Alpha-lipoic acid for diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a frequent complication in people living with type 1 or type 2 diabetes. There is currently no effective treatment for DPN. Although alpha-lipoic acid (ALA, also known as thioctic acid) is widely used, there is no consensus about its benefits and harms. OBJECTIVES: To assess the effects of alpha-lipoic acid as a disease-modifying agent in people with diabetic peripheral neuropathy. SEARCH METHODS: On 11 September 2022, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and two clinical trials registers. We also searched the reference lists of the included studies and relevant review articles for additional references not identified by the electronic searches. SELECTION CRITERIA: We included randomised clinical trials (RCTs) that compared ALA with placebo in adults (aged 18 years or older) and that applied the study interventions for at least six months. There were no language restrictions. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. The primary outcome was change in neuropathy symptoms expressed as changes in the Total Symptom Score (TSS) at six months after randomisation. Secondary outcomes were change in neuropathy symptoms at six to 12 months and at 12 to 24 months, change in impairment, change in any validated quality of life total score, complications of DPN, and adverse events. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: Our analysis incorporated three trials involving 816 participants. Two studies included people with type 1 or type 2 diabetes, while one study included only people with type 2 diabetes. The duration of treatment was between six months and 48 months. We judged all studies at high risk of overall bias due to attrition. ALA compared with placebo probably has little or no effect on neuropathy symptoms measured by TSS (lower score is better) after six months (mean difference (MD) -0.16 points, 95% confidence interval (CI) -0.83 to 0.51; 1 study, 330 participants; moderate-certainty evidence). The CI of this effect estimate did not contain the minimal clinically important difference (MCID) of 0.97 points. ALA compared with placebo may have little or no effect on impairment measured by the Neuropathy Impairment Score-Lower Limbs (NIS-LL; lower score is better) after six months (MD -1.02 points, 95% CI -2.93 to 0.89; 1 study, 245 participants; low-certainty evidence). However, we cannot rule out a significant benefit, because the lower limit of the CI surpassed the MCID of 2 points. There is probably little or no difference between ALA and placebo in terms of adverse events leading to cessation of treatment within six months (risk ratio (RR) 1.48, 95% CI 0.50 to 4.35; 3 studies, 1090 participants; moderate-certainty evidence). No studies reported quality of life or complications associated with DPN. AUTHORS' CONCLUSIONS: Our analysis suggests that ALA probably has little or no effect on neuropathy symptoms or adverse events at six months, and may have little or no effect on impairment at six months. All the studies were at high risk of attrition bias. Therefore, future RCTs should ensure complete follow-up and transparent reporting of any participants missing from the analyses.

Criteria and Non-Criteria Antiphospholipid Antibodies and Cancer in Patients with Involuntary Weight Loss.

Cancer patients have higher prevalences of antiphospholipid antibodies (aPLs), occasionally associated with thrombotic events. A cross-sectional study regarding the presence of criteria (IgG/IgM anti-cardiolipin-aCL, anti-ß2 glycoprotein I-aß2GPI) and non-criteria (IgG/IgM anti-phosphatidylserine-aPS, anti-phosphatidylethanolamine-aPE, anti-prothrombin-aPT) aPLs in 146 patients with involuntary weight loss was performed. None of the patients had thrombotic events during the study. Out of the 36 cancer patients, 33 had non-hematologic malignancies. In the cancer subgroup, 60% of the patients had at least one positive aPL, with significantly more patients being positive for aß2GPI IgG compared with the non-cancer subgroup-p = 0.03, OR = 2.23 (1.02-4.88). When evaluating the titres, aCL IgG/IgM, aß2GPI IgG, aPE IgG, and aPS IgG had significantly higher values in cancer patients, the best cancer predictor being aß2GPI IgG-AUC 0.642 (0.542-0.742). Gastrointestinal cancer patients were studied separately, and aCL IgM positivity was significantly higher-p = 0.008, OR = 6.69 (1.35-33.02). Both the titres of aCL IgM (p = 0.006) and aPS IgM (p = 0.03) were higher in the gastrointestinal cancer subgroup, with aCL IgM being the best predictor for gastrointestinal cancer development-AUC 0.808 (0.685-0.932). Despite criteria and non-criteria aPLs being frequent in cancer, their connection with thrombosis in these patients is probably dependent on other important risk factors and needs further research.

Criteria and Non-Criteria Antiphospholipid Antibodies in Antiphospholipid Syndrome: How Strong Are They Correlated?

The place of non-criteria antiphospholipid antibodies (aPLs) in the diagnosis of antiphospholipid syndrome (APS) is still debatable. The aim of this research was to evaluate the correlations between the titres of non-criteria aPLs (anti-phosphatidylethanolamine (aPE), anti-phosphatidylserine (aPS), and anti-prothrombin (aPT) antibodies), and the ones of the already studied criteria aPLs (anti-cardiolipin (aCL) and anti-ß2 glycoprotein I-aß2GPI antibodies). Altogether, 72 APS (30 primary and 42 secondary) patients were included in our study. High correlation coefficients (rs) were found between aPS IgM and aCL IgM, overall (0.77, p < 0.01), as well as in the primary (0.81, p < 0.01), and secondary (0.75, p < 0.01) APS subgroups. Low or statistically insignificant correlations were observed between IgG/IgM isotypes of aPT and aCL, or aß2GPI, in the entire study population, and when evaluating the subgroups. Therefore, moderate correlations were mainly identified between the tested non-criteria antibodies and the criteria ones, suggesting little added value for the use of the tested non-criteria aPLs, with the exception of aPT, which seems to have different kinetics and might be a promising APS diagnostic tool.

Causes of Polyserositis: A Systematic Review.

At present, polyserositis (PS) remains a challenging entity, which resides both in the fact that there is confusion regarding the terminology, and that it is still understudied. We aimed to identify the etiologies of PS, reported in adult patients. METHODS: We performed a systematic review of the literature on PubMed(MEDLINE) database, using the following (MESH) terms: pleurisy/etiology, pleural effusion/etiology, pericarditis/etiology, pericardial effusion/etiology, pericardial effusion chronic, ascites/etiology, ascitic fluid/etiology, polyserositis, serositis, and serositides. RESULTS: A total of 1979 articles were identified, dating from 1973 onwards. After screening the articles, we included 114 patients from 23 articles (one case series including 92 patients and 22 case reports) in the final report. The most common diagnosis was neoplasia (30; 26.3%), followed by autoimmune diseases (19, 16.7%) and infections (16, 12.3%). Still, in 35 cases, the etiology of PS remained unkown. CONCLUSION: PS is a challenging and understudied entity, which is associated with a wide range of diagnoses. However, prospective studies should be developed in order to have a clear understanding regarding its etiologies and their prevalences.

The Impact of Antibiotic Use on Mortality in Patients Hospitalized in a COVID-19 Centre from Romania: A Retrospective Study.

Background and Objectives: Considering the significant number of patients worldwide that received empirical antibiotic therapy for COVID-19 infection due to their critical condition and the lack of therapeutical guidelines, we wanted to find out the consequences of antibiotic use in our study population. Materials and Methods: We conducted a retrospective cohort study including symptomatic patients older than 18 years, hospitalized for SARS-CoV-2 between March and December 2020 in the Internal Medicine and Pneumology Departments of Colentina Clinical Hospital. The elected outcome was death, while independent variables were antibiotic therapy and literature-cited parameters associated with mortality in this disease. Results: Out of 198 included patients, 96 (48.48%) patients received antibiotic therapy during hospitalization. Female gender (OR = 2.61, p = 0.04), history of neoplasm (OR = 7.147, p = 0.01), heart failure (OR = 8.62, p = 0.002), and diabetes mellitus (OR = 3.05, p = 0.02) were significantly associated with death in multivariate analysis. Antibiotic treatment showed a higher probability of death both in bivariate (OR = 5.333, p < 0.001) and multivariate analysis adjusted for the aforementioned prognostic factors (OR = 3.55, p = 0.01). Conclusions: After adjusting for confounders, in-hospital antibiotic administration did not improve survival in COVID-19 patients.

White Blood Cells, COVID-19, and Mendelian Randomization.

Many observational studies have shown an association between the severity of COVID-19 and the different white blood cell counts, most frequently neutrophils, lymphocytes, and eosinophils. The studies aimed to predict the prognosis, and therefore, a causal relationship was unnecessary. However, if we begin to look at these biomarkers as potential therapeutic targets, then causality is essential. Observational studies cannot prove a causal relationship, and randomized trials are not always feasible. In this case, Mendelian randomization studies, considered more valid than observational studies, could add to the arguments for causality. Two Mendelian randomization studies tested for a causal relationship between the number of different white cell populations and COVID-19 severity, but their results are different; therefore, the problem of causality is not settled in this case.

Antibiotic Prescription and In-Hospital Mortality in COVID-19: A Prospective Multicentre Cohort Study.

BACKGROUND: Since the beginning of the COVID-19 pandemic, empiric antibiotics (ATBs) have been prescribed on a large scale in both in- and outpatients. We aimed to assess the impact of antibiotic treatment on the outcomes of hospitalised patients with moderate and severe coronavirus disease 2019 (COVID-19). METHODS: We conducted a prospective multicentre cohort study in six clinical hospitals, between January 2021 and May 2021. RESULTS: We included 553 hospitalised COVID-19 patients, of whom 58% (311/553) were prescribed antibiotics, while bacteriological tests were performed in 57% (178/311) of them. Death was the outcome in 48 patients-39 from the ATBs group and 9 from the non-ATBs group. The patients who received antibiotics during hospitalisation had a higher mortality (RR = 3.37, CI 95%: 1.7-6.8), and this association was stronger in the subgroup of patients without reasons for antimicrobial treatment (RR = 6.1, CI 95%: 1.9-19.1), while in the subgroup with reasons for antimicrobial therapy the association was not statistically significant (OR = 2.33, CI 95%: 0.76-7.17). After adjusting for the confounders, receiving antibiotics remained associated with a higher mortality only in the subgroup of patients without criteria for antibiotic prescription (OR = 10.3, CI 95%: 2-52). CONCLUSIONS: In our study, antibiotic treatment did not decrease the risk of death in the patients with mild and severe COVID-19, but was associated with a higher risk of death in the subgroup of patients without reasons for it.

Electrocardiographic and Echocardiographic Predictors of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy.

Background: Patients with hypertrophic cardiomyopathy (HCM) have an increased prevalence of atrial fibrillation (AF) compared to the general population, and left atrium (LA) remodeling is strongly correlated with the risk of AF. This prospective, monocentric study aimed to assess the role of LA electrocardiographic and echocardiographic (structural and functional) parameters in predicting the risk for incident AF in patients with HCM. Methods and Results: The study population consisted of 126 HCM patients in sinus rhythm (52.6 ± 16.2 years, 54 men), 118 of them without documented AF. During a median follow-up of 56 (7-124) months, 39 (30.9%) developed a new episode of AF. Multivariable analysis showed that LA booster pump function (assessed by ASr, HR = 4.24, CI = 1.84-9.75, and p = 0.038) and electrical dispersion (assessed by P wave dispersion - Pd, HR = 1.044, CI = 1.029-1.058, and p = 0.001), and not structural parameters (LA diameter, LA volume) were independent predictors of incident AF. Seventy-two patients had a LA diameter < 45 mm, and 16 of them (22.2%) had an AF episode during follow-up. In this subgroup, only Pd emerged as an independent predictor for incident AF (HR = 1.105, CI = 1.059-1.154, and p = 0.002), with good accuracy (AUC = 0.89). Conclusion: Left atrium booster pump function (ASr) and electrical dispersion (Pd) are related to the risk of incident AF in HCM patients. These parameters can provide further stratification of the risk for AF in this setting, including in patients considered at lower risk for AF based on the conventional assessment of LA size.

In-Hospital Antibiotic Use for COVID-19: Facts and Rationales Assessed through a Mixed-Methods Study.

It is well known that during the coronavirus disease 2019 (COVID-19) pandemic, antibiotics were overprescribed. However, less is known regarding the arguments that have led to this overuse. Our aim was to understand the factors associated with in-hospital antibiotic prescription for COVID-19, and the rationale behind it. We chose a convergent design for this mixed-methods study. Quantitative data was prospectively obtained from 533 adult patients admitted in six hospitals (services of internal medicine, infectious diseases and pneumology). Fifty-six percent of the patients received antibiotics. The qualitative data was obtained from interviewing 14 physicians active in the same departments in which the enrolled patients were hospitalized. Thematic analysis was used for the qualitative approach. Our study revealed that doctors based their decisions to prescribe antibiotics on a complex interplay of factors regarding the simultaneous appearance of consolidation on the chest computer tomography together with a worsening of clinical conditions suggestive of bacterial infection and/or an increase in inflammatory markers. Besides these features which might suggest bacterial co-/suprainfection, doctors also prescribed antibiotics in situations of uncertainty, in patients with severe disease, or with multiple associated comorbidities.

COVID-19: a trigger for severe thrombotic microangiopathy in a patient with complement gene variant.

The evidence regarding thrombotic microangiopathy (TMA) related to Coronavirus Infectious Disease 2019 (COVID-19) in patients with complement gene mutations as a cause of acute kidney injury (AKI) are limited. We presented the case of a 23-year-old male patient admitted with an asymptomatic form of COVID-19, but with uncontrolled hypertension and AKI. Kidney biopsy showed severe lesions of TMA. In evolution patient had persistent microangiopathic hemolytic anemia, decreased level of haptoglobin and increased LDH level. Decreased complement C3 level and the presence of schistocytes were found for the first time after biopsy. Kidney function progressively decreased and the patient remained hemodialysis dependent. Complement work-up showed a heterozygous variant with unknown significance in complement factor I (CFI) c.-13G>A, affecting the 5' UTR region of the gene. In addition, the patient was found to be heterozygous for the complement factor H (CFH) H3 haplotype (involving the rare alleles of c.-331C>T, Q672Q and E936D polymorphisms) reported as a risk factor of atypical hemolytic uremic syndrome. This case of AKI associated with severe TMA and secondary hemolytic uremic syndrome highlights the importance of genetic risk modifiers in the alternative pathway dysregulation of the complement in the setting of COVID-19, even in asymptomatic forms.

COVID-19 Vaccine Does Not Increase the Risk of Disease Flare-Ups among Patients with Autoimmune and Immune-Mediated Diseases.

BACKGROUND: Reports describing post-vaccine autoimmune phenomena, in previously healthy individuals, increased the concerns regarding the risk of disease flare-ups in patients with immune diseases. We aimed to assess the potential risk of disease flare-up, after receiving the COVID-19 (Coronavirus disease 2019) vaccine, during a follow-up period of 6 months. METHODS: We performed a prospective cohort study, enrolling the patients with autoimmune- and immune-mediated diseases who voluntarily completed our questionnaire, both online and during hospital evaluations. Based on their decision to receive the vaccine, the patients were divided into two groups (vaccinated and non-vaccinated). Participants who chose not to receive the vaccine served as a control group in terms of flare-ups. RESULTS: A total of 623 patients, 416 vaccinated and 207 non-vaccinated, were included in the study during hospital evaluations (222/623) and after online (401/623) enrolment. There was no difference concerning the risk of flare-up between vaccinated and non-vaccinated patients (1.16, versus 1.72 flare-ups/100 patients-months, p = 0.245). The flare-ups were associated with having more than one immune disease, and with a previous flare-up during the past year. CONCLUSIONS: We did not find an increased risk of flare-up following COVID-19 vaccination in patients with autoimmune-/immune-mediated diseases, after a median follow-up of 5.9 months. According to our results, there should not be an obvious reason for vaccine hesitancy among this category of patients.

COVID-19 Impact and Vaccination Willingness among Romanian Patients with Autoimmune/Immune-Mediated Diseases.

BACKGROUND: During the COVID-19 pandemic, patients with immune diseases are a vulnerable population. We aimed to evaluate their access to medical care, as well as their awareness and willingness to obtain the vaccine after a year of the SARS-CoV-2 pandemic. METHODS: A cross-sectional, multicenter study was conducted on a questionnaire basis, handled both online as well as in person. RESULTS: 651 patients with autoimmune or immune mediated diseases were enrolled. More than half (339/641 [53%]) reported difficulties in obtaining medical care throughout the pandemic and 135/651 ([21%]) of them were confirmed with COVID-19; 442/651, ([68%]) expressed their willingness to be vaccinated against SARS-CoV-2. The factors associated with an increased probability of vaccination were the male gender (OR = 2.01, CI95% 1.2-3.7, p = 0.001), the patient's opinion that she/he was well informed (OR = 3.2, CI 95% 2.1-6.01, p < 0.001), physician's advice (OR = 2.1, CI 95% 1.3-3.5, p < 0.001), and flu vaccination in the past (OR = 1.5, CI 95% 1.1-2.3, p < 0.001), while those associated with a decreased probability of vaccination were COVID-19 disease in the past medical history (OR = 0.7, CI 95% 0.3-0.95, p = 0.02), and the opinion that patients with autoimmune diseases are at increased risk for adverse reactions (OR = 0.7, CI95% 0.53-0.89, p = 0.001). CONCLUSIONS: Given the fact that considering themselves informed regarding vaccination is the most important factor in order to be immunized against SARS-CoV-2, effective information campaigns would substantially increase willingness.

COVID-19 pandemic preparedness period through healthcare workers' eyes: A qualitative study from a Romanian healthcare facility.

INTRODUCTION: Healthcare providers represent a limited resource, and their mental health is crucial for patient care and for ensuring containment of the pandemics. We aimed to explore how healthcare workers experienced the preparedness period of COVID-19 pandemic, in order to ascertain the perceived weaknesses and strengths. METHODS: Interviews were conducted with 17 participants encompassing senior physicians, residents, and nurses. They were audio-recorded, and the transcription was verbatim. We used thematic analysis. RESULTS: We identified four themes, with subsequent subthemes: dealing with the unknown, human versus doctors, sense of helplessness, and a bridge to heaven, which explore how healthcare workers experienced the lack of knowledge, their feeling of losing control, and how they managed their internal fights. The disappointment provoked by the authorities and their colleagues was further evaluated. We identified factors involved in their well-being. CONCLUSIONS: COVID-19 pandemic represented and will still pose a challenge for healthcare workers (HCWs) from all over the world. They felt unprepared for such a crisis. Further measures should be implemented in every hospital to maintain HCWs awareness and to prevent physical imbalance. Appropriate standards of care should be further stated by the authorities so that the healthcare providers may find easier a balance between their safety and their patients' needs. Conducting qualitative research involving HCWs during pandemic times may help in informing more significant policy decisions.

S100A6, Calumenin and Cytohesin 2 as Biomarkers for Cutaneous Involvement in Systemic Sclerosis Patients: A Case Control Study.

BACKGROUND: Systemic sclerosis (Ssc) is an autoimmune disease with incomplete known physiopathology. There is a high number of candidate proteomic biomarkers for Ssc that have not yet been confirmed on independent Ssc cohorts. The aim of the study was to confirm circulating S100A6, calumenin, and cytohesin 2 as biomarkers for Ssc. METHODS: 53 Ssc patients and 26 age- and gender-matched controls were included. Serum S100A6, calumenin, and cytohesin 2 were evaluated with commercial ELISA kits. Associations between serum expression and clinical Ssc characteristics were evaluated. RESULTS: Serum calumenin, S100A6, and cytohesin 2 were higher in Ssc patients compared to controls. Calumenin associated with extensive cutaneous fibrosis, frequency of Raynaud phenomenon, and low complement level, and had a tendency to be higher in Ssc patients with pulmonary fibrosis. S100A6 correlated with the number of active digital ulcers. Serum cytohesin 2 levels were higher in patients with teleangiectasia and associated with pulmonary artery pressure. CONCLUSIONS: Serum calumenin, S100A6, and cytohesin 2 were confirmed as biomarkers on an independent group of Ssc patients. Calumenin had the best predictive capacity for cutaneous Ssc manifestations. Future studies are needed to evaluate the prognostic value of these biomarkers and evaluate them as possible therapeutic targets.

Candidate proteomic biomarkers in systemic sclerosis discovered using mass-spectrometry: an update of a systematic review (2014-2020).

Background. Systemic sclerosis (Ssc) is an autoimmune disease characterized by graduate cutaneous and tissue fibrosis development and irreversible fibroproliferative vascular changes.The aim of the current systematic review was to update the list of proteomic candidate biomarkers identified from Ssc samples with mass spectrometry techniques.Methods. Medline and Scopus databases were searched on 1st September 2020. Relevant articles were searched from March 2014 until September 2020. Two independent reviewers evaluated the retrieved articles.Results. From a total of 97 articles, 9 articles were included in the final analysis summarizing 539 candidate proteomic biomarkers from various samples from Ssc patients (a larger number compared to the previous systematic review). Most biomarkers were identified from cutaneous biopsies. Only 5 articles included a validation step of the findings with only 13 biomarkers being validated.Conclusions. Although many candidate biomarkers were additionally identified, independent validation studies are needed in order to evaluate the importance of these biomarkers for Ssc patients.