into 3 time frames: 2008-2014, 2014-2016, and 2016-2018. RESULTS: Following TAVI, 190 (23.7%) patients developed fever (mean age 82.3 ± 5.2 years, 64.2% female). An infectious etiology was evident in only 32.1% of cases. The frequency decreased gradually and significantly across timeframes (32.8, 23.6, and 14.5%, respectively, p < 0.001). In a multivariate regression analysis, 1st generation CoreValve (HR 1.91; CI 95% 1.2-3.04, p = 0.006) was found to be associated with higher incidence of fever in addition to female gender, vascular complications, transfemoral access, and reduced GFR. CONCLUSIONS: Fever incidence post TAVI decreased significantly throughout the last decade. The higher rate of fever in the early years of TAVI was likely associated with first-generation devices, vascular complications, and reduced GFR.

Markers of Chronic Inflammation in Overweight and Obese Individuals and the Role of Gender: A Cross-Sectional Study of a Large Cohort.

OBJECTIVE: During the last decade, obesity has become an epidemic. As obesity is now considered a state of low-grade inflammation, the purpose of this study was to assess the prevalence of four common elements of inflammation, in individuals with increased BMI. These findings were compared to those of subjects with normal BMI. The effect of gender was also noted. METHODS: Data were collected from medical records of individuals examined at a screening center in Israel between the years 2000-2014. Cross-sectional analysis was carried out on 7526 men and 3219 women. White blood cell count (WBC); platelet (PLT) count; erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were assessed in four BMI categories: normal, overweight, obese and morbidly obese. RESULTS: Mean (SD) age of the study sample was 47.5 (9.7) and 46.7 (9.8) years for men and women, respectively. The prevalence of each inflammatory marker increased significantly when comparing abnormal to normal BMI (p<0.0001). The odds ratio (OR) of the prevalence of increased inflammatory markers was compared between subjects with overweight, obese and morbid obesity and subjects with normal BMI. This study showed that the higher the BMI, the higher the OR. For those in the morbid obesity group, the OR for the different inflammatory markers adjusting for age, diabetes mellitus hypertension and kidney function were as follows: WBC levels, 5.1 (2.9-8.7) and 4.7 (2.4-9.1) for men and women, respectively; PLT levels, 1.7 (0.3-8.5) and 2.0 (0.6-7.2) for men and women, respectively; ESR levels, 4.2 (3.2-5.4) and 4.6 (3.2-6.6) for men and women, respectively, and CRP levels, 13.4 (10.0-18.2) and 19.2 (12.9-28.6) for men and women, respectively. CONCLUSION: Inflammatory markers are significantly higher in subjects with abnormal compared to normal BMI. This difference was found to be greater in women than in men.

A real-life setting evaluation of the effect of remdesivir on viral load in COVID-19 patients admitted to a large tertiary centre in Israel.

OBJECTIVES: The effectiveness of remdesivir, a Food and Drug Administration-approved drug for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been repeatedly questioned during the current coronavirus disease 2019 (COVID-19) pandemic. Most of the recently reported studies were randomized controlled multicentre clinical trials. Our goal was to test the efficiency of remdesivir in reducing nasopharyngeal viral load and hospitalization length in a real-life setting in patients admitted to a large tertiary centre in Israel. METHODS: A total of 142 COVID-19 patients found to have at least three reported SARS-CoV-2 quantitative RT-PCR tests during hospitalization were selected for this study. Of these, 29 patients received remdesivir, while the remaining non-treated 113 patients served as controls. RESULTS: Among the tested parameters, the control and remdesivir groups differed significantly only in the intubation rates. Remdesivir treatment did not significantly affect nasopharyngeal viral load, as determined by comparing the differences between the first and last cycle threshold values of the SARS-CoV-2 quantitative RT-PCR tests performed during hospitalization (cycle threshold 7.07 ± 6.85 vs. 7.08 ± 7.27, p 0.977 in the control and treated groups, respectively). Remdesivir treatment shortened hospitalization length by less than a day compared with non-treated controls and by 3.1 days when non-intubated patients from both groups were compared. These differences, however, were not statistically significant, possibly because of the small size of the remdesivir group. DISCUSSION: Remdesivir was not associated with nasopharyngeal viral load changes, but our study had a significant disease severity baseline imbalance and was not powered to detect viral load or clinical differences.

Sex Differences in Folate Levels: A Cross Sectional Study of a Large Cohort from Israel.

BACKGROUND: Low folate levels are associated with megaloblastic anemia, neural tube defects, and an increased risk of cancer. Data are scarce regarding the sex aspect of this deficiency. OBJECTIVES: To assess sex differences in folate levels in a large cohort of patients and to investigate the effect of low folate levels on homocysteine concentrations. METHODS: Data were collected from medical records of patients examined at a screening center in Israel between 2000 and 2014. Cross sectional analysis was conducted on 9214 males and 4336 females. RESULTS: The average age was 48.4 ± 9.5 years for males and 47.6 ± 9.4 years for females. Average folate levels were 19.2 ± 8.6 and 22.4 ±10.3 nmol/L in males and females, respectively (P < 0.001). The prevalence of folate levels below 12.2 nmol/L was 19.5% in males compared to 11.6% in females (P < 0.001). In patients with low folate levels and normal B12 levels, homocysteine levels above 15 µmol/L were found in 32.4% of males and 11.4% of females (P < 0.001). Males had a significantly higher odds ratio (OR) of having folate levels below 12.2 nmol/L: OR 1.84 (95% confidence interval [95%CI] 1.66-2.05) in a non-adjusted model, and OR 2.02 (95%CI 1.82-2.27) adjusted for age, smoking status, body mass index, kidney function, albumin, and triglycerides levels. CONCLUSIONS: Folate levels are lower in males compared to females, which may contribute to the higher homocysteine levels found in males and thus to their increased risk of developing atherosclerosis and coronary artery disease.

How do I manage nocardiosis?

BACKGROUND: Nocardiosis is a rare infection that is often difficult to treat and may be life-threatening. There is no consensus on its management. OBJECTIVES: Our aim was to provide the current evidence for the diagnosis and management of individuals with nocardiosis, and to propose a management approach for this uncommon infection. SOURCES: We systematically searched the medical literature on nocardiosis for studies published between 2010 and 2020 and describing ten or more individuals. CONTENT: Nocardiosis, a primarily opportunistic infection which may occur in immunocompetent persons, most commonly involves the lungs and frequently disseminates to other sites including the central nervous system. The reference standard for Nocardia species identification is molecular biology, and the preferred method for antibiotic susceptibility testing (AST) is broth microdilution. Monotherapy seems appropriate for patients with primary skin nocardiosis or non-severe pulmonary disease; we reserve a multidrug regimen for more severe infections. Species identification and AST results are often missing at initiation of antibiotics. Trimethoprim-sulfamethoxazole is the preferred agent for initial therapy, because Nocardia is very often susceptible to this agent, and because it has been the keystone of nocardiosis treatment for years. Linezolid, to which Nocardia is almost always susceptible, may be an alternative. When combination therapy is required, the repertoire of companion drugs includes third-generation cephalosporins, amikacin and imipenem. Therapeutic modifications should take into account clinical response to initial therapy and AST results. Treatment duration of 6 months is appropriate for most situations, but longer durations are preferred for disseminated nocardiosis and shorter durations are reasonable in low-risk situations. Secondary prophylaxis may be considered in selected individuals with permanent immunosuppression. IMPLICATIONS: We hereby provide the clinician with an easy-to-use algorithm for the management of individuals with nocardiosis. We also illuminate gaps in evidence and suggest future research directions.

A possible increased risk of metamizole-associated neutropenia among COVID-19 patients.

Metamizole is commonly used as analgesic and antipyretic drug. The use of metamizole is prohibited in several countries due to its rare side effect of neutropenia and even agranulocytosis. Among the many symptoms of COVID-19, fever and diffuse pain predominant and therefore it can be assumed that metamizole may be widely used in the current epidemic period. So far, there have been no reports on the safety of metamizole in COVID-19 patients. We describe a series of 3 patients who developed severe neutropenia under metamizole treatment, raising a concern of a possible increased risk of this side effect among COVID-19 patients.

Clinical correlates of nocardiosis.

Nocardia is an opportunistic pathogen that most frequently affects the lungs. Evidence is limited regarding the risk factors for nocardiosis. The current study assessed clinical correlates of nocardiosis. A retrospective study was conducted based on medical records of consecutive adult patients (N = 60) with nocardiosis hospitalized during 2007-2018 at a tertiary hospital in central Israel. A matched comparison group of 120 patients was randomly selected among hospitalized patients with community-acquired pneumonia. Multivariable conditional logistic regression models were fitted. Immunosuppressive pharmacotherapy was positively associated with nocardiosis (matched odds ratio [OR] 4.40, 95% confidence interval [CI] 2.25-8.62, p < 0.001), particularly corticosteroid therapy (matched OR 4.69, 95% CI 2.45-8.99, p < 0.001). Systemic corticosteroid therapy was strongly associated with pulmonary nocardiosis (matched OR 5.90, 95% CI 2.75-12.66, p < 0.001). The positive association between solid organ transplantation and nocardiosis was attenuated following adjustment for systemic corticosteroids in a multivariable model. The association between corticosteroid therapy and nocardiosis appeared stronger in patients with chronic pulmonary disease (OR 5.74, 95% CI 2.75-12.66, p < 0.001) than in the pooled analysis of all nocardiosis cases. In conclusion, corticosteroid therapy was strongly correlated with nocardiosis, particularly among individuals with chronic pulmonary disease and in pulmonary nocardiosis.