Mitochondrial structural alterations in fibromyalgia: a pilot electron microscopy study.

OBJECTIVES: The pathogenesis of fibromyalgia (FM), characterised by chronic widespread pain and fatigue, remains notoriously elusive, hampering attempts to develop disease modifying treatments. Mitochondria are the headquarters of cellular energy metabolism, and their malfunction has been proposed to contribute to both FM and chronic fatigue. Thus, the aim of the current pilot study, was to detect structural changes in mitochondria of peripheral blood mononuclear cells (PBMCs) of FM patients, using transmission electron microscopy (TEM). METHODS: To detect structural mitochondrial alterations in FM, we analysed PBMCs from seven patients and seven healthy controls, using TEM. Patients were recruited from a specialised Fibromyalgia Clinic at a tertiary medical centre. After providing informed consent, participants completed questionnaires including the widespread pain index (WPI), symptoms severity score (SSS), fibromyalgia impact questionnaire (FIQ), beck depression inventory (BDI), and visual analogue scale (VAS), to verify a diagnosis of FM according to ACR criteria. Subsequently, blood samples were drawn and PBMCs were collected for EM analysis. RESULTS: TEM analysis of PBMCs showed several distinct mitochondrial cristae patterns, including total loss of cristae in FM patients. The number of mitochondria with intact cristae morphology was reduced in FM patients and the percentage of mitochondria that completely lacked cristae was increased. These results correlated with the WPI severity. Moreover, in the FM patient samples we observed a high percentage of cells containing electron dense aggregates, which are possibly ribosome aggregates. Cristae loss and possible ribosome aggregation were intercorrelated, and thus may represent reactions to a shared cellular stress condition. The changes in mitochondrial morphology suggest that mitochondrial dysfunction, resulting in inefficient oxidative phosphorylation and ATP production, metabolic and redox disorders, and increased reactive oxygen species (ROS) levels, may play a pathogenetic role in FM. CONCLUSIONS: We describe novel morphological changes in mitochondria of FM patients, including loss of mitochondrial cristae. While these observations cannot determine whether the changes are pathogenetic or represent an epiphenomenon, they highlight the possibility that mitochondrial malfunction may play a causative role in the cascade of events leading to chronic pain and fatigue in FM. Moreover, the results offer the possibility of utilising changes in mitochondrial morphology as an objective biomarker in FM. Further understanding the connection between FM and dysfunction of mitochondria physiology, may assist in developing both novel diagnostic tools as well as specific treatments for FM, such as approaches to improve/strengthen mitochondria function.

Long COVID-19 Enigma: Unmasking the Role of Distinctive Personality Profiles as Risk Factors.

Background: The COVID-19 (Coronavirus disease 2019) pandemic has prompted extensive research into lingering effects, especially in 'Long COVID' patients. Despite exploration, contributing factors remain elusive; Objective: This study explores the potential link between distinctive personality profiles, particularly type D personality, and an increased risk of Long COVID; Methods: A retrospective cross-sectional study at Tel-Aviv Sourasky Medical Center's Post-COVID clinic analyzed data from 373 Long COVID patients through comprehensive questionnaires covering Long COVID syndrome, Fibromyalgia criteria, personality assessments, social support, and subjective evaluations of cognitive decline, health and life quality. In total, 116 out of 373 patients completed the questionnaire, yielding a 31% participation rate; Results: Cluster analysis revealed two groups, with Cluster 1 (N = 58) exhibiting Type D personality traits while Cluster 2 (N = 56) not meeting criteria for Type D personality. In comparison to Cluster 2, Cluster 1 patients reported heightened anxiety, depression, reduced social support, increased pain symptoms, manifestations of fibromyalgia, cognitive decline, and poor sleep quality, contributing to a diminished quality-of-life perception; Conclusions: findings highlight diverse personality profiles among Long COVID patients, emphasizing the need for tailored care. This approach shows potential for improving Long COVID patient care, aligning with the evolving personalized medicine paradigm.

Hyperbaric oxygen therapy vs. pharmacological intervention in adults with fibromyalgia related to childhood sexual abuse: prospective, randomized clinical trial.

Fibromyalgia syndrome (FMS) is a chronic pain syndrome characterized by disruptions in pain processing within the central nervous system. It exhibits a high prevalence among patients with a history of traumatic experiences, notably childhood sexual abuse (CSA). This study compared the efficacy of hyperbaric oxygen therapy (HBOT) to the current pharmacological standard of care for individuals suffering from CSA-related FMS. Forty-eight participants diagnosed with FMS and a history of CSA were randomly assigned to either the HBOT group (60 sessions of 100% oxygen at 2 ATA for 90 min, with air breaks every 5 min) or the medication (MED) group (FDA-approved medications, Pregabalin and Duloxetine). The primary endpoint was the Fibromyalgia impact questionnaire (FIQ) score, while secondary endpoints encompassed emotional status and daily functioning questionnaires, as well as pain thresholds and conditioned pain modulation tests. Brain activity was evaluated through single photon emission computed tomography (SPECT). Results revealed a significant group-by-time interaction for the FIQ score favoring HBOT over MED (p < 0.001), with a large effect size (Cohen's d = - 1.27). Similar findings were observed in emotional symptoms and functional measures. SPECT imaging demonstrated an increase in activity in pre-frontal and temporal brain areas, which correlated with symptoms improvement. In conclusion, HBOT exhibited superior benefits over medications in terms of physical, functional, and emotional improvements among FMS patients with a history of CSA. This associated with increased activity in pre-frontal and temporal brain areas, highlighting the neuroplasticity effect of HBOT.

Dual anti-viral treatment for persistent COVID-19 in immunocompromised hemato-oncological patients is associated with a favorable prognosis and minor side effects.

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19.

TMS in combination with a pain directed intervention for the treatment of fibromyalgia - A randomized, double-blind, sham-controlled trial.

BACKGROUND: Fibromyalgia Syndrome (FMS) is a highly prevalent condition, that causes chronic pain and severe reduction in quality of life and productivity, as well as social isolation. Despite the significant morbidity and economic burden of FMS, current treatments are scarce. OBJECTIVE: To investigate whether stimulation of ACC -mPFC activity by dTMS enhances a pain-directed psychotherapeutic intervention. METHODS: 19 FMS patients were randomised to receive either 20 sessions of dTMS or sham stimulation, each followed by a pain-directed psychotherapeutic intervention. With the H7 HAC coil or sham stimulation, we targeted the ACC -mPFC; specific brain areas that play a central role in pain processing. Clinical response to treatment was assessed with the McGill Pain Questionnaire Short Form (SF-MPQ), the Visual Analogue Fibromyalgia Impact Questionnaire, the Brief Pain Inventory questionnaire, and the Hamilton Depression Rating Scale. RESULTS: DTMS treatment was safe and well tolerated by FMS patients. A significant decrease in the combined sensory and affective pain dimensions was specifically demonstrated in the dTMS cohort, as measured by the SF-MPQ (Significant group × time interaction [F(2, 32) = 3.51, p < .05,ηp2 = 0.18]; No significant changes were found in depressive symptoms in both the dTMS and sham groups. CONCLUSION: Our results suggest that a course of dTMS combined with a pain-directed psychotherapeutic intervention can alleviate pain symptoms in FMS patients. Beyond clinical possibilities, future studies are needed to substantiate the innovative hypothesis that it is not dTMS alone, but rather dTMS-induced plasticity of pain-related networks, that enables the efficacy of pain-directed psychotherapeutic interventions.

Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis.

Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium. Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)-converting enzyme. A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested. These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis.

The Liver Can Deliver: Utility of Hepatic Function Tests as Predictors of Outcome in COVID-19, Influenza and RSV Infections.

BACKGROUND: liver test abnormalities have been described in patients with Coronavirus-2019 (COVID-19), and hepatic involvement may correlate with disease severity. With the relaxing of COVID-19 restrictions, seasonal respiratory viruses now circulate alongside SARS-CoV-2. AIMS: we aimed to compare patterns of abnormal liver function tests in patients suffering from COVID-19 infection and seasonal respiratory viruses: respiratory syncytial virus (RSV) and influenza (A and B). METHODS: a retrospective cohort study was performed including 4140 patients admitted to a tertiary medical center between 2010-2020. Liver test abnormalities were classified as hepatocellular, cholestatic or mixed type. Clinical outcomes were defined as 30-day mortality and mechanical ventilation. RESULTS: liver function abnormalities were mild to moderate in most patients, and mainly cholestatic. Hepatocellular injury was far less frequent but had a strong association with adverse clinical outcome in RSV, COVID-19 and influenza (odds ratio 5.29 (CI 1.2-22), 3.45 (CI 1.7-7), 3.1 (CI 1.7-6), respectively) COVID-19 and influenza patients whose liver functions did not improve or alternatively worsened after 48 h had a significantly higher risk of death or ventilation. CONCLUSION: liver function test abnormalities are frequent among patients with COVID-19 and seasonal respiratory viruses, and are associated with poor clinical outcome. The late liver tests' peak had a twofold risk for adverse outcome. Though cholestatic injury was more common, hepatocellular injury had the greatest prognostic significance 48 h after admission. Our study may provide a viral specific auxiliary prognostic tool for clinicians facing patients with a respiratory virus.

Neurophysiological and psychosocial mechanisms of fibromyalgia: A comprehensive review and call for an integrative model.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Neutrophil-to-lymphocyte ratio trend at admission predicts adverse outcome in hospitalized respiratory syncytial virus patients.

Background and aims: Severe cases of respiratory syncytial virus (RSV) infection are relatively rare but may lead to serious clinical outcomes, including respiratory failure and death. These infections were shown to be accompanied by immune dysregulation. We aimed to test whether the admission neutrophil-to-leukocyte ratio, a marker of an aberrant immune response, can predict adverse outcome. Methods: We retrospectively analyzed a cohort of RSV patients admitted to the Tel Aviv Medical Center from January 2010 to October 2020d. Laboratory, demographic and clinical parameters were collected. Two-way analysis of variance was used to test the association between neutrophil-lymphocyte ratio (NLR) values and poor outcomes. Receiver operating characteristic (ROC) curve analysis was applied to test the discrimination ability of NLR. Results: In total, 482 RSV patients (median age 79 years, 248 [51%] females) were enrolled. There was a significant interaction between a poor clinical outcome and a sequential rise in NLR levels (positive delta NLR). The ROC curve analysis revealed an area under curve (AUC) of poor outcomes for delta NLR of (0.58). Using a cut-off of delta = 0 (the second NLR is equal to the first NLR value), multivariate logistic regression identified a rise in NLR (delta NLR>0) as being a prognostic factor for poor clinical outcome, after adjusting for age, sex and Charlson comorbidity score, with an odds ratio of 1.914 (P = 0.014) and a total AUC of 0.63. Conclusions: A rise in NLR levels within the first 48 h of hospital admission can serve as a prognostic marker for adverse outcome.

Risk factors, clinical characteristics and prognostic value of acute kidney injury in COVID-19 compared with influenza virus and respiratory syncytial virus.

BACKGROUND: Acute Kidney Injury (AKI) complicates a substantial part of patients with COVID-19. Direct viral penetration of renal cells through the Angiotensin Converting Enzyme 2 receptor, and indirect damage by the aberrant inflammatory response characteristic of COVID-19 are likely mechanisms. Nevertheless, other common respiratory viruses such as Influenza and Respiratory Syncytial Virus (RSV) are also associated with AKI. METHODS: We retrospectively compared the incidence, risk factors and outcomes of AKI among patients who were admitted to a tertiary hospital because of infection with COVID-19, influenza (A + B) or RSV. RESULTS: We collected data of 2593 patients hospitalized with COVID-19, 2041 patients with influenza and 429 with RSV. Patients affected by RSV were older, had more comorbidities and presented with higher rates of AKI at admission and within 7 days (11.7% vs. 13.3% vs. 18% for COVID-19, influenza and RSV, respectively p = 0.001). Nevertheless, patients hospitalized with COVID-19 had higher mortality (18% with COVID-19 vs. 8.6% and 13.5% for influenza and RSV, respectively P < 0.001) and higher need of mechanical ventilation (12.4% vs. 6.5% vs.8.2% for COVID-19, influenza and RSV, respectively, P = 0.002). High ferritin levels and low oxygen saturation were independent risk factors for severe AKI only in the COVID-19 group. AKI in the first 48 h of admission and in the first 7 days of hospitalization were strong independent risk factors for adverse outcome in all groups. CONCLUSION: Despite many reports of direct kidney injury by SARS-COV-2, AKI was less in patients with COVID-19 compared to influenza and RSV patients. AKI was a prognostic marker for adverse outcome across all viruses.

Hyperbaric oxygen therapy compared to pharmacological intervention in fibromyalgia patients following traumatic brain injury: A randomized, controlled trial.

Fibromyalgia is a chronic pain syndrome with unsatisfactory response to current treatments. Physical trauma, including traumatic brain Injury (TBI) is among the etiological triggers. Hyperbaric Oxygen therapy (HBOT) is an intervention that combines 100% oxygen with elevated atmospheric pressure. HBOT has been applied as a neuro-modulatory treatment in central nervous system-related conditions. The current study investigated the utility of HBOT for TBI-related fibromyalgia. Fibromyalgia patients with a history of TBI were randomized to either HBOT or pharmacological intervention. HBOT protocol comprised 60 daily sessions, breathing 100% oxygen by mask at 2 absolute atmospheres (ATA) for 90 minutes. Pharmacological treatment included Pregabalin or Duloxetine. The primary outcome was subjective pain intensity on visual analogue scale (VAS); Secondary endpoints included questionnaires assessing fibromyalgia symptoms as well as Tc-99m-ECD SPECT brain imaging. Pain threshold and conditioned pain modulation (CPM) were also assessed. Results demonstrated a significant group-by-time interaction in pain intensity post-HBOT compared to the medication group (p = 0.001), with a large net effect size (d = -0.95) in pain intensity reduction following HBOT compared to medications. Fibromyalgia related symptoms and pain questionnaires demonstrated significant improvements induced by HBOT as well as improvements in quality of life and increase in pain thresholds and CPM. SPECT demonstrated significant group-by-time interactions between HBOT and medication groups in the left frontal and the right temporal cortex. In conclusion, HBOT can improve pain symptoms, quality of life, emotional and social function of patients suffering from FMS triggered by TBI. The beneficial clinical effect is correlated with increased brain activity in frontal and parietal regions, associated with executive function and emotional processing.

Effect of patient COVID-19 vaccine hesitancy on hospital care team perceptions.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic posed new challenges in patient care worldwide. Vaccinations, which have proven efficacious in lowering the COVID-19 hospital burden, are still avoided by large populations. We, therefore, hypothesized that hospital care teams would have worse perceptions regarding the characteristics and care of patients with vaccine hesitancy. AIM: To evaluate whether patient vaccine hesitancy affected the hospital care team (HCT) perceptions. METHODS: We performed a prospective clinical study using structured questionnaires. We approached physicians and nurses with previous experience caring for COVID-19 patients from 11 medical centers across Israel during the fourth COVID-19 surge (September and October 2021). The participants completed a questionnaire with the following parts: (1) Sociodemographic characteristics; (2) Assessment of anger (STAXI instrument) and chronic workplace stress (Shirom-Melamed burnout measure); and (3) Three tools to assess the effect of patient vaccine hesitancy on the HCT perceptions (the difficult doctor-patient relation questionnaire, the medical staff perception of patient's responsibility questionnaire and the characterological derogation questionnaire). Results were evaluated according to each part of the questionnaire and the questionnaire as a whole. Associations between HCT perceptions and their baseline characteristics, anger or chronic workplace stress were assessed. RESULTS: The HCT experienced their relationship with unvaccinated patients as more difficult (P < 0.001, Cohen's d = 0.85), perceived unvaccinated patients as responsible for their medical condition (P < 0.001, d = 1.39) and perceived vaccinated patients as having a higher character value (P < 0.001, d = 1.03). Unvaccinated patients were considered selfish (P < 0.001), less mature (P < 0.001) and less satisfying to care for (P < 0.001). The relationship with unvaccinated patients was more difficult among HCT with higher burnout (r = 0.37, n = 66, P = 0.002). No correlations with baseline characteristics were found. All three study tools showed high internal consistency (α between 0.72 and 0.845). CONCLUSION: Our results should raise awareness of the possible effects of vaccine hesitancy on HCT perceptions regarding unvaccinated patients. In order to minimize the potential negative impact on patient care, designated departments should promote specific patient-centered preparations. Further investigations should assess whether vaccine hesitancy directly affects patient quality of care.

CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a-) variant.

The complement system regulator CD55 was initially found to carry the Cromer blood group system antigens, and its complete loss of function was subsequently revealed to cause a severe monogenic gastrointestinal syndrome characterized by protein-losing enteropathy and susceptibility to venous thrombosis. Here we present homozygosity to the CD55 c.596C>T; p.Ser199Leu variant, which was previously described as the Cromer Dr(a-) genotype, in two Bukharan Jewish CD55-deficiency patients with variable disease severity. We confirm that this missense variant causes aberrant splicing and deletion of 44 bp in exon 5, leading to premature termination and low expression of the CD55 protein. Furthermore, Patient 1 exhibited a mildly abnormal B cell immunophenotyping profile. By population screening we established that this variant is highly prevalent in the Bukharan Jewish population, with a carrier frequency of 1:17, suggesting that many similar patients are un- or mis-diagnosed. The phenotypic variability, ranging from abdominal pain when eating a high-fat diet to the full CD55-deficiency phenotype, is likely related to modifiers affecting the proportion of the variant that is able to escape aberrant splicing. Establishing the diagnosis of CD55-deficiency in a timely manner, even in patients with milder symptoms, may have a critical effect on their management and quality-of-life since treatment with the complement inhibitor eculizumab is highly effective in ameliorating disease manifestations. Awareness of founder mutations within certain populations can further guide genetic testing and prevent a diagnostic odyssey, by placing this CD55 variant high on the differential diagnosis.

Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia.

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive 'threat' system and underactive 'soothing' system, might keep the 'salience network' (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.

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

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

The economic burden of fibromyalgia: A systematic literature review.

INTRODUCTION: Fibromyalgia (FM) is a common disorder characterised by heterogeneous symptoms often leading to decreased functioning, work productivity and quality of life. Although a multimodal approach is used to treat FM, a significant proportion of patients show low satisfaction with perceived care, potentially resulting in an inefficient use of health care resources. The aim of the present review is to summarize the available evidence about the economic impact of FM and the specific cost drivers of health care expenditure for the syndrome. METHODS: MedLine and Web of Science databases were searched to identify eligible articles. Studies reporting direct medical and non-medical costs and/or indirect costs of FM were included. Annual costs per person were extrapolated from each study and converted to United States Dollars ($) after adjusting the local currency for inflation in year 2019. RESULTS: The 36 studies included in the final synthesis differed considerably in their design and in the cost categories analysed. Overall risk of bias was high. Estimates for the total annual direct costs per patient ranged from $ 1750 to $ 35,920 in the USA and from $ 1250 to $ 8504 in Europe. In most included studies, medications were the major contributor to overall expenditures. CONCLUSION: Fibromyalgia represents a substantial economic burden to health care systems and society. A better understanding of this complex disorder may not only improve quality of life of FM patients, but also have a significant impact on direct and indirect costs associated with the syndrome.