Disease Severity Research Articles

Consistent Efficacy of Apremilast in Patients with Psoriasis Regardless of Baseline Disease Severity or Special Area Involvement: Subgroup Analysis from PROMINENT.

Psoriasis involvement in special areas (e.g., scalp or nails) is associated with a great disease burden yet it is often inadequately treated with topical treatments. The efficacy and tolerability of apremilast plus existing topical therapy in Japanese patients with mild to moderate plaque psoriasis were demonstrated in PROMINENT, a phase 3b, multicenter, open-label, single-arm study. We evaluated the efficacy of apremilast across disease severities and special areas involved in these patients. In PROMINENT, patients received apremilast 30mg twice daily for 16weeks in addition to their existing topical therapy, with the option of topical therapy reduction at the discretion of their physician while continuing apremilast treatment from Weeks 16 to 32. We performed a post hoc analysis, assessing apremilast efficacy and safety in Japanese patients stratified by baseline static Physician Global Assessment (sPGA) score (2 [mild] or 3 [moderate]) and special area involvement. Of patients with baseline sPGA = 2 and sPGA = 3, 62.7% and 30.7%, respectively, achieved sPGA score 0 or 1 at Week 32. At Week 32, improvements in skin, nail, scalp, and quality of life assessments were observed regardless of baseline sPGA score. Improvements in these endpoints at Week 32 were also observed in patients with special area (scalp or nail) involvement (n = 134). Incidence of adverse events was similar between patients with baseline sPGA = 2 and sPGA = 3. Apremilast in combination with topical therapy may be a beneficial treatment for Japanese patients, who have limited systemic treatment options for mild to moderate psoriasis or psoriasis in special areas. NCT03930186.

Ebola Virus-Specific Neutralizing Antibody Persists at High Levels in Survivors 2 Years After Resolution of Disease in a Sierra Leonean Cohort.

Ebola virus (EBOV) infection results in Ebola virus disease (EVD), an often severe disease with a nonspecific presentation. Since its recognition, periodic outbreaks of EVD continue to occur in sub-Saharan Africa. The 2013-2016 West African EVD outbreak was the largest recorded, resulting in a substantial cohort of EVD survivors with persistent health complaints and variable immune responses. In this study, we characterize humoral immune responses in EVD survivors and their contacts in Eastern Sierra Leone. We found high levels of EBOV IgG in EVD survivors and lower yet substantial antibody levels in household contacts, suggesting subclinical transmission. Neutralizing antibody function was prevalent but variable in EVD survivors, raising questions about the durability of immune responses from natural infection with EBOV. Additionally, we found that certain discrete symptoms-ophthalmologic and auditory-are associated with EBOV IgG seropositivity, while an array of symptoms are associated with the presence of neutralizing antibody.

Endothelial cell-derived extracellular vesicles modulate the therapeutic efficacy of mesenchymal stem cells through IDH2/TET pathway in ARDS

BackgroundAcute respiratory distress syndrome (ARDS) is a severe and fatal disease. Although mesenchymal stem cell (MSC)-based therapy has shown remarkable efficacy in treating ARDS in animal experiments, clinical outcomes have been unsatisfactory, which may be attributed to the influence of the lung microenvironment during MSC administration. Extracellular vesicles (EVs) derived from endothelial cells (EC-EVs) are important components of the lung microenvironment and play a crucial role in ARDS. However, the effect of EC-EVs on MSC therapy is still unclear. In this study, we established lipopolysaccharide (LPS) - induced acute lung injury model to evaluate the impact of EC-EVs on the reparative effects of bone marrow-derived MSC (BM-MSC) transplantation on lung injury and to unravel the underlying mechanisms.MethodsEVs were isolated from bronchoalveolar lavage fluid of mice with LPS - induced acute lung injury and patients with ARDS using ultracentrifugation. and the changes of EC-EVs were analysed using nanoflow cytometry analysis. In vitro assays were performed to establish the impact of EC-EVs on MSC functions, including cell viability and migration, while in vivo studies were performed to validate the therapeutic effect of EC-EVs on MSCs. RNA-Seq analysis, small interfering RNA (siRNA), and a recombinant lentivirus were used to investigate the underlying mechanisms.ResultsCompared with that in non-ARDS patients, the quantity of EC-EVs in the lung microenvironment was significantly greater in patients with ARDS. EVs derived from lipopolysaccharide-stimulated endothelial cells (LPS-EVs) significantly decreased the viability and migration of BM-MSCs. Furthermore, engrafting BM-MSCs pretreated with LPS-EVs promoted the release of inflammatory cytokines and increased pulmonary microvascular permeability, aggravating lung injury. Mechanistically, LPS-EVs reduced the expression level of isocitrate dehydrogenase 2 (IDH2), which catalyses the formation of α-ketoglutarate (α-KG), an intermediate product of the tricarboxylic acid (TCA) cycle, in BM-MSCs. α-KG is a cofactor for ten-eleven translocation (TET) enzymes, which catalyse DNA hydroxymethylation in BM-MSCs.ConclusionsThis study revealed that EC-EVs in the lung microenvironment during ARDS can affect the therapeutic efficacy of BM-MSCs through the IDH2/TET pathway, providing potential strategies for improving the therapeutic efficacy of MSC-based therapy in the clinic.

Biomarkers of inflammation and neoangiogenesis in premature rupture of membranes

BACKGROUND: Premature rupture of membranes complicates up to 2–10% of full-term pregnancies and up to 40% of all premature pregnancies. It is believed that the main cause of premature rupture of membranes is inflammation caused by both infectious agents and autoimmune processes. Numerous studies are aimed at searching for biomarkers that can predict inflammation in premature rupture of membranes. AIM: The aim of this study was to determine the levels of pro-inflammatory cytokines such as interleukin-6, -18 and procalcitonin, as well as interferon-α and soluble endoglin, in the blood serum of pregnant women with premature rupture of membranes and women in labor with timely discharge of amniotic fluid and evaluate the possibility of using these parameters to optimize obstetric tactics. MATERIALS AND METHODS: This study included 69 patients delivered at the Clinic of Obstetrics and Gynecology of the Academician I.P. Pavlov First Saint Petersburg State Medical University from January 2022 to March 2023. The main study group consisted of 53 pregnant women with premature rupture of membranes, the control group included 16 women with term labor and timely discharge of amniotic fluid, or amniotomy performed in the first stage of labor. The levels of interleukin-6, -18, interferon-α, procalcitonin and soluble endoglin in maternal peripheral blood were assessed using enzyme-linked immunosorbent assay. Pregnancies complicated by severe preeclampsia, placenta abruption and chronic maternal diseases in the acute stage were excluded from the study. RESULTS: At the time of rupture, the minimum gestational age was 33+0 weeks and the maximum age — 41+3 weeks. The median duration of the anhydrous interval was 31.8 hours. No significant differences in interleukin-6, -18, procalcitonin and soluble endoglin concentrations were revealed in the main and control groups, interferon-α level being higher in the comparison group. The median concentration of interferon-α in pregnant women with premature rupture of membranes was 1.64 pg/ml and in women with timely discharge of amniotic fluid — 4.61 pg/ml (p = 0.001). A weak direct correlation was revealed between soluble endoglin and interleukin-18 concentrations (R = 0.26; p = 0.03), as well as a moderate direct correlation between soluble endoglin and procalcitonin levels (R = 0.4; p 0.001). CONCLUSIONS: The study did not reveal differences in the concentrations of interleukin-6, -18, procalcitonin and soluble endoglin in the comparison groups. A decrease in interferon-α level in the blood in pregnant women increases the risk of developing premature rupture of membranes. The correlations between soluble endoglin and interleukin-18 or procalcitonin concentrations may indicate an association between different mechanisms of the pathogenesis of premature rupture of membranes. In this regard, an integrated approach and analysis of a combination of several cellular bioregulators are eligible to predict infectious complications in premature rupture of membranes.

Surgical treatment of inflammatory bowel disease: From the gastroenterologist’s stand-point

Treatment of ulcerative colitis (UC) and Crohn’s disease (CD) represents, in the majority of cases, a real challenge to the gastroenterologist’s abilities and skills as well as a clinical test concerning his/her levels of medical knowledge and experience. During the last two decades, our pharmaceutical arsenal was significantly strengthened, especially after the introduction of the so-called biological agents, drugs which to a large extent not only improved the results of conservative treatment but also changed the natural history of the disease. However, colectomy is still necessary for some patients with severe UC although smaller compared to the past, precisely because of the improvements achieved in the available conservative treatment. Nevertheless, surgeries to treat colon dysplasia and cancer are increasing to some extent. At the same time, satisfactory improvements in surgical techniques, the pre-and post-operative care of patients, as well as the selection of the appropriate time for performing the surgery have been noticed. Regarding patients with CD, the improvement of conservative treatment did not significantly change the need for surgical treatment since two-thirds of patients need to undergo surgery at some point in the course of their disease. On the other hand, the outcome of the operation has improved through good preoperative care as well as the wide application of more conservative surgical techniques aimed at keeping as much of the bowel in situ as possible. This article discusses the indications for surgical management of UC patients from the gastroenterologist’s point of view, the results of the emerging new techniques such as transanal surgery and robotics, as well as alternative operations to the classic ileo-anal-pouch anastomosis. The author also discusses the basic principles of surgical management of patients with CD based on the results of the relevant literature. The self-evident is emphasized, that is, to achieve an excellent therapeutic result in patients with severe inflammatory bowel disease in today’s era; the close cooperation of gastroenterologists with surgeons, pathologists, imaging, and nutritionists is of paramount importance.

Larger putamen in individuals at risk and with manifest bipolar disorder.

Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations. In 410 male and female participants aged 17-35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPIbipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites. Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake. Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.

The dark side of apnea: altered 24-hour melatonin secretion in obstructive sleep apnea (OSAS) is disease severity dependent.

Melatonin aids in the synchronization of the circadian rhythm to the external environment. Few studies have tried to elucidate the relationship between melatonin and obstructive sleep apnea syndrome (OSAS). These often include few patients, do not differentiate between OSAS severity and/or do not analyse a 24-h melatonin profile. This study set out to investigate disease severity dependent differences in 24-h salivary melatonin secretion of OSAS patients compared to a reference population in a retrospective design. 24-h salivary melatonin profiles of 169 OSAS patients were analysed (55 light, 66 moderate, 48 severe) as well as 91 reference patients. Several aspects of the melatonin curve were analysed and stratified according to OSAS severity. Parameters included: dim light melatonin onset (DLMO), time of returning below DLMO (DLMOoff), peak melatonin concentration and time, and total melatonin exposure. Significant effects were corrected for confounding by age and sex using linear regression. Our analysis shows that, compared to reference and in a disease dependent manner, OSAS patients have a significantly lower 24-h melatonin curve, lower melatonin peak concentration, lower total melatonin exposure and a smaller proportion of patients reach DLMO. The differences in peak melatonin production and total melatonin exposure were resistant to confounding by age and/or sex. This study describes clear OSAS severity dependent abnormalities in melatonin production in OSAS patients, independent of sex and/or age. Future research should indicate whether oral melatonin supplementation has beneficial effects in OSAS patients with attenuated endogenous melatonin production.

Microbiota treatment of functional constipation: Current status and future prospects

Functional constipation (FC) is a common disorder that is characterized by difficult stool passage, infrequent bowel movement, or both. FC is highly prevalent, recurs often, accompanies severe diseases, and affects quality of life; therefore, safe and effective therapy with long-term benefits is urgently needed. Microbiota treatment has potential value for FC treatment. Microbiota treatments include modulators such as probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT). Some probiotics and prebiotics have been adopted, and the efficacy of other microbiota modulators is being explored. FMT is considered an emerging field because of its curative effects; nevertheless, substantial work must be performed before clinical implementation.

Hematological Markers in Children and Adults with Atopic Dermatitis: A Retrospective Cohort Study.

Background Atopic dermatitis (AD) is a common chronic skin disease with an inflammatory pathophysiology that includes the activation of the innate and adaptive immune systems. Objectives We aimed to investigate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-lymphocyte ratio (ELR) and eosinophil-to-neutrophil ratio (ENR) in AD patients, according to age and disease severity. Methods This is a retrospective, population-based cohort study conducted between the years 2005 and 2020, comparing hematological markers of AD patients and sex-age-ethnicity matched controls. AD patients were further divided by age and disease severity (mild, moderate-to-severe AD). We created a decision tree to predict moderate-severe AD. Results A total of 13,928 patients with AD were included in this study: 6,828 adults and 7,100 children, with 13,548 controls. NLR, PLR, and ELR were lower in children compared to adults (p-values < 0.001). NLR, PLR, ELR, and ENR were increased in moderate-severe AD patients compared to mild AD patients (p-values < 0.001). PLR, ELR, and ENR were increased in AD patients versus controls (p-values < 0.001), with an additional increase in the NLR of moderate-to-severe AD patients. Patients with an ELR < 0.21, a PLR > 161, and ENR  0.016 should be considered high risk for developing severe AD, as well as patients with an ELR > 0.21 and age at diagnosis < 30 or age > 30 years and Mean Platelet Volume (MPV)  9. Conclusion Hematological ratios were significantly higher in moderate-to-severe AD patients, compared to mild AD patients. Hematological markers were lower in children with AD compared to adults, except for ENR, likely reflecting age-related changes in blood count parameters. These markers can assist in the management and follow-up of AD patients.

Predisposing, Enabling, and Need Factors Driving Palliative Care Use in Head and Neck Cancer.

Characterizing factors associated with palliative care (PC) use in patients with stage III and VI head and neck cancer using Anderson's behavioral model of health service use. A retrospective study of the 2004 to 2020 National Cancer Database.gg METHODS: We used multivariate logistic regression to assess the association of predisposing, enabling, and need factors with PC use. We also investigated the association of these factors with interventional PC type (chemotherapy, radiotherapy, surgery) and refusal of curative treatment in the last 6 months of life. Five percent of patients received PC. "Predisposing factors" associated with less PC use include Hispanic ethnicity (adjusted odds ratio [aOR], 086; 95% confidence interval [CI], 0.76-0.97) and white and black race (vs white: aOR, 1.14; 95% CI, 1.07-1.22). "Enabling factors" associated with lower PC include private insurance (vs uninsured: aOR, 064; 95% CI, 0.53-0.77) and high-income (aOR, 078; 95% CI, 0.71-0.85). "Need factors" associated with higher PC use include stage IV (vs stage III cancer: aOR, 2.25; 95% CI, 2.11-2.40) and higher comorbidity index (vs Index 1: aOR, 1.58; 95% CI, 1.42-1.75). High-income (aOR, 0.78; 95% CI, 0.71-0.85) and private insurance (aOR, 0.6; 95% CI, 0.53, 0.77) were associated with higher interventional PC use and lower curative treatment refusal (insurance: aOR, 0.82; 95% CI, 0.55, 0.67; income aOR, 0.48; 95% CI, 0.44, 0.52). Low PC uptake is attributed to patients' race/culture, financial capabilities, and disease severity. Culturally informed counseling, clear guidelines on PC indication, and increasing financial accessibility of PC may increase timely and appropriate use of this service.

Genetic predisposition to metabolic dysfunction-associated fatty liver disease

The literature review highlights the issue of genetic risk factors associated with the development of metabolic dysfunction-associated fatty liver disease. Human genetic examinations revealed 132 genes among which 32 loci are strongly associated with the pathogenesis of metabolic dysfunction-associated fatty liver disease. It has been found that the risk of developing metabolic dysfunction-associated fatty liver disease is carried by single-nucleotide variants of various genes whose products are involved in lipid and carbohydrate metabolism, maintenance of the redox state, the development of inflammation and fibrosis of liver tissue, which are components of metabolic dysfunction-associated fatty liver disease reactome. The authors presented a detailed list of genetic factors singling out those that influence the risk of metabolic dysfunction-associated fatty liver disease and directly metabolic dysfunction-associated steatohepatitis and liver fibrosis. Also, they emphasized that it is the single-nucleotide variants of the genes of protein 3 containing a patatin-like phospholipase domain, transmembrane 6 superfamily member 2, and 17b-hydroxysteroid dehydrogenase type 13 that are characte­rized by the highest degree of association with metabolic dysfunction-associated fatty liver disease (odds ratio > 1.6) compared to single-nucleotide variants of other genes identified by gene association studies. The combination of several polymorphisms increases the risk of development and severity of metabolic dysfunction-associated fatty liver disease. The additive steatogenic effect of protein 3 single-nucleotide gene variants containing a patatin-like phospholipase domain and transmembrane 6 superfamily member 2 is probably due to an increased expression of genes involved in de novo lipogenesis. The authors emphasize the need for genetic risk assessment of metabolic dysfunction-associated fatty liver disease, which should include molecular genetic testing at an early stage of examination.

Bacterial profile, drug resistance pattern, clinical and laboratory predictors of ascites infection in cirrhosis patients

Ascites is a pathological collection of free fluid in the peritoneal cavity, which is a common complication in patients with cirrhosis, an advanced liver disease. Bacterial infection increases the mortality rate of hospitalized patients with cirrhosis, irrespective of the severity of the liver disease. Around 60% of patients with compensated cirrhosis developed ascites within 10 years during the course of their disease. The in-hospital mortality rate due to spontaneous bacterial peritonitis (SBP) could exceed 90%, but with early diagnosis and prompt antibiotic therapy, this rate has been shown to decrease to 20%. Here, we enrolled adult (age ≥ 18) patients with liver disease with evidence of cirrhosis who developed ascites and assessed the presence of spontaneous ascites fluid infection (SAFI) in these patients. Of the total 218 patients, 22.9% (50/218) develop ascites infection. The liver organ function tests like alanine aminotransferase, aspartate aminotransferase, total bilirubin, and direct bilirubin were found to be significantly (P < 0.05) higher in patients with ascites fluid infection compared to patients with non-ascites fluid infection. Of the gram-negative bacteria, K. pneumonia and E. coli were isolated and found to be 100% resistant to amoxicillin and clavulanate. From the gram-positive bacterial isolates, S. aureus was only resistant to penicillin, whereas Str. viridans was resistant to ceftriaxone, cefotaxime, cefepime, and penicillin. On the other hand, clinical features such as a history of jaundice, low arterial blood pressure, and ultrasound results such as a shrunken liver and enlarged spleen were also independent predictors of spontaneous bacterial peritonitis. In conclusion, given the high probability of death following SAFI, early detection, and treatment, as well as knowledge of the microbial agent, resistance profile, and predictive markers in various contexts, are essential for the timely diagnosis and management of SAFI in these patients.

The Serological Evidence of Positive Rheumatoid Factor in Morphea Patients and Its Relation to Disease Severity

The Serological Evidence of Positive Rheumatoid Factor in Morphea Patients and Its Relation to Disease Severity

Mirikizumab Exposure-Response Relationships in Patients with Moderately-to-Severely Active Ulcerative Colitis in Randomized Phase II and III Studies.

Mirikizumab is a humanized anti-interleukin-23p19 monoclonal antibody being developed for ulcerative colitis (UC) and Crohn's disease. We characterized the relationship of mirikizumab systemic exposure with efficacy and safety end points in patients with UC using phase II (NCT02589665) and III (NCT03518086, NCT03524092) trial data. Exposure-response models were developed for clinical remission, clinical response, endoscopic remission, and change in modified Mayo score following induction (50-1,000 mg i.v. every 4 weeks) and maintenance (200 mg s.c. every 4 or 12 weeks) treatment. These models evaluated observed and pharmacokinetic model-predicted mirikizumab exposures as the exposure measure. Key safety event rates were compared across mirikizumab exposure quartiles in the phase III trial. Mirikizumab efficacy in patients with UC showed an apparent positive association with systemic exposure following both induction and maintenance. However, further analysis found this relationship to be overstated by the presence of confounding factors that were not among the tested patient covariates. While prior biologic experience and baseline disease severity showed statistically significant influences on estimated placebo effect, no patient factors affected the mirikizumab effect parameters in any of the phase III exposure-response models. There was no apparent mirikizumab concentration relationship with any adverse event of special interest. When the phase II and III data and confounding are considered together, efficacy was unlikely to be strongly affected by variation in exposures across individual patients at the phase III dose. Together with the previously demonstrated mirikizumab exposure insensitivity to patient factors, these findings indicate that mirikizumab dose adjustment to patient characteristics is not required.

Cardiovascular mechanisms of thyroid hormones and heart failure: Current knowledge and perspectives

A multiple hormonal imbalance that accompanies heart failure (HF) may have a significant impact on the clinical course in such patients. The non-thyroidal illness syndrome (NTIS), also referred to as euthyroid sick syndrome or low triiodothyronine syndrome, can be found in about 30% of patients with HF. NTIS represents a systemic adaptation to chronic illness that is associated with increased cardiac and overall mortality in patients with HF. While conclusions on thyroid-stimulating hormone, free triiodothyronine, total and free thyroxine are currently unresolved, serum total triiodothyronine levels and the ratio of free triiodothyronine to free thyroxine seem to provide the best correlates to the echocardiographic, laboratory and clinical parameters of disease severity. HF patients with either hyper- or hypothyroidism should be treated according to the appropriate guidelines, but the therapeutic approach to NTIS, with or without HF, is still a matter of debate. Possible treatment options include better individual titration of levothyroxine therapy, combined triiodothyronine plus thyroxine therapy and natural measures to increase triiodothyronine. Future research should further examine the cellular and tissue mechanisms of NTIS as well as new therapeutic avenues in patients with HF.

Calcium deficiency is associated with malnutrition risk in patients with inflammatory bowel disease

ABSTRACT Background and Aim Patients with inflammatory bowel disease (IBD) often have the condition of malnutrition, which can be presented as sarcopenia, micronutrient deficiencies, etc. Trace elements (magnesium, calcium, iron, copper, zinc, plumbum and manganese) belonging to micronutrients, are greatly vital for the assessment of nutritional status in humans. Trace element deficiencies are also the main manifestation of malnutrition. Calcium (Ca) has been proved to play an important part in maintaining body homeostasis and regulating cellular function. However, there are still a lack of studies on the association between malnutrition and Ca deficiency in IBD. This research aimed to investigate the role of Ca for malnutrition in IBD patients. Methods We prospectively collected blood samples from 149 patients and utilized inductively coupled plasma mass spectrometry to examine their venous serum trace element concentrations. Logistic regression analyses were used to investigate the association between Ca and malnutrition. Receiver operating characteristic (ROC) curves were generated to calculate the cutoffs for determination of Ca deficiency. Results Except Ca, the concentrations of the other six trace elements presented no statistical significance between non-malnutrition and malnutrition group. In comparison with non-malnutrition group, the serum concentration of Ca decreased in malnutrition group (89.36 vs 87.03 mg/L, p = 0.023). With regard to ROC curve, Ca <87.21 mg/L showed best discriminative capability with an area of 0.624 (95% CI: 0.520, 0.727, p = 0.023). Multivariate analyses demonstrated that Ca <87.21 mg/L (OR = 3.393, 95% CI:1.524, 7.554, p = 0.003) and age (OR = 0.958, 95% CI:0.926, 0.990, p = 0.011) were associated with malnutrition risk. Serum Ca levels were significantly lower in malnutrition group than those in non-malnutrition group among UC patients, those who with severe disease state or the female group. Conclusions In patients with IBD, Ca deficiency is an independent factor for high malnutrition risk.

International validation of meaningfulness of postural sway and gait to assess myeloneuropathy in adults with adrenoleukodystrophy.

The most common manifestation of X-linked adrenoleukodystrophy (ALD) is a slowly progressive myeloneuropathy, which leads to imbalance and gait disturbances. The variable progression of the disease complicates evaluation of its progression rate. Wearable sensors allow for easy and frequent balance and gait collection. This study reports baseline data from a longitudinal study on the quantitative assessment of balance and gait with wearable sensors and their clinical relevance. Data were collected from adult patients in two institutions. Postural body sway and gait parameters were measured using accelerometers. Disease severity was measured by the Expanded Disability Severity Scale (EDSS). Falling frequency and quality of life (QOL) were collected in men. The relationship between sway and gait variables and EDSS score, participants' use of a walking aid, and falling frequency was evaluated. One hundred twenty individuals with ALD were included. Sway variables significantly differentiate participants' assistive device use. Sway and gait variables were correlated to the EDSS in both sexes. Both gait speed and sway were correlated with falling frequency in men from one institution. Select QOL subscores were correlated with the EDSS in males from one institution. Accelerometry generated comparable results across sites. This study confirms the clinical correlation between spinal cord disease and imbalance and gait in ALD. For the first time, this study shows clinically meaningful relationships for sway and gait with use of an assistive device, falling frequency and QOL. Wearable accelerometers are a valid means to measure sway and gait in ALD. These measures are promising outcomes for clinical trial designs to assess myeloneuropathy in ALD and to monitor disease progression in individuals.

Avidity maturation of humoral response following primary and booster doses of BNT162b2 mRNA vaccine among nursing home residents and healthcare workers.

Infections, despite vaccination, can be clinically consequential for frail nursing home residents (NHR). Poor vaccine-induced antibody quality may add risk for such subsequent infections and more severe disease. We assessed antibody binding avidity, as a surrogate for antibody quality, among NHR and healthcare workers (HCW). We longitudinally sampled 112 NHR and 52 HCWs who received the BNT162b2 mRNA vaccine after each dose up to the Wuhan-BA.4/5-based Omicron bivalent boosters. We quantified anti-spike, anti-receptor binding domain (RBD), and avidity levels to the ancestral Wuhan, Delta, and Omicron BA.1 & 4/5 strains. The primary vaccination series produced substantial anti-spike and RBD levels which were low in avidity against all strains tested. Antibody avidity progressively increased in the 6-8months that followed. Avidity significantly increased after the 1st booster but not for subsequent boosters. This study underscores the importance of booster vaccination among NHR and HCWs. The 1st booster dose increases avidity, increasing vaccine-induced functional antibody. The higher cross-reactivity of higher avidity antibodies to other SARS-CoV-2 strains should translate to better protection from ever-evolving strains. Higher avidities may help explain how the vaccine's protective effects persist despite waning antibody titers after each vaccine dose.

Prognostic significance of chronic kidney disease and impaired renal function in Japanese patients with COVID-19

BackgroundRenal impairment is a predictor of coronavirus disease (COVID-19) severity. No studies have compared COVID-19 outcomes in patients with chronic kidney disease (CKD) and patients with impaired renal function without a prior diagnosis of CKD. This study aimed to identify the impact of pre-existing impaired renal function without CKD on COVID-19 outcomes.MethodsThis retrospective study included 3,637 patients with COVID-19 classified into three groups by CKD history and estimated glomerular filtration rate (eGFR) on referral: Group 1 (n = 2,460), normal renal function without a CKD history; Group 2 (n = 905), impaired renal function without a CKD history; and Group 3 (n = 272), history of CKD. We compared the clinical characteristics of these groups and assessed the effect of CKD and impaired renal function on critical outcomes (requirement for respiratory support with high-flow oxygen devices, invasive mechanical ventilation, or extracorporeal membrane oxygen, and death during hospitalization) using multivariable logistic regression.ResultsThe prevalence of comorbidities (hypertension, diabetes, and cardiovascular disease) and incidence of inflammatory responses (white blood counts, and C-reactive protein, procalcitonin, and D-dimer levels) and complications (bacterial infection and heart failure) were higher in Groups 2 and 3 than that in Group 1. The incidence of critical outcomes was 10.8%, 17.7%, and 26.8% in Groups 1, 2, and 3, respectively. The mortality rate and the rate of requiring IMV support was lowest in Group 1 and highest in Group 3. Compared with Group 1, the risk of critical outcomes was higher in Group 2 (adjusted odds ratio [aOR]: 1.32, 95% confidence interval [CI]: 1.03–1.70, P = 0.030) and Group 3 (aOR: 1.94, 95% CI: 1.36–2.78, P < 0.001). Additionally, the eGFR was significantly associated with critical outcomes in Groups 2 (odds ratio [OR]: 2.89, 95% CI: 1.64–4.98, P < 0.001) and 3 (OR: 1.87, 95% CI: 1.08–3.23, P = 0.025) only.ConclusionsClinicians should consider pre-existing CKD and impaired renal function at the time of COVID-19 diagnosis for the management of COVID-19.

The impact of smoking on COVID-19-related mortality: a Brazilian national cohort study

IntroductionCurrent evidence suggests the potential heightened vulnerability of smokers to severe coronavirus disease (COVID-19) outcomes. AimsThis study aimed to analyze the clinical outcomes and mortality related to tobacco use in a cohort of hospitalized Brazilian COVID-19 patients. MethodsThis retrospective cohort study analyzed adults hospitalized for COVID-19 in Brazil using the SIVEP-Gripe database (official data reported by public and private healthcare facilities for monitoring severe acute respiratory syndrome cases in Brazil). The inclusion criteria were patients over 18 years of age with a positive RT-qPCR test for SARS-CoV-2. The analysis focused on in-hospital mortality, considering smoking as an exposure variable, and included covariates such as age, gender, and comorbidities. Smoking history was collected from the self-reported field in the database. Statistical analyses included descriptive statistics, crude Odds Ratios, and multivariable binary logistic regression. ResultsThis study included 2,124,285 COVID-19 patients, among whom 44,774 (2.1 %) were smokers. The average age of the smokers was higher than that of the never-smokers (65.3 years vs. 59.7 years). The clinical outcomes revealed that smokers had higher rates of intensive care unit admission (51.6 % vs. 37.2 % for never-smokers), invasive ventilatory support (31.5 % vs. 20.2 % for never-smokers), and higher mortality (42.7 % vs. 31.8 % for never smokers). In the multivariable analysis, smokers demonstrated a heightened risk of death (aOR 1.23; 95 % CI 1.19–1.25). ConclusionsThis large populational-based cohort study confirms the current evidence and underscore the critical importance of recognizing smoking as a substantial risk factor for adverse outcomes in COVID-19 patients.