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.

Effects of Cigarette Smoking on Cardiac Autonomic Responses: A Cross-Sectional Study.

It has been suggested that some of the adverse, long-term cardiovascular outcomes of smoking are mediated by impaired autonomic nervous system (ANS) activity. Yet, this association is currently inconclusive. Heart rate variability (HRV) and the deep breathing test (DBT) represent common quantitative markers of ANS activity due to their simplicity and reliability. This large cross-sectional study was designed to assess the effect of active smoking on ANS function as manifested by HRV or DBT abnormalities. Electrocardiograms were recorded at rest for 5 min and during forced metronomic breathing. HRV and DBT were calculated according to accepted standards. Participants were divided into two groups based on current smoking status. The study included 242 healthy volunteers (196 nonsmokers and 46 smokers). There were no significant differences in age, sex, and BMI between groups. Cumulative smoking exposure burden (CSEB) for the study group was 5.3 ± 1.3 pack-years. Comparative analysis of HRV and DBT parameters according to smoking status revealed no significant differences between groups. Significant (p < 0.05), yet weak or moderate correlations (r < 0.7) were found between CSEB and abnormal change in HRV parameters consistent with sympathetic overactivity and decreased parasympathetic tone. In conclusion, smoking for a relatively short period in healthy adults does not seem to lead to significant impairment in ANS function. Yet, the consequences of smoking seem to be amplified when cumulative exposure burden increases.

Effects of Workplace-Related Factors on the Prevalence of Fibromyalgia among Israeli Kindergarten Teachers.

Background: Fibromyalgia syndrome (FMS), a chronic widespread pain disorder, has been associated with various models of stress, including those that are workplace-related. In a previous study, we have documented the significantly increased prevalence of FMS among schoolteachers, as well as correlating symptoms with stressful workplace-related factors. In the current study, we have focused on the specific population of kindergarten teachers and attempted to document both the prevalence of FMS symptoms among this group and the association with stress and symptoms of posttrauma. Methods: All participants in the study were working as kindergarten teachers in Israel at the time of the study. Participants responded to a questionnaire documenting FMS symptom, which included the widespread pain index (WPI) and symptom severity scale (SSS), which together constitute the suggested American College of Rheumatology (ACR) FMS diagnostic criteria. Additional items on the questionnaire documented work motivation and performance, the occurrence of workplace-related stressful events, and the presence of posttraumatic symptoms. Results: 242 participants were recruited to the current study, including 239 (98.8%) females and 3 (1.2%) males. 62 individuals (25.6%) were found to fulfill ACR FMS criteria. Significant differences in work performance were found between teachers fulfilling FMS criteria compared with those not fulfilling criteria. Thus, FMS-positive teachers reported significantly higher rates of missing workdays, leaving work early, and a lower quality of interaction with children in the kindergarten and with peers and supervisors. Motivation to work was also significantly lower among these individuals. The widespread pain index (WPI) and symptom severity scale (SSS), which together constitute the components of the FMS diagnostic criteria, were positively correlated with both stress and posttraumatic symptoms. In addition, widespread pain, disordered sleep, difficulty with concentration, and other FMS symptoms were strongly correlated with many specific stressful factors at the workplace, including the number of children in the kindergarten, interaction with parents, lack of optimal physical conditions in the classrooms, and various demands on behalf of the educational system. Conclusion: FMS symptoms were found to be highly prevalent among Israeli kindergarten teachers, at a rate that greatly exceeds the prevalence in the general Israeli population. Stressful work-related events appear to be positively associated with the occurrence of FMS symptoms and may serve as triggers for their development. Healthcare professionals treating individuals engaged in this occupation should be vigilant for the occurrence of symptoms that are clinically associated with FMS and overlapping functional disorders.

High prevalence of fibromyalgia among Israeli school teachers.

OBJECTIVES: Fibromyalgia syndrome (FM), characterised by widespread pain and fatigue, has frequently been associated with stress in various models, including workplace related stress. In the current study we have evaluated the prevalence of FM symptoms among Israeli school teachers and have attempted to correlate such symptoms with work-related stress. METHODS: Individuals, all currently employed as school teachers in Israel, were recruited to the study. Participants were asked to answer a questionnaire evaluating symptoms of FM, based on the current diagnostic criteria, which include the widespread pain index (WPI) and the symptom severity scale (SSS). Participants were further questioned regarding stressful experiences during their work and about post-traumatic symptoms as well as regarding work performance and motivation. RESULTS: 321 participants were recruited (79.4% female, 20.6 male). 30 individuals (9.3%) of the sample fulfilled current criteria for a diagnosis of FM, with a rate of 11.4% among females and 1.5% among males. While specific symptoms such as fatigue and irritable bowel symptoms were negatively correlated with work performance, no significant difference was found between teachers with or without fibromyalgia regarding work attendance and performance. FM symptoms were strongly correlated with work-related stress and were strongly correlated with post-traumatic stress disorder (PTSD) related symptoms. Motivation to work was significantly lower among teachers fulfilling FM criteria, but other performance-related parameters did not differ between teachers fulfilling or not fulfilling FM criteria. CONCLUSIONS: Fibromyalgia symptoms are highly prevalent among Israeli school teachers, and may be related to stress encountered in the classroom. These results are relevant both for physicians treating individuals involved in educational careers as well as for educators and decision-makers involved in planning and managing educational strategies.

Self-Reported Childhood Maltreatment and Traumatic Events among Israeli Patients Suffering from Fibromyalgia and Rheumatoid Arthritis.

Objective. The association between Fibromyalgia Syndrome (FMS) and childhood maltreatment and adversity has frequently been proposed but limited data exists regarding the transcultural nature of this association. Methods. 75 Israeli FMS patients and 23 Rheumatoid Arthritis (RA) patients were compared. Childhood maltreatment was assessed by the Childhood Trauma Questionnaire (CTQ) and potential depressive and anxiety disorders were assessed by the Patient Health Questionnaire-4. FMS severity was assessed by the Widespread Pain Index (WPI), the Symptom Severity Score (SSS), and the FIQ. PTSD was diagnosed according to the DSM IV. RA severity was assessed by the RA Disease Activity Index. Health status was assessed by the SF-36. Results. Similar to reports in other countries, high levels of self-reported childhood adversity were reported by Israeli FMS patients. PTSD was significantly more common among FMS patients compared with RA patients, as well as childhood emotional abuse and physical and emotional neglect. Levels of depression and anxiety were significantly higher among FMS patients. Conclusion. The study demonstrated the cross cultural association between FMS and childhood maltreatment, including neglect, emotional abuse, and PTSD. Significant differences were demonstrated between FMS patients and patients suffering from RA, a model of an inflammatory chronic rheumatic disease.

Is adenosine a modulator of peripheral vasoconstrictor responses?

BACKGROUND: Local vasoconstrictor reflexes, the vascular myogenic response (VMR) and the veno-arterial reflex (VAR) are necessary for the maintenance of regional blood flow and systemic arterial blood pressure during orthostatic stress. Their molecular mechanism is unknown. We postulated that adenosine is involved in the activation of these local reflexes. METHODS: This hypothesis was tested in 10 healthy male volunteers (age 29 ± 3 years, BMI 24 ± 1 kg/m(2)). We used veno-occlusive plethysmography method for the assessment of forearm arterial blood flow at baseline and upon causing local venous congestion by inflating a second cuff to 40 mmHg for 4 min (VAR) and during placement of the forearm 40 cm below cardiac level for 4 min (VMR). These measurements were repeated after local infusion of either saline or aminophylline, non-selective adenosine blockers, using the Bier block method. RESULTS: Rest baseline forearm blood flow was comparable in both arms. Saline did not affect the baseline forearm blood flow. However, aminophylline causes a significant increase in baseline forearm blood flow of 34 ± 6 % (p = 0.002). VAR demonstrated a decrease in forearm blood flow of 49 ± 4.5 % and after saline infusion it remained unchanged, 49 ± 5 % (p = 0.92). However, aminophylline causes significant decrease in the VAR by 35 ± 3 % (p = 0.02). But, both, saline and aminophylline did not affect the VMR. CONCLUSION: Arterial vasoconstriction triggered by venous congestion, which is the veno-arterial reflexis seems to be modulated by adenosine, at least partially. This "sensory" reflex requires further pharmacologic physiologic investigation.

High prevalence of fibromyalgia symptoms among healthy full-term pregnant women.

The impact of fibromyalgia on the course of pregnancy is not clearly defined. We evaluate the frequency of FMS symptoms among full-term healthy pregnant women and the impact on the course of delivery. The 2011 modification of the ACR 2010 criteria for FMS diagnosis was used as well as the FIQ, SF-36 and AIMS questionnaires. The 1990 ACR classification criteria were documented. Data were collected relating to course of the delivery, induction, length of stage 1, 2 and 3 of delivery, epidural anesthesia, artificial rupture of membranes, instrumental delivery and cesarean section. A VAS recording pain intensity during delivery was documented. Out of 100 women recruited, 27 (27 %) fulfilled Modified FMS criteria. Only one of these women fulfilled ACR 1990 criteria, women who fulfilled the ACR criteria differed significantly from women who did not fulfill these criteria on a broad range of parameters including widespread pain and fatigue, social functioning, emotional well-being, role limitation and physical functioning. A significant correlation was found between length of stage 2 and results of the FIQ as well as with components of the SF-36. The intensity of pain during birth however was not correlated with the presence of FMS criteria. FMS symptoms were highly prevalent among healthy pregnant women at term. The presence of such symptoms may impact on the course of delivery and the need for anesthesia. Evaluating for features of centrally mediated pain may be of clinical relevance for physicians involved in the treatment of pregnant women.

SPECT/CT-plethysmography--non-invasive quantitation of bone and soft tissue blood flow.

Preserved blood flow to bone and soft tissue is essential for their normal function. To date only numerous methods are suitable for direct bone blood flow (BBF) measurement. Here, we introduce a novel quantitative method for bone and soft tissue blood flow (BBF and SBF, respectively) measurement. It involves a combination of SPECT/CT imaging for blood pool localization in a specific region of interest ("soft" and "hard" tissues composing a limb) with veno-occlusive plethysmography. Using it, we measured BBF and SBF in the four limbs of 10 healthy subjects. At steady state blood flow measurements in the four limbs were similar, ranging between 5.5-6.5 and 1.87-2.48 ml per 100 ml of tissue per minute for BBF and SBF, respectively. Our results are comparable to those in the literature. We concluded that SPECT/CT-plethysmography appears to be a readily available and easy to use method to measure BBF and SBF, and can be added to the armamentarium of methods for BBF measurements.

Hormonal influences on cardiovascular norepinephrine transporter responses in healthy women.

Gender differences in human cardiovascular norepinephrine transporter function may be mediated through female sex hormones. We studied 16 healthy eumenorrheic women (25+/-1 years) during the early follicular phase (day 5+/-0) and midluteal phase (day 22+/-0) of the menstrual cycle. In a randomized, crossover, double-blind fashion, subjects ingested 8 mg of the selective norepinephrine transporter inhibitor reboxetine or placebo. We monitored heart rate, blood pressure, and thoracic bioimpedance at rest and during standard autonomic function tests, including head-up tilt. Venous estradiol and progesterone concentrations were higher in the luteal than in the follicular phase but did not differ between placebo and norepinephrine transporter inhibition testing days. On placebo, hemodynamics at rest and in response to different stressors were mostly identical between cycle phases. In the supine position, norepinephrine transporter inhibition increased blood pressure and stroke volume to a greater extent during the follicular than during the luteal phase. Conversely, the increase in heart rate and cardiac output with norepinephrine transporter inhibition was augmented in the luteal compared with the follicular phase. During head-up tilt with norepinephrine transporter inhibition, blood pressure and stroke volume decreased to a greater extent in the follicular than in the luteal phase. The tachycardic response to head-up tilt with norepinephrine transporter inhibition was augmented in the follicular phase. Our study suggests that sex hormones alter the hemodynamic response to norepinephrine transporter inhibition in women. The phenomenon may be explained by an effect of female sex hormones on norepinephrine transporter function, on compensatory cardiovascular responses, or both.

Hormonal and volume dysregulation in women with premenstrual syndrome.

Premenstrual syndrome (PMS) presents with emotional and physical symptoms. Although the emotional symptoms have been extensively studied, the pathophysiology of the fluid-retention symptoms is not currently known. We tested the hypothesis that the fluid regulatory mechanisms are disturbed in PMS. Nine regularly menstruating women with PMS were compared with 9 healthy age-matched women. Hemodynamic parameters and upright plasma volume shift (extrapolated from changes in hematocrit), plasma renin activity (PRA), and plasma aldosterone and sex hormones were measured at different times during the menstrual cycle. During the early follicular and the midluteal phases, the plasma volume shift, supine and upright PRA, and plasma aldosterone were similar in both groups, and none of the participants had edema. However, during the late luteal phase, ankle edema was present only in women with PMS, and their maximal plasma volume shift was lower compared with controls (11.7+/-1.3 versus 15.6+/-0.6; P=0.004). The area under the curve (estimates the amount of the total plasma shift during 30 minutes standing) was 300+/-28 and 406+/-16 in PMS and controls, respectively (P=0.01). PRA and aldosterone levels were higher during the late luteal phase in women with PMS compared with controls (supine PRA: 1.4+/-0.3 [PMS] versus 1.1+/-0.4 [control; P value not significant], upright PRA: 3.9+/-0.08 versus 1.6+/-0.3 ng/mL per hour [P=0.015], supine plasma aldosterone: 131+/-30 versus 68+/-17 pg/mL [P=0.09], and upright plasma aldosterone: 208+/-40 versus 102+/-16 pg/mL [P=0.03]). We, therefore, conclude that women with PMS have increased plasma fluid-regulatory hormones and disturbed fluid distribution only during their late luteal menstrual phase.

Factor analysis of risk variables associated with low-grade inflammation.

BACKGROUND: Chronic subclinical inflammation, manifesting as elevated levels of inflammatory markers such as C-reactive protein (CRP), predicts future atherothrombotic events. The pathophysiology of low-grade inflammation is complex, and multiple intercorrelated conditions have been associated with elevated CRP. METHODS: Principal factor analysis was used to investigate clustering of variables associated with elevated CRP using data from 1435 subjects without known coronary disease. Components of the metabolic syndrome, uric acid, liver enzymes, pulmonary function tests, smoking status, cardiorespiratory fitness (measured by maximal treadmill test), and high-sensitivity C-reactive protein were determined in each subject. RESULTS: Factor analysis identified three factors, which explained 51.0% of the total variance in the dataset (24.4% factor 1, 17.3% factor 2, and 9.3% factor 3). Based on factor loadings of >or=0.5, these factors were interpreted as (1) "metabolic factor" including BMI, fasting glucose, HDL cholesterol, triglycerides, systolic blood pressure, and uric acid; (2) a cardiorespiratory factor that included fitness level, forced expiratory volume in 1s and sex; and (3) "smoking" factor that included cigarette smoking and age. Each of these factors was significantly associated with the presence of high-risk CRP (>or=3mg/L) in the study population. The ability of a multivariate model that included these three factors to predict high-risk CRP was comparable to a model containing the original 10 variables (area under the receiver-operator characteristics curve 0.7 vs. 0.72, respectively). CONCLUSION: Metabolic perturbations, cardiorespiratory fitness, and smoking are separate and largely independent factors in the pathophysiology of chronic, low-grade inflammation.

Effect of aging on the cardiovascular regulatory systems in healthy women.

Aging, independently from the hormonal status, is a major risk factor for cardiovascular morbidity in healthy women. Therefore, we studied the effect of healthy aging on the cardiovascular homeostatic mechanisms in premenopausal and postmenopausal women with similar estrogen levels. Twelve healthy postmenopausal women, confirmed by follicular-stimulating hormone (FSH) and luteal hormone (LH) levels, were compared with 14 normally menstruating women during the early follicular phase (young-EF), to avoid as much as possible the effects of estrogen. Systolic BP was 108 +/- 1.5 vs. 123 +/- 2.5 (P < 0.001), supine norepinephrine was 260 +/- 30 vs. 216 +/- 45 and upright 640 +/- 100 vs. 395 +/- 50 pg/ml (P = 0.05) in young-EF vs. postmenopausal, respectively. Plasma renin activity and aldosterone remained unchanged. Vagal cardiac tone indices decreased significantly with aging (young-EF vs. postmenopausal): high-frequency (HF) band, root mean square successive differences (rMSSD) and proportion of R-R intervals >50 ms (PNN50%) were 620 +/- 140 vs. 270 +/- 70 (P = 0.04), 53 +/- 7 vs. 30 +/- 3 (P = 0.02), and 23 +/- 5 vs. 10 +/- 3 (P = 0.04), respectively. LF to HF ratio was 0.85 +/- 0.17 in young-EF and became 1.5 +/- 0.22 in postmenopausal (P = 0.03). Both arms of the baroreflex, +BRS (29 +/- 5 vs. 13.5 +/- 2.5, P = 0.01) and -BRS (26 +/- 4 vs. 15 +/- 1.5, P = 0.02) decreased with aging. Cardiovascular alpha(1)-adrenoreceptor responsiveness significantly increased and beta-decreased in postmenopausal compared with young EF (P < 0.001, both). The corrected QT intervals (QTc) were similar, whereas corrected JT intervals (JTc) and JTc to QTc ratio were prolonged in the postmenopausal group. We conclude that in young women, parasympathetic control is the main regulator of the cardiovascular system and in postmenopausal women, sympathetic tone dominates. The transition from parasympathetic to sympathetic control may contribute to the increased cardiovascular morbidity with aging.

Fever due to aortitis.

We report a case of vasculitis with predominant aortic involvement. Vasculitis of large vessels has a limited number of tools for diagnosis and follow-up. A 78-year-old woman was referred to the internal medicine department with a 2-month history of fever of unknown origin (FUO), night sweats, weight loss and markedly elevated ESR and CRP. The results of an extended routine investigation found no infection, malignancy, hypersensitivity or autoimmune disorder. The patient did not suffer from claudication; systolic blood pressure difference between arms was 20 mm Hg. Temporal artery biopsies were negative. 2-18F-Fluorine-2-deoxy-D -glucose positron emission tomography (FDG PET) scan imaging demonstrated intense FDG uptake along the aorta and in the brachio-cephalic and carotid arteries consistent with arteritis. A high dose of corticosteroid therapy (1 mg/kg) was instituted with further tapering. The therapy was followed by complete resolution of the symptoms and pathological FDG uptake on repeated FDG PET. Second-line therapy was not added because of positive conversion of Mantaux test followed by rifampicin prophylaxis. FDG PET should be a part of the work-up of FUO when routine investigation fails to determine its etiology. FDG PET is useful both for diagnosis and assessment of response to therapy for large-vessel vasculitis.

Unusual cause of partially reversible severe cardiovascular autonomic failure.

We report an unusual case of partially reversible severe cardiovascular autonomic system failure in a patient with double primary malignancies. The patient presented with severe orthostatic hypotension preceding the detection of lymphoma and lung cancer. The patient had autonomic failure on presentation. One year after surgery and chemotherapy, there was a gradual improvement in both symptoms and autonomic function simultaneously. We conclude that paraneoplastic severe autonomic failure can be reversible.