Disease Severity Research Articles

The Efficacy of Combined “Oral Simvastatin Plus Narrowband UVB Phototherapy” Than “Phototherapy Alone” in Treating Skin Lesions in Patients with Vitiligo, a Double-Blind Add-On Randomized Controlled Clinical Trial

Background: A tailored therapy for vitiligo is crucial in enhancing patients' quality of life and decreasing the associated dimensions. In addition, statins play a significant function in modulating the immune system. Objectives: This study investigated the efficacy of oral simvastatin in treating skin lesions in patients with vitiligo. Methods: This interventional randomized clinical trial enrolled 50 vitiligo patients referred to Shahid Faghihi Hospital in Shiraz (Iran) in 2015. Participants were divided into control and intervention groups using block randomization. Participants in the control group received “NB-UVB phototherapy plus placebo,” and those in the intervention group received “NB-UVB phototherapy with 40, 60, and 80 mg simvastatin by a monthly increase in the drug dosage”. A reduction in the Vitiligo Area Scoring Index (VASI) score and side effects were measured for four months, and the results were compared between the two groups. Results: At the start of the study, the mean score for the disease severity was equal for both groups (P ˃ 0.05). However, the disease severity was significantly reduced in the following stages of the study in the simvastatin group compared to the placebo group (P = 0.0001). Conclusions: Oral simvastatin enhances the photothermal outcomes while exerting trivial side effects. Thus, combining oral simvastatin with phototherapy is recommended as a potent strategy for treating patients with vitiligo.

Abstract A011: Assessing pro-tumorigenicity of the aging microenvironment in a murine ovarian cancer model

Abstract Over 70% of high-grade serous ovarian cancer (HGSOC) patients are diagnosed after age 55 and the average patient who succumbs to HGSOC is 70 years old. Despite this, the majority of ovarian cancer studies, and cancer studies generally, utilize young mice that are more representative of human children. This approach overlooks age as a variable, despite its status as a top risk factor for cancer. Our preliminary studies reveal tumor burden and disease severity is significantly higher in aged mice compared to young animals. We have developed an epithelial cell line derived from C57BL/6 oviducts and used CRISPR-Cas9 genome editing to establish tumorigenic lines for syngeneic studies. One line harbors Trp53, Pten, and Brca2 deletions, is tumorigenic, and can be serially passaged in vitro. When injected intraperitoneally (IP) into 8-week and 56-week-old mice, equating to approximately 10- and 45-year-old humans respectively, a stark increase in tumor mass was evident in aged mice. Furthermore, the aged mice succumbed to disease at a faster rate after inoculation than the young group, where all mice succumbed to disease within 1-month of IP injection compared to some young mice surviving up to 3 months after injection. These findings, combined with epidemiologic data, suggest a metastatic driver in the aged microenvironment that facilitates worsened ovarian cancer progression. We are investigating two factors that change with age, (1) a suppressed immune system and (2) age-related changes to adipose tissue, as possible mechanisms driving this difference. Histologic analysis of tumors from each cohort showed decreased cleaved caspase-3 in aged tumors, indicating a reduction in tumor cell killing in older animals. Characterization of the pre-cancerous, tumor-naive microenvironment via flow cytometry and cytokine array have revealed that aged mice microenvironment is highly inflamed and features changes in immune populations and inflammatory states. Meanwhile, total RNA-sequencing of tumors harvested from aged and young mice showed minimal changes, but DEGs point to possible roles of fat transport and metabolism in these aged tumors, indicated by upregulated CD36 and lipoprotein lipase. Follow-up ex vivo experiments had demonstrated increased adhesion and proliferation of the previously described murine cancer cells to fat pads when cultured in vitro. When assessing tumor-naive fat depots, aged adipose tissue is comprised of significantly larger adipocytes and the omentum, a common secondary site of ovarian cancer and fatty organ, was found to have increased phospholipid content in older animals. Both findings point to a change in metabolic function in aged mice. Our preliminary findings indicate an important role of the aged microenvironment in driving enhanced diseases progression in older individuals and identifying the mechanisms behind this phenotype are critical; an improved understanding of how age affects HGSOC progression could enable the development of treatment strategies to prevent cancer cells from establishing in the peritoneum. Citation Format: Katherine A. Cummins, Ronny Drapkin. Assessing pro-tumorigenicity of the aging microenvironment in a murine ovarian cancer model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A011.

Validation of the Russian version of the pelvic pain and urgency/frequency patient symptom scale (C.L. Parsons, 2000) for patients with chronic recurrent uncomplicated cystitis

BACKGROUND: Questionnaires allow to objectify and quantify the disease severity, especially at the patient’s initial visit, its impact on the patients’ quality of life, as well as the dynamics of symptoms during treatment. AIM: To validate the Russian version of the Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF scale; C.L. Parsons, 2000) for patients with chronic recurrent uncomplicated cystitis. MATERIALS AND METHODS: The Russian version of the PUF Scale was suggested to two respondent groups aged 19 to 53 years: relatively healthy volunteers, 15 women who did not complains of urinary disorders or pain/discomfort in the bladder, and 14 patients with verified diagnosis of chronic recurrent uncomplicated cystitis. RESULTS: The resulting data demonstrate the validity of the proposed Russian version of the PUF Scale. Statistically significant differences were noted in the answers to most of the questionnaire issues between two respondent groups: conditionally healthy volunteers and patients with chronic recurrent uncomplicated cystitis. A high level of internal consistency of the questionnaire was found. Cronbach’s alpha coefficient in the main group was 0.888, in the control group — 0.819. CONCLUSIONS: The study findings proved that the Russian version of the Pelvic Pain and Urgency/Frequency Patient Symptom Scale (C.L. Parsons, 2000) is a valid tool for subjective assessment of the severity of chronic recurrent uncomplicated cystitis symptoms.

Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment.

Advanced age increases the risk of severe disease from SARS-CoV-2 infection, as well as incidence of long COVID and SARS-CoV-2 reinfection. We hypothesized that perturbations in the aged antiviral CD8+ T cell response predisposes elderly individuals to severe coronavirus infection, re-infection, and postinfectious cognitive sequelae. Using MHV-A59 as a murine model of respiratory coronavirus, we found that aging increased CNS infection and lethality to MHV infection. This was coupled with increased CD8+ T cells within the aged CNS but reduced antigen specificity. Aged animals also displayed a decreased proportion of CD103+ resident memory cells (TRM), which correlated with increased severity of secondary viral challenge. Using a reciprocal adoptive transfer paradigm, data show that not only were fewer aged CD8+ T cells retained within the adult brain post-infection, but also that adult CD8+ cells expressed lower levels of TRM marker CD103 when in the aged microenvironment. Furthermore, aged animals demonstrated spatial learning impairment following MHV infection, which worsened in both aged and adult animals following secondary viral challenge. Spatial learning impairment was accompanied by increased TUNEL positivity in hippocampal neurons, suggestive of neuronal apoptosis. Additionally, primary cell coculture showed that activated CD8+ T cells induced TUNEL positivity in neurons, independent of antigen-specificity. Altogether, these results show that non-antigen specific CD8+ T cells are recruited to the aged brain and cause broad neuronal death without establishing a TRM phenotype that confers lasting protection against a secondary infection.

Personality and Psychoneuroimmunology: A Systems Biology Perspective.

Research in psychoneuroimmunology (PNI) underscores the intricate connections within the "whole mind-body system." Personality plays a pivotal role, with specific traits linked to stress influencing neural behavior and psychophysiological disorders. Gene expression networks associated with personality affect neuronal plasticity, epigenetic processes, and adaptive behaviors, highlighting the importance of systems biology mechanisms. Systemic inflammation correlates with key personality traits. Understanding the roles of inflammatory and oxidative biomarkers in personality traits and disorders can help identify diagnostic and therapeutic targets for various diseases. Neurobiological features contribute to our understanding of personality disorders and related conditions. Personality traits are linked to distributed neuroendocrine networks, particularly the hypothalamic-pituitary-adrenal (HPA) axis, rather than localized brain areas. Correlations have also been identified between personality traits and thyroid hormones. Disrupted hypothalamic-pituitary-thyroid (HPT) axis functions may be associated with disease severity, depression, and distress, highlighting the need for comprehensive endocrinological and psychopathological evaluations. The gut-brain axis influences personality traits, emotions, stress, and social behaviors. Altered gut microbiota is common in psychiatric conditions, suggesting potential treatments targeting the microbiota. Chronic stress impacts cognitive functions and correlates with personality and mental health, emphasizing the need for comprehensive, multi-dimensional patient profiles for effective prevention and therapy. A biopsychosocial model integrating personality traits will advance personalized and systems medicine.

Disease activity at the onset of diagnosis as a predictor of disease outcomes in a cohort of patients with systemic lupus erythematosus: A post hoc retrospective analysis of the COMOSLE-EGYPT study.

Systemic lupus erythematosus (SLE) has a non-uniform course directly reflected in changes in disease activity and anticipation of damage. To determine the impact of disease activity at the onset of disease diagnosis, measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) disease activity score, on different disease parameters and outcomes. This multicentre, retrospective cohort study included 823 SLE patients. Disease damage was measured by the Systemic Lupus International Collaborating Clinics Damage Index (SLICC), and comorbidities were measured by the Charlson Comorbidity Index (CCI). According to the mean SLEDAI at onset of disease diagnosis, patients were classified into two groups: I included patients with a mean SLEDAI ≤ 10 (non-severe disease activity), and II included patients with a mean SLEDAI > 10 (severe disease activity). SLEDAI at onset of disease diagnosis was a predictor of damage and comorbidities. A higher SLEDAI score at onset of disease diagnosis was associated with damage accrual. Patients who are younger at disease onset are more likely to have more severe disease. Severe disease activity at the onset of disease diagnosis was also associated with future comorbidity occurrences, but it was not significantly associated with mortality. SLEDAI at the onset of disease diagnosis could be a prognostic marker predicting the damage, which may help in the identification of patients who are at higher risk of adverse outcomes. Special care should be directed towards patients who are younger at disease onset as they may have a higher disease activity at diagnosis. Key Points • This is a unique study as it is the first to focus on the impact of SLE disease activity at the onset of disease diagnosis measured by SLEDAI disease activity score on different disease parameters and outcomes. • Previous studies, though these are scarce, have highlighted the impact of disease activity throughout the disease course and not specifically at the beginning of the SLE disease.

Leveraging Real-World Evidence to Define Severe RSV Lower Respiratory Tract Disease in Adults.

As no standard case definitions for respiratory syncytial virus-associated lower respiratory tract disease (RSV-LRTD) in adults are available, this study analyzed definitions for severe RSV-LRTD from previously published data in hospital and community cohorts of adults with RSV-associated symptoms. The frequency, sensitivity, and specificity of acute respiratory disease symptoms among hospitalized and community cohorts of adults with RSV were analyzed. RSV-LRTD signs/symptoms assessed included shortness of breath (dyspnea), cough and/or fever, wheezing/rales/rhonchi (abnormal lung sounds by auscultation), sputum production, tachypnea, hypoxemia, and pleuritic chest pain. Dyspnea and tachypnea provided the best differentiation between hospitalized and community RSV-positive cases. The severe RSV-LRTD case definition yielding one of the highest and best-balanced sensitivity and specificity was dyspnea paired with either abnormal lung sounds by auscultation, hypoxemia, tachypnea, cough and/or fever, sputum, or chest pain. Dyspnea alone, and in combination with certain other lower respiratory tract disease signs/symptoms, was a leading symptomatic indicator for severe RSV outcomes. These results contribute to the harmonization of case definitions for RSV disease.

Web-based pulmonary telehabilitation: a systematic review.

Web-based pulmonary telerehabilitation (WBPTR) can serve as a valuable tool when access to conventional care is limited. This review assesses a series of studies that explore pulmonary telerehabilitation programmes delivered via web-based platforms. The studies involved participants with moderate to severe chronic obstructive pulmonary disease (COPD). Of the 3190 participants, 1697 engaged in WBPTR platforms, while the remaining 1493 comprised the control groups. Sixteen studies were included in the meta-analysis. Web-based pulmonary telerehabilitation led to an increase in daily step count (MD 446.66, 95% CI 96.47 to 796.86), though this did not meet the minimum clinically important difference. Additionally, WBPTR did not yield significant improvements in the six-minute walking test (MD 5.01, 95% CI - 5.19 to 15.21), health-related quality of life as measured by the St. George's Respiratory Questionnaire (MD - 0.15, 95% CI - 2.24 to 1.95), or the Chronic Respiratory Disease Questionnaire (MD 0.17, 95% CI - 0.13 to 0.46). Moreover, there was no significant improvement in dyspnoea-related health status, as assessed by the Chronic Respiratory Disease Questionnaire (MD - 0.01, 95% CI - 0.29 to 0.27) or the modified Medical Research Council Dyspnoea Scale (MD - 0.14, 95% CI - 0.43 to 0.14). Based on these findings, this review concludes that WBPTR does not offer substantial advantages over traditional care. While slight improvements in exercise performance were observed, no meaningful enhancements were noted in dyspnoea or quality of life metrics. Overall, WBPTR remains a complementary and accessible option for managing and monitoring COPD patients. However, further research and innovation are required to improve its efficacy and adapt it to various clinical environments.

Lessons Learned From Clinical Trials of Immunotherapeutics for COVID-19.

The COVID-19 pandemic caused by the SARS-CoV-2 virus was arguably one of the worst public health disasters of the last 100 years. As many infectious disease experts were focused on influenza, MERS, ZIKA, or Ebola as potential pandemic-causing agents, SARS-CoV-2 appeared to come from nowhere and spread rapidly. As with any zoonotic agent, the initial pathogen was able to transmit to a new host (humans), but it was poorly adapted to the immune environment of the new host and resulted in a maladapted immune response. As the host-pathogen interaction evolved, subsequent variants of SARS-CoV-2 became less pathogenic and acquired immunity in the host provided protection, at least partial protection, to new variants. As the host-pathogen interaction has changed since the beginning of the pandemic, it is possible the clinical results discussed here may not be applicable today as they were at the start of the pandemic. With this caveat in mind, we present an overview of the immune response of severe COVID-19 from a clinical research perspective and examine clinical trials utilizing immunomodulating agents to further elucidate the importance of hyperinflammation as a factor contributing to severe COVID-19 disease.

Higher Long-Term Visit-to-Visit Blood Pressure Variability Is Associated With Severe Cerebral Small Vessel Disease in the General Population.

Long-term visit-to-visit blood pressure (BP) variability is linked to various diseases, but its impact on cerebral small vessel disease (cSVD) burden, and its features remains uncertain. We analyzed 1284 participants from the Kailuan cohort (2006-2022). Visit-to-visit systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) variability were categorized into tertiles (low, middle, high). Magnetic resonance imaging identified white matter hyperintensities (WMH), lacunae of presumed vascular origin (LA), cerebral microbleeds (CMBs), and visible perivascular spaces (PVS). Total cSVD burden was classified as none (0), mild (1), moderate (2), or severe (3-4) based on the presence of these features. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). High SBP variability was associated with moderate cSVD burden (OR = 1.89, 95% CI: 1.09-3.29) and PVS (OR = 1.62, 95% CI: 1.10-2.39). High DBP variability was associated with LA (OR = 1.74, 95% CI: 1.06-2.84). High PP variability showed a significant risk for severe cSVD burden (OR = 2.49, 95% CI: 1.34-4.63). These associations were modified by age and hypertension status. Among young adults (age < 60 years), high PP variability was associated with severe cSVD burden (OR = 3.33, 95% CI: 1.31-8.44), LA (OR = 3.02, 95% CI: 1.31-6.93), and PVS (OR = 1.86, 95% CI: 1.20-2.88). The risk effects of SBP and PP variability on cSVD burden were significant only in participants with hypertension. High long-term visit-to-visit BP variability (BPV), particularly in combination with hypertension, is a significant risk factor for total cSVD. Special attention should be given to PP variability in younger adults.

Evaluation of Novel Picolinamide Fungicides (QiI) for Controlling Cercospora beticola Sacc. in Sugar Beet

Studies were initiated to find new effective fungicides to use under field conditions to discover novel approaches for optimizing disease management in sugar beet crops. Cercospora leaf spot (CLS), a prevalent foliar disease in sugar beet crops worldwide, is caused by the fungal pathogen Cercospora beticola Sacc. This disease has become the most prevalent pathogen in sugar beet crops across nearly all European growing regions, including Hungary. The epidemic spread of this disease can cause up to 50% yield loss. The use of fungicides has been a cornerstone in managing CLS of sugar beet due to the limited efficacy of non-chemical alternatives. However, the emergence of fungicide-resistant strains of Cercospora beticola Sacc. in recent decades has compromised the effectiveness of certain fungicides, particularly those belonging to the QoI (FRAC Group 11) and DMI (FRAC Group 3) classes. Hungary is among the many countries where resistance to these fungicides has developed due to their frequent application. Picolinamides represent a novel class of fungal respiration inhibitors targeting Complex III within the Quinoine-Inside Inhibitor (QiI) group. Two innovative fungicides from this class, fenpicoxamid and florylpicoxamid (both classified under FRAC Group 21), were evaluated for their efficacy in managing CLS of sugar beet in Hungary during the 2020 and 2021 growing seasons. Both fungicides were applied as formulated products at various application rates and demonstrated superior efficacy in controlling CLS compared to untreated control plots and the reference fungicides difenoconazole and epoxiconazole. The results consistently demonstrated that all tested application rates of fenpicoxamid and florylpicoxamid effectively controlled CLS in sugar beet, exhibiting a clear dose–response relationship. Disease severity, as measured by the area under the disease progress curve (AUDPC), was significantly correlated with yield reduction but showed no significant association with root sugar content. Moreover, data from both study years indicated that picolinamide fungicides applied at a rate of 75 g ai/ha significantly outperformed difenoconazole (100 g ai/ha) in controlling the CLS of sugar beet. Additionally, higher application rates of picolinamides at 100–150 g ai/ha outperformed epoxiconazole at 125 g ai/ha in disease suppression. Fenpicoxamid is currently registered for use in cereals within Europe, and outside of Europe in Banana against Black Sigatoka (eff. Mycosphaerella fijiensis). Florylpicoxamid, while not yet registered in Europe, is undergoing approval processes in various countries worldwide for a range of crops and is continually being evaluated for potential market introduction. Additional details regarding the efficacy of florylpicoxamid against CLS in sugar beet were presented at ‘The 10th International Conference on Agricultural and Biological Sciences (ABS 2024, Győr-Hungary)’ in 2024.

Economic Burden of Haemophilia from a Societal Perspective: A Scoping Review.

Haemophilia is a rare genetic bleeding disorder that leads to musculoskeletal complications. The high cost of haemophilia treatment necessitates a thorough evaluation of its economic burden. However, due to the difficulty of estimating direct non-medical, indirect, and intangible costs, studies often underestimate the actual economic burden of haemophilia. This scoping review aims to summarise economic studies in haemophilia conducted from a societal perspective. A systematic search across eight scholarly databases, grey literature, and reference lists until the5th of July 2023 was conducted to identify relevant studies. The inclusion criteria encompassed full-text, English-language publications of economic analyses in congenital haemophilia from a societal perspective. Model-based studies and those adopting a payer perspective were excluded. Costs were adjusted to international dollars (I$) and US dollars (US$) in 2022 for comparability. Out of 2993 potential sources identified, 25 studies met the inclusion criteria, covering 7226 persons with haemophilia across 22 countries. All studies reported direct medical costs, with four excluding the cost of haemostatic therapy. Fifteen studies reported direct formal non-medical costs, while eight reported direct informal non-medical costs. All but one study reported the indirect costs. The average annual costs of haemophilia varied widely based on treatment modality, disease severity, geographical location, and included cost categories. When including the cost of clotting factor replacement therapy (CFRT), the total cost for severe haemophilia without inhibitors ranged from 1566 I$ to 700,070 I$ per person per year (lowest value reported in India and highest in the United States). CFRT represented up to 99.9% of the total cost for those receiving prophylaxis and up to 95.1% for episodic treatment. Haemostatic therapies accounted for 82% of the total cost in patients with inhibitors. There is a significant heterogeneity in defining cost categories required for a comprehensive economic analysis from a societal perspective. While haemostatic therapies constitute a substantial portion of the overall cost, direct non-medical and indirect costs are crucial as they are often paid out-of-pocket and may impede access to treatment. It is essential for haematologists and economists to establish a standardised costing framework for future studies, particularly in the era of novel therapies.

Cellular senescence in acute human infectious disease: a systematic review

IntroductionAcute infectious disease represents a significant cause of mortality and morbidity in elderly individuals admitted to the hospital. In its extreme, it presents as sepsis, a systematic inflammatory and immunologic response responsible for self-injurious organ injury. As individuals age, a unique set of factors including immunosenescence predispose them to acquiring an infection and a worse clinical prognosis. This systematic review explores the relationship between cellular senescence, an age-related inflammatory phenomenon, with acute human infectious disease.MethodsEmbase via OVID, Scopus, Web of Science, Global Index Medicus, Cochrane Library via Wiley, and ClinicalTrials.gov were queried. Included studies must have compared at least one of the following measures of cellular senescence between patients with an infection and without an infection: cell cycle inhibition measured via levels of p16INK4a and/or p21CIP1, short telomere length, DNA damage via ɣH2AX, high senescence-associated β galactosidase activity, and inflammation via the detection of senescence associated secretory phenotype (SASP). Manuscripts were screened and data collected via two independent reviewers.ResultsA total of 15,828 studies were screened after duplicates were removed. One hundred and fifty-three full-text articles were assessed for eligibility and a total of 16 original articles were included in analysis. Of the 16 original articles included, 12 (75%) articles were centered on SARS-CoV-2, 2 (12.5%) articles utilized patients infected with Leishmania braziliensis, 1 (6.25%) with Plasmodium falciparum, and 1 (6.25%) with Hepatitis C.ConclusionCurrent literature demonstrates robust upregulation of markers of cellular senescence in the setting of acute SARS-CoV-2, P. falciparum, L. braziliensis, and hepatitis C virus, and that markers of senescence correlate with disease severity and persist for months after resolution. Limitations in the number and types of infectious organisms studied, low sample sizes, modest longitudinal sampling, and a lack of consistency in markers measured, the method of measurement, and the definition of normal values represent ongoing gaps in the literature.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=421473, Identifier CRD42023421473.

Genetic Analysis of Stripe Rust Resistance in the Chinese Wheat Cultivar Luomai 163.

Stripe or yellow rust (YR) caused by Puccinia striiformis tritici (Pst) is an important foliar disease affecting wheat production globally. Resistant varieties are the most economically and environmentally effective way to manage this disease. The common winter wheat (Triticum aestivum L.) cultivar Luomai 163 exhibited resistance to the Pst races CYR32 and CYR33 at the seedling stage and showed a high level of adult plant resistance in the field. To understand the genetic basis of YR resistance in this cultivar, 142 F5 recombinant inbred lines (RILs) derived from cross Apav#1 × LM163 and both parents were genotyped with the 16K SNP array and bulked segregant analysis sequencing. The analysis detected a major gene, YrLM163, at the seedling stage associated with the 1BL.1RS translocation. Additionally, three genes for resistance at the adult plant stage were detected on chromosome arms 1BL (Lr46/Yr29/Pm39/Sr58), 6BS, and 6BL in Luomai 163, whereas Apav#1 contributed resistance at a quantitative trait locus (QTL) on 2BL. These QTL explained YR disease severity variations ranging from 6.9 to 54.8%. The kompetitive allele-specific PCR (KASP) markers KASP-2BL, KASP-6BS, and KASP-6BL for the three novel loci QYr.hzau-2BL, QYr.hzau-6BS, and QYr.hzau-6BL were developed and validated. QYr.hzau-1BL, QYr.hzau-2BL, and QYr.hzau-6BS showed varying degrees of resistance to YR when present individually or in combination based on genotype and phenotype analysis of a panel of 570 wheat accessions. Six RILs combining resistance alleles of all QTL, showing higher resistance to YR in the field than Luomai 163 with disease severities of 10.7 to 16.0%, are important germplasm resources for breeding programs to develop YR-resistant wheat varieties with good agronomic traits.

Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.

Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.

Impact of antiplatelets, anticoagulants and cyclic nucleotide stimulators on neutrophil extracellular traps (NETs) and inflammatory markers during COVID-19.

While the association between coronavirus disease-19 (COVID-19) and neutrophils extracellular traps (NETs) is recognized, uncertainties remain regarding its precise onset, timing of resolution and target therapy. To assess changes in inflammatory and NET markers during the first week of COVID-19 hospitalization, and the association with disease severity. "In vitro" experiments investigated the effect of antiplatelets, anticoagulants, and cyclic nucleotide stimulators on NETs release. Prospective cohort study, changes in interleukin (IL)-6, IL-8, IL-17, TNF-α, RANTES, PF4, and citrullinated-H3 (citH3) levels within each outcome group was evaluated using ANOVA. Differences between moderately ill, critically ill, and non-survivors were determined using Kruskal-Wallis and logistic regression. Healthy neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) or COVID-19 sera and treated with unfractionated heparin (UFH), low molecular weight heparin (LMWH), aspirin (ASA), ticagrelor, cinaciguat, sildenafil, and milrinone. The proportion of NETosis was assessed using IncuCyte Cell Imager. Of the 125 patients, 40.8% had moderate COVID-19, 40.8% had critical COVID-19 but recovered, and 18.4% died. From admission to hospitalization day 8, IL-6 levels decreased in moderately and critically ill, but not in non-survivors, while citH3 levels increased in critically ill and non-survivors. IL-6, IL-8, and TNF-α levels were associated with critical and fatal COVID-19. The release of NETs by neutrophils stimulated with PMA or COVID-19 sera was decreased in the presence of ASA, UFH, LMWH and cyclic nucleotide stimulators in a dose-dependent manner. In the first week of hospitalization, NET markers rose later than inflammatory markers in severe COVID-19 cases. Cyclic nucleotide stimulators, ASA and heparin may emerge as treatment approaches as they may modulate NETosis.

Laser therapy for Bell's palsy: a systematic review and meta-analysis of randomized trials.

This meta-analysis investigated therapeautic effects of laser therapies in patients with Bell's palsy (BP). The authors performed the literature search in the PubMed, Embase, and Cochrane Library databases using the following search terms: (facial paralysis OR Bell's palsy OR facial palsy OR idiopathic facial paralysis) AND (laser OR low-level laser OR photobiomodulation OR phototherapy). Relevant studies published before October 29th 2024 were identified. Randomized trials comparing the outcomes of laser therapies with other interventions, including electrical stimulation and control or usual care in patients with BP were included. The mean difference (MD) was determined as the effect size for continuous outcomes, and outcome accuracy was determined using 95% confidence intervals (CIs). Twelve studies were included, with a total of 597 patients. Nine studies were further included in the quantitative analysis. Our meta-analysis revealed that laser therapy significantly improved disease severity (House-Brackmann facial paralysis scale) (MD = -1.51, 95% CI = -2.43 to -0.59), facial asymmetry (Sunnybrook facial grading system) (MD = 20.63, 95% CI = 10.33 to 30.94), and facial function and disability (Facial disability index) (MD = 17.91, 95% CI = 5.60 to 30.22) when compared with control care in adult patients. Moreover, laser therapy significantly improved facial severity (MD = 21.05, 95% CI = 16.77 to 25.33) when compared with electrical stimulation. In addition, no adverse effects of laser therapy were reported. Laser therapy has favorable effects on disease severity, facial asymmetry, and facial function and disability for patients with BP.

Blood CD45+/CD3+ lymphocyte-released extracellular vesicles and mortality in hospitalized patients with coronavirus disease 2019.

The global pandemic of coronavirus disease 2019 (COVID-19) represented a major public health concern. Growing evidence shows that plasma of COVID-19 patients contains large numbers of circulating extracellular vesicles (cEVs) that correlate with disease severity and recovery. In this study, we sought to characterize the longitudinal cEV signature in critically ill COVID-19 patients during hospitalization and its relation to mortality risk. cEVs were quantitatively and phenotypically analysed in hospitalized non-surviving COVID-19 patients at baseline (n = 42) and before exitus (n = 40) and in 40 healthy volunteers as a reference group by high sensitivity nano flow cytometry using specific markers for parental cell sources and activation. Levels of cEV subtypes differed between patients with severe COVID-19 and healthy subjects, specifically those from platelets and endothelial, inflammatory and viral infected cells, which associate to high mortality risk. In the longitudinal analysis from baseline to the time point immediately preceding death, no changes were found for platelet, pan-leukocyte, and lung epithelial cell-shed cEVs, while endothelial cell releases of EVs (eEVs) significantly differed. Vascular endothelial growth factor receptor 2-positive eEVs were significantly increased before death compared to admission whereas endoglin and E-selectin-containing eEVs did not change. Conversely, lymphocyte (ℓEV), monocyte, macrophage, pericyte and progenitor cell-derived cEVs displayed significant reductions before exitus. Noteworthy, levels of CD45+/CD3+-ℓEVs were significantly associated to the patient's survival time. An evolving cEV profile able to discriminate prompt risk of death during hospitalization has been defined suggesting a role for circulating and vascular cell-derived EVs in COVID-19 pathogenesis.

Identifying amyotrophic lateral sclerosis using diffusion tensor imaging, and correlation with neurofilament markers.

To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL (r = -0.813, p < 0.001), Serum-NFL (r = -0.493, p = 0.001), CSF-pNFH (r = -0.637, p < 0.001), and Serum-pNFH (r = -0.672, p < 0.001); Peduncle-FA negatively with CSF-NFL (r = -0.562, p < 0.001), CSF-pNFH (r = -0.506, p = 0.001), and Serum-pNFH (r = -0.488, p = 0.001); Peduncle-MD positively with CSF-NFL (r = 0.516, p < 0.001), CSF-pNFH (r = 0.494, p = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.

COMPARATIVE ANALYSIS OF COVID-19 PATIENTS DURING DELTA AND OMICRON WAVES OF COVID-19 PANDEMIC: AN EXPERIENCE FROM RURAL TERTIARY CARE HOSPITAL IN NORTH INDIA

Objective: In this study, an effort has been made to find out possible clinical parameters that may have played role in differences in the disease outcome in the delta and omicron waves. Methods: This is a retrospective observational study conducted at a rural tertiary care center of North India. We recorded sociodemographic and clinicopathological parameters of the admitted patients during delta and omicron waves in India. The outcome measures were demographic, baseline clinical, disease severity, ICU admissions and hospital mortality. Results: In our study, 1731 patients were tested positive for SARS-CoV-2, out of which 16 patients were admitted during the omicron wave and 878 admissions during the delta wave. In delta wave, the ratio of male to female was 1:2 and in omicron wave, it was 1:3. There were 271 deaths in delta wave and 2 deaths in omicron wave. A significantly lower number of admissions were noted during omicron wave (p&lt;0.001). Patients without previous history of COVID-19 and unvaccinated status had significantly higher admission (p&lt;0.001). The admission rate among comorbid patients was also significantly low in the omicron wave (p&lt;0.001). 251 patients had one or more comorbidities and were mostly in severe (13.4%) or critical (88.4%) conditions in delta wave while among 13 comorbid patients in omicron wave, 7.7% were in severe and 15.4% were in critical condition. Conclusion: The hospital admissions were very low in comparison to delta wave. During delta wave, the degree of severity and number of deaths were also very high.