Effect of Cigarette Smoking on Clinical and Molecular Endpoints in COPD Patients.

Cigarette smoking is a primary contributor to mortality risks and is associated with various diseases. Among these, COPD represents a significant contributor to global mortality and disability. The objective of this study is to investigate the effect of smoking on a selected battery of variables, with an emphasis on DNA damage. A total of 87 elderly patients diagnosed with COPD, divided into three groups based on their smoking history (current, former, never-smokers), were evaluated using a cross-sectional approach. Clinical features including mortality and inflammatory/oxidative parameters (Lymphocytes/Monocytes, Neutrophils/Lymphocytes, Platelets/Lymphocytes ratio), SII, MDA, 8-Oxo-dG, and IL6 (ELISA assay), as well as DNA damage (comet assay), were investigated. Virus infection, i.e., influenza A virus subtype H1N1, JC polyomavirus (JCPyV), BK polyomavirus (BKPyV), and Torquetenovirus (TTV), was also tested. Current smokers exhibit higher levels of comorbidity (CIRS; p < 0.001), Platelets/Lymphocytes ratio (p < 0.001), systemic immune inflammation (p < 0.05), and DNA damage (p < 0.001). Former smokers also showed higher values for parameters associated with oxidative damage and showed a much lower probability of surviving over 5 years compared to never- and current smokers (p < 0.0017). This study showed a clear interaction between events which are relevant to the oxidative pathway and cigarette smoking. A category of particular interest is represented by former smokers, especially for lower survival, possibly due to the presence of more health problems. Our findings raise also the attention to other parameters which are significantly affected by smoking and are useful to monitor COPD patients starting a program of pulmonary rehabilitation (DNA damage, inflammation parameters, and selected viral infections).

Assessing the Long-Term (48-Week) Effectiveness, Safety, and Tolerability of Fremanezumab in Migraine in Real Life: Insights from the Multicenter, Prospective, FRIEND3 Study.

INTRODUCTION: Long-term (1-year) fremanezumab treatment proved to be effective, safe, and well tolerated in individuals with migraine and < 2 medication clusters in a randomized controlled trial (RCT). We aimed to assess real-world evidence (RWE), long-term effectiveness, tolerability, and safety of fremanezumab in people with high-frequency episodic migraine (HFEM) or chronic migraine (CM) with > 3 treatment failures and various comorbidities. METHODS: A 48-week, prospective, multicenter (n = 26), cohort study assessed fremanezumab's effectiveness, safety, and tolerability in consecutive adults with HFEM or CM with > 3 treatment failures. Primary endpoint was variation from baseline in monthly migraine days (MMD) in HFEM and monthly headache days (MHD) in CM at weeks 45-48. Secondary endpoints were changes in monthly analgesic medications, Numerical Rating Scale (NRS), Headache Impact Test (HIT-6), and the Migraine Disability Assessment Scale (MIDAS) scores and ≥ 50%, ≥ 75%, and 100% responder rates. RESULTS: Of 533 participants who had received ≥ 1 fremanezumab dose, 130 were treated for ≥ 48 weeks and considered for effectiveness analysis. No participant missed any treatment dosage every other consecutive month during the 12-month period. PRIMARY ENDPOINT: fremanezumab significantly (p < 0.001) reduced both MMD (- 6.4) in HFEM and MHD (- 14.5) in CM. Secondary endpoints: a significant reduction (p < 0.001) was observed in monthly analgesic medications (HFEM - 6.0; CM -16.5), NRS (HFEM - 3.4; CM - 3.4), HIT-6 (HFEM - 16.9; CM - 17.9) and MIDAS score (HFEM - 50.4; CM - 76.6). The ≥ 50%, ≥ 75%, and 100% response rates to fremanezumab were 75.5%, 36.7%, and 2% in HFEM and 71.6%, 44.4%, and 3.7% in CM. Corresponding response rates were 60.5%, 37.2%, and 2.3% in individuals with psychiatric comorbidities, 74.2%, 50%, and 4.8% in CM with medication overuse, and 60.9%, 39.1%, and 4.3% in CM with medication overuse and psychiatric comorbidities. Mild and transient treatment-emergent adverse events occurred in 7.8% of the participants. No subject discontinued the treatment for any reason. CONCLUSION: This RWE study documents that long-term fremanezumab treatment is highly effective and remarkably well tolerated in subjects with HFEM or CM with multiple (> 3) therapeutic failures, even in the presence of concomitant medication overuse, psychiatric comorbidities, or both. The effectiveness-to-tolerability ratio appears to be better in RWE than in RCTs.

Persistent increase of cardiovascular and cerebrovascular events in COVID-19 patients: a 3-year population-based analysis.

AIMS: We evaluated the incidence and relative risk of major post-acute cardiovascular consequences of SARS-CoV-2 infection in a large real-world population from a primary care database in a region at moderate cardiovascular risk followed up in the period 2020-22. METHODS AND RESULTS: This is a retrospective cohort analysis using data from a cooperative of general practitioners in Italy. Individuals aged >18 affected by COVID-19 starting from January 2020 have been followed up for 3 years. Anonymized data from 228 266 patients in the period 2020-22 were considered for statistical analysis and included 31 764 subjects with a diagnosis of COVID-19. An equal group of subjects recorded in the same database in the period 2017-19 was used as propensity score-matched comparison as an unquestionable COVID-19-free population. Out of the 228 266 individuals included in the COMEGEN database during 2020-22, 31 764 (13.9%) were ascertained positive with SARS-CoV-2 infection by a molecular test reported to general practitioners. The proportion of individuals with a new diagnosis of major adverse cardiovascular and cerebrovascular events was higher in the 2020-22 COVID-19 group than in the 2017-19 COMEGEN propensity score-matched comparator, with an odds ratio of 1.73 (95% confidence interval: 1.53-1.94; P < 0.001). All major adverse cardiovascular and cerebrovascular events considered showed a significantly higher risk in COVID-19 individuals. Incidence calculated for each 6-month period after the diagnosis of COVID-19 in our population was the highest in the first year (1.39% and 1.45%, respectively), although it remained significantly higher than in the COVID-19-free patients throughout the 3 years. CONCLUSION: The increase of cardiovascular risk associated with COVID-19 might be extended for years and not limited to the acute phase of the infection. This should promote the planning of longer follow-up for COVID-19 patients to prevent and promptly manage the potential occurrence of major adverse cardiovascular and cerebrovascular events.

Impact of multiple treatment cycles with anti-CGRP monoclonal antibodies on migraine course: focus on discontinuation periods. Insights from the multicenter, prospective, I-GRAINE study.

OBJECTIVES: While a single 12-month treatment cycle (TrC) with anti-CGRP mAbs is not disease-modifying for most patients, there is limited understanding of the effects of multiple TrCs on migraine course. We evaluated whether a second TrC might modify the migraine course by comparing the occurrence of migraine relapse after discontinuation of the second TrC to that following the cessation of the first TrC. METHODS: In a real-life, multicenter, prospective study we considered all consecutive patients diagnosed with high-frequency episodic migraine (HFEM) or chronic migraine (CM) with > 3 treatment failures and treated with any anti-CGRP mAbs for ≥ 2 consecutive 12-month TrCs who were responders at week 12. The primary endpoint was the change in monthly migraine days (MMD) for HFEM or monthly headache days (MHD) for CM at the first month of treatment discontinuation after the second TrC (D2) compared to the first TrC (D1). Secondary endpoints included variations in monthly analgesic medications (MAM), Numeric Rating Scale (NRS), and Headache Impact Test (HIT-6) scores, ≥ 50%, ≥ 75%, and 100% response rates, and relapse from episodic migraine to CM and from no-medication overuse (MO) to MO at D2 vs. D1. RESULTS: One-hundred-seventy-eight patients completed two 12-month TrCs with anti-CGRP mAbs. At D2, patients experienced a significant reduction in MMD (- 0.6, p = 0.028), MHD (- 2.6, p < 0.001), monthly analgesic medications (- 2.0, p < 0.001), and HIT-6 score (- 2.2, p < 0.001) compared to D1, indicating improved effectiveness. The ≥ 50% response rate at weeks 45-48 during the first TrC was 95.5%, while at weeks 45-48 of the second TrC was 99.4%. Corresponding rates at D1 was 20.2% whereas at D2 was 51.6% (p < 0.0001). No statistical difference emerged in ≥ 75% and 100% responders. The relapse rate from episodic migraine to CM at D2 was lower than at D1 (12.3% vs 30.4%; p = 0.0002) Fewer patients experienced relapse from no-MO to MO at D2 compared to D1 (29.5% vs 68.7%; p = 0.00001). DISCUSSION: A second TrC with anti-CGRP mAbs demonstrated clinical improvements compared to the first one, as indicated by a milder migraine relapse at D2 compared to D1. Multiple TrCs with anti-CGRP mAbs could progressively modify migraine evolution by reducing CGRP-dependent neuroinflammatory nociceptive inputs to the brain.

Ultra-late response (> 24 weeks) to anti-CGRP monoclonal antibodies in migraine: a multicenter, prospective, observational study.

OBJECTIVE: Nearly 60% of migraine patients treated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway experience a ≥ 50% reduction in monthly migraine days (MMD) at 12 weeks compared to baseline (responders). However, approximately half of the patients not responding to anti-CGRP mAbs ≤ 12 weeks do respond ≤ 24 weeks (late responders). We assessed frequency and characteristics of patients responding to anti-CGRP mAbs only > 24 weeks (ultra-late responders). METHODS: In this multicenter (n = 16), prospective, observational, real-life study, we enrolled all consecutive adults affected by high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM), with ≥ 3 prior therapeutic failures, treated with any anti-CGRP mAbs for ≥ 48 weeks. We defined responders patients with a ≥ 50% response rate ≤ 12 weeks, late responders those with a ≥ 50% response rate ≤ 24 weeks, and ultra-late responders those achieving a ≥ 50% response only > 24 weeks. RESULTS: A total of 572 migraine patients completed ≥ 48 weeks of anti-CGRP mAbs treatment. Responders accounted for 60.5% (346/572), late responders for 15% (86/572), and ultra-late responders for 15.7% (90/572). Among ultra-late responders, 7.3% (42/572) maintained the ≥ 50% response rate across all subsequent time intervals (weeks 28, 32, 36, 40, 44, and 48) and were considered persistent ultra-late responders, while 8.4% (48/572) missed the ≥ 50% response rate at ≥ 1 subsequent time interval and were classified as fluctuating ultra-late responders. Fifty patients (8.7%) did not respond at any time interval ≤ 48 weeks. Ultra-late responders differed from responders for higher BMI (p = 0.033), longer duration of medication overuse (p < 0.001), lower NRS (p = 0.017) and HIT-6 scores (p = 0.002), higher frequency of dopaminergic symptoms (p = 0.002), less common unilateral pain-either alone (p = 0.010) or in combination with UAS (p = 0.023), allodynia (p = 0.043), or UAS and allodynia (p = 0.012)-a higher number of comorbidities (p = 0.012), psychiatric comorbidities (p = 0.010) and a higher proportion of patients with ≥ 1 comorbidity (p = 0.020). CONCLUSION: Two-thirds of patients not responding to anti-CGRP mAbs ≤ 24 weeks do respond later, while non-responders ≤ 48 weeks are quite rare (8.7%). These findings suggest to rethink the duration of migraine prophylaxis and the definition of resistant and refractory migraine, currently based on the response after 2-3 months of treatment.

Health-related quality of life in children with coeliac disease and in their families: A long-term follow-up study.

OBJECTIVES: The aim of the study was to assess long-term health-related quality of life (HRQoL) in children and adolescents with coeliac disease (CD), and their parents. METHODS: We re-evaluated prospectively the HRQoL and clinical characteristics of 80 families, assessed 5 years earlier, using a disease-specific questionnaire, the CD Dutch Questionnaire (CDDUX), and a generic questionnaire, the Paediatric Quality of Life Inventory (PedsQL). RESULTS: After a 10-year follow-up, there was no significant change in the total CDDUX and PedsQL scores in children and their parents when compared to the evaluation conducted 5 years earlier. The total CDDUX score reflected a neutral QoL, while for the generic PedsQL was good-very good. The only significant decrease after 5 years was the PedsQL subdomain Emotional functioning. Patients who admitted voluntarily eating gluten reported lower score in CDDUX Diet. Lower scores in subdomain "Physical functioning" (PedsQL) were reported in patients with positivity of TTG or associated diseases. CONCLUSIONS: The CDDUX score indicated a consistently stable and neutral QoL perception among coeliac patients and caregivers, even after 10-year postdiagnosis, suggesting minimal fluctuations in the impact of CD on disease-specific health domains over time. Furthermore, the consistently good PedsQL score could be a reflection of the resilience of coeliac families in coping with this chronic condition. Gluten-free diet compliance was confirmed to be determinant of HRQoL in the long term. The study confirms the importance of extending surveillance on these patients, possibly using different questionnaires, to assess QoL from different perspectives.

Very-low-calorie ketogenic diet vs hypocaloric balanced diet in the prevention of high-frequency episodic migraine: the EMIKETO randomized, controlled trial.

BACKGROUND: Migraine is the second world's cause of disability. Among non-pharmacological treatments, nutritional intervention, particularly ketogenic diet, represents one of the most promising approaches. METHODS: This a prospective, single center, randomized, controlled study aimed at evaluating the efficacy of a very low-calorie ketogenic diet (VLCKD) compared to a hypocaloric balanced diet (HBD) in migraine prophylaxis in patients affected by high-frequency episodic migraine (HFEM) with a Body Mass Index (BMI) > 27 kg/m2. Fifty-seven patients were randomly assigned to a VLCKD (group 1) or HBD (group 2). Group 1 patients followed a VLCKD for 8 weeks, followed by a low calorie diet (LCD, weeks 9-12), and a HBD (weeks 13-24), whereas group 2 patients followed a HBD from week 0 to 24. Anthropometric indexes, urine and blood chemistry were assessed at enrollment, baseline, weeks 4, 8, 12, and 24. Migraine characteristics were evaluated at baseline, weeks 8, 12 and 24. Change in monthly migraine days (MMDs) at weeks 5-8 compared to baseline was the primary endpoint. Secondary endpoints encompassed changes in visual analogue scale (VAS), Headache Impact Test-6 (HIT-6) and Short Form Health Survey-36 (SF-36) scores. We also studied effects on circulating lymphocytes and markers of inflammation, changes in plasma aldosterone and renin levels before and after VLCKD or HBD treatment. RESULTS: Reduction from baseline in MMDs was greater in VLCKD compared to HBD group at week 8 (p = 0.008), at week 12 (p = 0.007), when ketosis had been interrupted by carbohydrates reintroduction, and at week 24 (p = 0.042), when all patients were following the same dietary regimen. Quality of life scores (SF-36) were improved in VLCKD group at week 8 and 12, and were also improved in HBD group, but only at week 12. Weight-loss was significantly higher in VLCKD group at week 8 (p = 0.002) and week 12 (p = 0.020). At the end of the study weight loss was maintained in VLCKD group whereas a slight weight regain was observed in HBD group. Inflammatory indexes, namely C reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and total white blood cell count (WBC) were significantly reduced (p < 0.05) in VLCKD group at week 12. Aldosterone plasma level were significantly increased in both groups at week 8, particularly in VLCKD group. However, electrolytes and renin plasma levels were never altered throughout the study in both groups. CONCLUSIONS: VLCKD is more effective than HBD in reducing MMD in patients with HFEM and represents an effective prophylaxis in patients with overweight/obesity. Trial registration ClinicalTrials.gov identifier: NCT04360148.

Physical activity and neurotrophic factors as potential drivers of neuroplasticity in Parkinson's Disease: A systematic review and meta-analysis.

Parkinson's disease (PD) is a neurodegenerative disorder, characterized by motor and non-motor symptoms, that still lacks of a disease-modifying treatment. Consistent evidence proved the benefits of physical therapy on motor and non-motor symptoms in PD patients, leading the scientific community to propose physical activity as disease-modifying therapy for PD and suggesting the involvement of neurotrophic factors (NFs) as key mediators of neuroplasticity. However, the lack of standardized exercise training and methodological flaws of clinical trials have limited the evidence demonstrating the exercise-induced changes in serum and plasma neurotrophic factors concentration. A systematic search, covering 20 years of research in this field and including randomized and non-randomized controlled trials (RCTs and non-RCTs), which reported changes in serum and plasma NFs after a specific intervention, were reviewed. Pooled effect sizes (p-ESs) and 95% confidence intervals (95%CIs) were calculated using a random effects model with R software. A total of 18 articles, of which exercise programs of interventions were codified in terms of type, intensity and duration adopting a standardisation methodology, were included in the systematic review. Six papers, describing the effect of different training programs on BDNF and IGF-1 levels, were included and independently analysed in two meta-analyses. Quantitative analysis for BDNF indicated a statistically significant improvement in serum concentration of PD patients (MD: 5.99 ng/mL; 95%IC: 0.15 -11.83; I2 = 77%) performing physical activity compared with control conditions in RCTs. Preliminary evidence supported the hypothesis that a moderate intensity aerobic exercise (MIAE) would be necessary to induce the changes in NFs. However, sensitivity analysis of meta-analysis and the few studies included in subgroup analysis did not support these results. Alongside, meta-analysis followed by sensitivity analysis revealed a potential change in serum IGF-1 (MD: 33.47 ng/mL; 95%IC: 8.09-58.85) in PD patients performing physical activity with respect controls in RCT studies. Considering the limited evidence to support or refute the increase in NFs levels in PD patients performing physical activity, there is a need to develop a rigorous controlled randomized trial, with standardization for loading intensity of physical activity, greater sample size, and a correct stratification of PD patients to establish a well-defined correlation between physical activity and NFs levels.

Efficacy of non-immersive virtual reality-based telerehabilitation on postural stability in Parkinson's disease: a multicenter randomized controlled trial.

BACKGROUND: The implementation of regular prolonged, and effective rehabilitation in people with Parkinson's disease is essential for ensuring a good quality of life. However, the continuity of rehabilitation care may find barriers related to economic, geographic, and social issues. In these scenarios, telerehabilitation could be a possible solution to guarantee the continuity of care. AIM: To investigate the efficacy of non-immersive virtual reality-based telerehabilitation on postural stability in people with Parkinson's disease, compared to at-home self-administered structured conventional motor activities. DESIGN: Multicenter randomized controlled trial. SETTING: Five rehabilitation hospitals of the Italian Neuroscience and Rehabilitation Network. POPULATION: Individuals diagnosed with Parkinson's disease. METHODS: Ninety-seven participants were randomized into two groups: 49 in the telerehabilitation group (non-immersive virtual reality-based telerehabilitation) and 48 in the control group (at-home self-administered structured conventional motor activities). Both treatments lasted 30 sessions (3-5 days/week for, 6-10 weeks). Static and dynamic balance, gait, and functional motor outcomes were registered before and after the treatments. RESULTS: All participants improved the outcomes at the end of the treatments. The primary outcome (mini-Balance Evaluation Systems Test) registered a greater significant improvement in the telerehabilitation group than in the control group. The gait and endurance significantly improved in the telerehabilitation group only, with significant within-group and between-group differences. CONCLUSIONS: Our results showed that non-immersive virtual reality-based telerehabilitation is feasible, improves static and dynamic balance, and is a reasonably valuable alternative for reducing postural instability in people with Parkinson's disease. CLINICAL REHABILITATION IMPACT: Non-immersive virtual reality-based telerehabilitation is an effective and well-tolerated modality of rehabilitation which may help to improve access and scale up rehabilitation services as suggested by the World Health Organization's Rehabilitation 2030 agenda.

A Nutritional Supplement as Adjuvant of Gabapentinoids for Adults with Neuropathic Pain following Spinal Cord Injury and Stroke: Preliminary Results.

Gabapentinoids are first choice drugs for central neuropathic pain (CNP) despite limited evidence of efficacy and side effects affecting therapy outcomes. Nutraceuticals could improve their efficacy and tolerability. Our aim is to investigate the effect of NACVAN®, in addition to gabapentinoids, on pain symptomatology in CNP patients. The effect of 6 weeks of treatment of NACVAN® was preliminary observed among 29 adult inpatients with spinal cord injury (SCI) or stroke-related CNP recruited to the experimental group. Pain intensity, neuropathic pain, and quality-of-life were measured at baseline (T0) and after 3 (T1) and 6 weeks (T2). Change in each outcome over time was assessed through a repeated measures analysis of variance or Wilcoxon matched-pairs test. Preliminary results show a significant reduction in pain intensity (T0 → T1, p = 0.021; T0 → T2, p = 0.011; T1 → T2, p = 0.46), neuropathic symptoms (T0 → T1, p = 0.024; T0 → T2, p = 0.003), and evoked pain (T0 → T2, p = 0.048). There were no significant reductions in other neuropathic pain dimensions and in quality-of-life components. No side-effects were detected. NACVAN® could have a beneficial adjuvant effect when used as an add-on to gabapentinoids in patients suffering from CNP due to SCI or stroke, with no adverse effect. Future analysis on a larger sample, compared with a placebo condition, could confirm these preliminary results.

Which items of the modified Barthel Index can predict functional independence at discharge from inpatient rehabilitation? A secondary analysis retrospective cohort study.

The modified Barthel Index (mBI) is a well-established patient-centered outcome measure commonly administrated in rehabilitation settings to evaluate the functional status of patients at admission and discharge. This study aimed to detect which mBI items collected on admission can predict the total mBI at discharge from first inpatient rehabilitation in large cohorts of orthopedic (n = 1864) and neurological (n = 1684) patients. Demographic and clinical data (time since the acute event 11.8 ±â€…17.2 days) at patients' admission and mBI at discharge were collected. Univariate and multiple binary logistic regressions were performed to study the associations between independent and dependent variables for each cohort separately. In neurological patients, the shorter time between the acute event and rehabilitation admission, shorter length of stay, and being independent with feeding, personal hygiene, bladder, and transfers were independently associated with higher total mBI at discharge (R 2  = 0.636). In orthopedic patients, age, the shorter time between the acute event and rehabilitation admission, shorter length of stay, and being independent with personal hygiene, dressing, and bladder were independently associated with higher total mBI at discharge (R 2  = 0.622). Our results showed that different activities in neurological (i.e. feeding, personal hygiene, bladder, and transfer) and orthopedic sample (i.e. personal hygiene, dressing, and bladder) are positively associated with better function (measured by mBI) at the discharge. Clinicians have to take into account these predictors of functionality when they plan an appropriate rehabilitation treatment.

Therapeutic education for empowerment and engagement in patients with Parkinson's disease: A non-pharmacological, interventional, multicentric, randomized controlled trial.

Background: In 1997 the European Parkinson's Disease Associations launched the Charter for People with Parkinson's disease that stated the right of patients to be informed and trained on the disease, its course, and treatments available. To date, few data analyzed the effectiveness of education program on motor and non-motor symptoms of PD. Objective: The aim of this study was to evaluate the efficacy of an education program as it was a pharmacological treatment, thus choosing as the primary endpoint the change in daily OFF hours, the most widely used outcome in pharmaceutical clinical trials on PD patients with motor fluctuations. Secondary outcomes were change in motor and non-motor symptoms, quality of life and social functioning. The long-term efficacy of the education therapy was also evaluated by analyzing data collected at 12- and 24-weeks follow-up outpatient visits. Methods: One hundred and twenty advanced patients and their caregivers were assigned to the intervention or control group in a single-blind, multicentric, prospective, randomized study evaluating an education program structured in individual and group sessions over a 6-weeks period.At the end of study, the intervention group showed a significant reduction in daily OFF hours compared to control patients (-1.07 ± 0.78 vs. 0.09 ± 0.35, p < 0.0001) and a significant improvement was also reported in most secondary outcomes. Patients retained significant medication adherence and daily OFF hours reduction at 12- and 24-weeks follow-up. Conclusion: The results obtained demonstrated that education programs may translate in a notable improvement in motor fluctuations and non-motor symptoms in advanced PD patients.Clinical Trial Registration:Clinicaltrials.gov, identifier NCT04378127.

Late Response to Anti-CGRP Monoclonal Antibodies in Migraine: A Multicenter Prospective Observational Study.

OBJECTIVES: To assess the frequency and characteristics of late responders (>12 weeks) to monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP). METHODS: This is a multicenter (n = 16) prospective real-life study considering all consecutive adults with high-frequency or chronic migraine treated with anti-CGRP mAbs for ≥24 weeks. We defined responder patients with a ≥50% reduction from baseline in monthly migraine/headache days at weeks 9-12 and late responders as those achieving a ≥50% reduction only afterward. RESULTS: A total of 771 people with migraine completed ≥24 weeks of anti-CGRP mAb treatment. Responders at 12 weeks were 65.6% (506/771) of the patients, while nonresponders were 34.4% (265/771). A total of 146 of the 265 nonresponders (55.1%) at 12 weeks responded afterward (late responders): they differed from responders for a higher BMI (+0.78, 95% CI [0.10; 1.45]; p = 0.024), more frequent treatment failures (+0.52, 95% CI [0.09; 0.95]; p = 0.017) and psychiatric comorbidities (+10.1%, 95% CI [0.1; 0.20]; p = 0.041), and less common unilateral pain, alone (-10,9%, 95% CI [-20.5; -1.2]; p = 0.025) or in combination with unilateral cranial autonomic symptoms (-12.3%, 95% CI [-20.2;-3.9]; p = 0.006) or allodynia (-10.7, 95% CI [-18.2; -3.2]; p = 0.01). DISCUSSION: Half of nonresponders to anti-CGRP mAbs at 12 weeks are indeed late responders. Efficacy of anti-CGRP mAbs should be assessed at 24 weeks while treatment duration should be extended beyond 12 months.

Early and sustained efficacy of fremanezumab over 24-weeks in migraine patients with multiple preventive treatment failures: the multicenter, prospective, real-life FRIEND2 study.

BACKGROUND: To verify the long-term (24-week) efficacy, safety, and tolerability of fremanezumab in real-life patients with high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM: ≥ 15 days/month), and multiple preventive treatment failures. METHODS: This is a prospective, cohort, real-life study at 28 headache centers on consecutive patients affected by HFEM or CM with multiple preventive treatment failures who were prescribed subcutaneous fremanezumab (225 mg monthly/675 mg quarterly) for ≥ 24 weeks. Primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM at weeks 21-24 compared to baseline. Secondary endpoints encompassed changes in monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS, HIT-6 and MIDAS scores at the same time interval. Changes in MMDs/MHDs, monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS and HIT-6 scores at week 4 were also monitored. RESULTS: Four hundred ten patients who had received ≥ 1 dose of fremanezumab were considered for safety analysis while 148 patients treated for ≥ 24 weeks were included in the efficacy analysis. At weeks 21-24, fremanezumab significantly (p < 0.001) reduced MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM compared to baseline. The proportions of ≥ 50%, ≥ 75% and 100% responders at weeks 21-24were 75.0%, 30.8%, 9.6% (HFEM), and 72.9, 44.8 and 1% (CM). A significant (p < 0.001) decrease in MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM was already present at week 4. The proportions of ≥ 50%, ≥ 75%, and 100% responders at week 4 were 67.6%, 32.4%, 11.8% (HFEM) and 67.3%, 40%, 1.8% (CM). CM remitted to episodic migraine and medication overuse to no-medication overuse in 83.3 and 75% of patients at week 24, and in 80 and 72.4% at week 4. Adverse events were rare (2.4%), mild and transient. No patient discontinued treatment for any reason. CONCLUSIONS: Fremanezumab is characterized by an early and sustained efficacy in HFEM and CM patients with multiple preventive treatment failures in real-life, revealing an optimal safety and tolerability profile.

The Influence of SARS-CoV-2 Pandemic on the Diagnosis of Celiac Disease and Clinical Practice in Pediatric Gastroenterology.

Celiac disease (CD) has a high prevalence but remains largely underdiagnosed. Although extensive studies have confirmed that children with CD do not have an increased risk of severe COVID-19, public health regulations associated with the SARS-CoV-2 pandemic may have exacerbated this problem. The aim of this study was to assess the effect of SARS-CoV-2 on the number of new-onset CD cases. Additionally, the role of SARS-CoV-2 in autoimmune diseases and its influence on clinical practice in pediatric gastroenterology were briefly reviewed. We described the data from the hospital electronic registry of new-onset CD, during the COVID-19 pandemic and 2 years before. A total of 423 children were diagnosed with CD between March 2018 and February 2022: 228 in the 2-year pre-COVID-19 period and 195 during the pandemic. The number of patients during the COVID-19 pandemic was 14.5% lower than in the previous years. The quarterly comparison of CD diagnoses showed a reduction in all quarters. A reduction in diagnoses during the lockdown and in the following months was evident and not compensated thereafter. This is the first study to evaluate the impact of SARS-CoV-2 on the diagnosis of CD in children. Further studies are necessary to improve the system of biopsy-sparing diagnosis and to evaluate the effect of the diagnostic delay. Special attention should be given to the implementation of telemedicine services.

A Systematic Review and Meta-Analysis on the Role of Nutraceuticals in the Management of Neuropathic Pain in In Vivo Studies.

The control of neuropathic pain is a leading challenge in modern medicine. Traditional medicine has, for a long time, used natural compounds such as nutraceuticals for this purpose, and extensive evidence has supported their role in controlling oxidative stress and persistent pain-related inflammation. Nutraceuticals are natural products belonging to the food sector whose consumption could be related to physiological benefits. Indeed, they are used to improve health, prevent chronic diseases, and delay the aging process. Here, we report a systematic review and meta-analysis to provide a more comprehensive report on the use of nutraceuticals in neuropathic pain, including evaluating confounding factors. A search of the literature has been conducted on principal databases (PubMed, MEDLINE, EMBASE, and Web of Science) following the PRISMA statement, and we retrieved 484 articles, 12 of which were selected for the meta-analysis. The results showed that administration of natural drugs in animals with neuropathic pain led to a significant reduction in thermal hyperalgesia, measured in both the injured paw (SMD: 1.79; 95% CI: 1.41 to 2.17; p < 0.0001) and in the two paws (SMD: −1.74; 95% CI: −3.36 to −0.11; p = 0.036), as well as a reduction in mechanical allodynia and hyperalgesia (SMD: 1.95, 95% CI: 1.08 to 2.82; p < 0.001) when compared to controls. The results of the review indicate that nutraceutical compounds could be clinically relevant for managing persistent neuropathic pain.

Baseline robot-measured kinematic metrics predict discharge rehabilitation outcomes in individuals with subacute stroke.

Background: The literature on upper limb robot-assisted therapy showed that robot-measured metrics can simultaneously predict registered clinical outcomes. However, only a limited number of studies correlated pre-treatment kinematics with discharge motor recovery. Given the importance of predicting rehabilitation outcomes for optimizing physical therapy, a predictive model for motor recovery that incorporates multidirectional indicators of a patient's upper limb abilities is needed. Objective: The aim of this study was to develop a predictive model for rehabilitation outcome at discharge (i.e., muscle strength assessed by the Motricity Index of the affected upper limb) based on multidirectional 2D robot-measured kinematics. Methods: Re-analysis of data from 66 subjects with subacute stroke who underwent upper limb robot-assisted therapy with an end-effector robot was performed. Two least squares error multiple linear regression models for outcome prediction were developed and differ in terms of validation procedure: the Split Sample Validation (SSV) model and the Leave-One-Out Cross-Validation (LOOCV) model. In both models, the outputs were the discharge Motricity Index of the affected upper limb and its sub-items assessing elbow flexion and shoulder abduction, while the inputs were the admission robot-measured metrics. Results: The extracted robot-measured features explained the 54% and 71% of the variance in clinical scores at discharge in the SSV and LOOCV validation procedures respectively. Normalized errors ranged from 22% to 35% in the SSV models and from 20% to 24% in the LOOCV models. In all models, the movement path error of the trajectories characterized by elbow flexion and shoulder extension was the significant predictor, and all correlations were significant. Conclusion: This study highlights that motor patterns assessed with multidirectional 2D robot-measured metrics are able to predict clinical evalutation of upper limb muscle strength and may be useful for clinicians to assess, manage, and program a more specific and appropriate rehabilitation in subacute stroke patients.

Corrigendum: Very low calorie ketogenic diet combined with physical interval training for preserving muscle mass during weight loss in sarcopenic obesity: A pilot study.

[This corrects the article DOI: 10.3389/fnut.2022.955024.].

Predictors of response to anti-CGRP monoclonal antibodies: a 24-week, multicenter, prospective study on 864 migraine patients.

BACKGROUND AND OBJECTIVES: The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8-14 days/month) or chronic migraine (CM). METHODS: This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician's choice, or patient's preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. RESULTS: Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57-11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05-2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15-3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04-2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07-0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42-8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14-2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22-3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. CONCLUSIONS: A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.