Multicenter Prospective Observational Cohort Study Research Articles

Anti–SARS-CoV-2 Antibody Responses in Patients With IBD Treated With Biologics: Are We Finding CLARITY?

Anti–SARS-CoV-2 Antibody Responses in Patients With IBD Treated With Biologics: Are We Finding CLARITY?

Lung Function, Radiological Findings and Biomarkers of Fibrogenesis in a Cohort of COVID-19 Patients Six Months After Hospital Discharge

IntroductionImpairment in pulmonary function tests and radiological abnormalities are a major concern in COVID-19 survivors. Our aim is to evaluate functional respiratory parameters, changes in chest CT, and correlation with peripheral blood biomarkers involved in lung fibrosis at two and six months after SARS-CoV-2 pneumonia. MethodsCOVID-FIBROTIC (clinicaltrials.gov NCT04409275) is a multicenter prospective observational cohort study aimed to evaluate discharged patients. Pulmonary function tests, circulating serum biomarkers, chest radiography and chest CT were performed at outpatient visits. ResultsIn total, 313, aged 61.12±12.26 years, out of 481 included patients were available. The proportion of patients with DLCO<80% was 54.6% and 47% at 60 and 180 days. Associated factors with diffusion impairment at 6 months were female sex (OR: 2.97, 95%CI 1.74–5.06, p=0.001), age (OR: 1.03, 95% CI: 1.01–1.05, p=0.005), and peak RALE score (OR: 1.22, 95% CI 1.06–1.40, p=0.005). Patients with altered lung diffusion showed higher levels of MMP-7 (11.54±8.96 vs 6.71±4.25, p=0.001), and periostin (1.11±0.07 vs 0.84±0.40, p=0.001). 226 patients underwent CT scan, of whom 149 (66%) had radiological sequelae of COVID-19. In severe patients, 68.35% had ground glass opacities and 38.46% had parenchymal bands. Early fibrotic changes were associated with higher levels of MMP7 (13.20±9.20 vs 7.92±6.32, p=0.001), MMP1 (10.40±8.21 vs 6.97±8.89, p=0.023), and periostin (1.36±0.93 vs 0.87±0.39, p=0.001). ConclusionAlmost half of patients with moderate or severe COVID-19 pneumonia had impaired pulmonary diffusion six months after discharge. Severe patients showed fibrotic lesions in CT scan and elevated serum biomarkers involved in pulmonary fibrosis.

988P Ocular complications of anti-neoplastic immune checkpoint inhibitor-associated Stevens-Johnson syndrome/toxic epidermal necrolysis: A multi-center prospective observational cohort study

Immune checkpoint inhibitors (ICIs)-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) has been reported. As ocular complications are the major long-term debilitating sequela following SJS/TEN, in this study, ocular manifestations of ICI-induced SJS/TEN are for the first time investigated.

Which factors are associated with anal incontinence after obstetric anal sphincter injury?

Obstetric anal sphincter injury (OASI) is an important factor in the etiology of anal incontinence. This study aimed to evaluate whether anal sphincter defects, levator avulsion or levator ballooning after OASI are associated with severity of anal incontinence. Furthermore, we evaluated whether factors such as constipation and altered stool consistency are associated with symptoms of incontinence after OASI. In this multicenter prospective observational cohort study, women with OASI were invited to participate at least 3 months after primary repair. All women completed validated questionnaires, including St Mark's incontinence score, Bristol stool scale (BSS) and Cleveland clinic constipation score (CCCS), and underwent four-dimensional (4D) transperineal ultrasound for assessment of the levator ani muscle and anal sphincter. In total, 220 women were included. Median follow-up was 4 months (range, 3-98 months). Univariate linear regression analysis showed an association of St Mark's incontinence score with a residual defect of the external anal sphincter (EAS) (β, 1.55 (95% CI, 0.04-3.07); P = 0.045), higher parity (β, 0.85 (95% CI, 0.02-1.67); P = 0.046), BSS (β, 1.28 (95% CI, 0.67-1.89); P < 0.001) and CCCS (β, 0.36 (95% CI, 0.18-0.54); P < 0.001). However, multivariate linear regression found an association of St Mark's incontinence score only with BSS (β, 1.50 (95% CI, 0.90-2.11); P < 0.001) and CCCS (β, 0.46 (95% CI, 0.29-0.63); P < 0.001). Residual defects of the EAS, detected on 4D transperineal ultrasound, are associated with severity of anal incontinence symptoms measured using St Mark's incontinence score 4 months after OASI repair. Furthermore, clinical factors such as constipation and altered stool consistency appear to influence this association and may therefore play a more important role in clinical management. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Association of Host Factors With Antibody Response to Seasonal Influenza Vaccination in Allogeneic Hematopoietic Stem Cell Transplant Patients.

BackgroundInfluenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood.MethodsWe investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison.ResultsBoth regression approaches yielded consistent results but regression on titers estimated associations with higher precision. HSCT patients required 2 vaccine doses to achieve average responses comparable to a single dose in HVs. Prevaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range, and treatment with calcineurin inhibitors lowered the odds of responding.ConclusionsHSCT patients show a highly heterogeneous vaccine response but, overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging identification of additional preventive strategies in the poorly responding groups.Clinical Trials RegistrationNCT03467074.

Clinical, obstetrical and anaesthesia outcomes in pregnant women during the first COVID-19 surge in France: A prospective multicentre observational cohort study

IntroductionClinical outcomes and critical care utilisation associated with Coronavirus Disease 2019 (COVID-19) in obstetric patients remain limited particularly in relation to severe cases. MethodsA retrospective multicentre cohort study was conducted during the first wave of COVID-19 in France in 18 tertiary referral maternity units. Consecutive women with confirmed or suspected COVID-19 during pregnancy or the delivery hospitalisation were included between March and July 2020 (17-week period). We report clinical, obstetrical and anaesthetic outcomes of pregnant women with COVID-19 and report the prevalence of severe forms and risk factors for respiratory support in this cohort. ResultsThere were 126 included cases; RT-PCR testing occurred in 82 cases, of which 64 (78%) had a positive test. The caesarean section rate was 52%, and preterm delivery (< 37 weeks) rate was 40%. Neuraxial anaesthesia was performed in 108 (86%) cases with an increasing proportion compared to general anaesthesia over time (p < 0.0002). Twenty-eight cases received oxygen supplementation (nasal oxygen therapy or mechanical ventilation); the SOFAresp score was associated with gestational age at the time of COVID-19 presentation (p = 0.0036) and at delivery (p < 0.0001). Postpartum intensive care unit (ICU) admission occurred in 21 cases (17%) with 17 (13%) receiving invasive or non-invasive ventilation. Pre-delivery factors associated with postpartum ventilation were oxygen support, oxygen saturation and haemoglobin levels. ConclusionIn our cohort, COVID-19 was associated with significant maternal morbidity resulting in high ICU admission rates (17%) and invasive or non-invasive ventilation utilisation (10%).

The psychological impact of gestational trophoblastic disease: a prospective observational multicentre cohort study.

ObjectiveTo evaluate the short‐term psychological consequences of gestational trophoblastic disease (GTD).DesignA prospective observational multicentre cohort study.SettingNationwide in the Netherlands.PopulationGTD patients.MethodsOnline questionnaires directly after diagnosis.Main outcome measuresHospital Anxiety and Depression Scale (HADS), Distress Thermometer (DT), Impact of Event Scale (IES) and Reproductive Concerns Scale (RCS).ResultsSixty GTD patients were included between 2017 and 2020. Anxious feelings (47%) were more commonly expressed than depressive feelings (27%). Patients experienced moderate to severe adaptation problems in 88%. Patients who already had children were less concerned about their reproductivity than were patients without children (mean score 10.4 versus 15.0, P = 0.031), and patients with children experienced lower distress levels (IES mean score 25.7 versus 34.7, P = 0.020). In addition, patients with previous pregnancy loss scored lower for distress compared with patients without pregnancy loss (IES mean score 21.1 versus 34.2, P = 0.002).DiscussionWe recommend that physicians monitor physical complaints and the course of psychological wellbeing over time in order to provide personalised supportive care in time for patients who have high levels of distress at baseline.ConclusionsGTD patients experience increased levels of distress, anxiety and depression, suggesting the diagnosis has a substantial effect on the psychological wellbeing of patients. The impact of GTD diagnosis on intrusion and avoidance seems to be ameliorated in patients who have children or who have experienced previous pregnancy loss.Tweetable abstractPatients with gestational trophoblastic disease (GTD) experience short‐term psychological consequences such as distress, anxiety and depression, suggesting that the diagnosis GTD has a substantial effect on the psychological wellbeing of patients. Various patient characteristics affect the impact of GTD diagnosis.

Patient satisfaction with calcipotriol/betamethasone dipropionate cutaneous foam for the treatment of plaque psoriasis: The LION real-life multicenter prospective observational cohort study.

Topical treatment is the mainstay for mild or moderate psoriasis, but patients are generally little satisfied. Calcipotriol/betamethasone dipropionate (Cal/BD) cutaneous foam has shown to improve signs and symptoms in plaque psoriasis patients. This study assessed patient's satisfaction with Cal/BD foam in a real‐life Italian dermatological clinical practice. A multicenter, 4‐week observational prospective cohort study enrolled, in 17 Italian dermatology clinics, adult patients with plaque psoriasis on the body and/or scalp. Treatment satisfaction was assessed by 9‐item Treatment Satisfaction Questionnaire for Medication (TSQM‐9), preference over previous treatments by Patient Preference Questionnaire (PPQ), and change in disease state by Psoriasis Area Severity Index (PASI). Overall 256 patients were eligible, with a mean (SD) age of 55.6 (15.4) years, 59.4% were males. Psoriasis severity was mild in 52.0% of patients, moderate in 43.3%, and severe in 4.7%. Scalp involvement was present in 36.7% of patients. Previous antipsoriatic treatments had been received by 80.5% of patients. TSQM‐9 median (25th–75th percentile) scores were 83.3 (66.7–88.9) for effectiveness, 77.8 (66.7–88.9) for convenience, and 78.6 (64.3–92.9) for global satisfaction. Mean (SD) PASI value decreased from 7.3 (4.8) to 2.1 (2.7) after 4 weeks. More than 90% of patients previously treated for psoriasis evaluated the Cal/BD foam more effective, easier to use and better tolerated compared to previous topical treatments at PPQ. This observational study provides real‐life evidence of a high level of satisfaction with effectiveness and convenience of the Cal/BD foam in a cohort of plaque psoriasis patients, with an objective improvement in PASI.

Pain induced by investigations and procedures commonly administered to older adults in the emergency department: a prospective cohort study

BackgroundThis study aimed to assess the level of pain induced by common interventions performed in older adults consulting to the ED.MethodsWe conducted a prospective multicentre observational cohort study in two...

Correlation Between the Spinal Instability Neoplastic Score (SINS) and Patient Reported Outcomes.

International multicenter prospective observational cohort study on patients undergoing radiation +/- surgical intervention for the treatment of symptomatic spinal metastases. To investigate the association between the total Spinal Instability Neoplastic Score (SINS), individual SINS components and PROs. Data regarding patient demographics, diagnostics, treatment, and PROs (SF-36, SOSGOQ, EQ-5D) was collected at baseline, 6 weeks, and 12 weeks post-treatment. The SINS was assessed using routine diagnostic imaging. The association between SINS, PRO at baseline and change in PROs was examined with the Spearmans rank test. A total of 307 patients, including 174 patients who underwent surgery+/- radiotherapy and 133 patients who underwent radiotherapy were eligible for analyses. In the surgery+/- radiotherapy group, 18 (10.3%) patients with SINS score between 0-6, 118 (67.8%) with a SINS between 7-12 and 38 (21.8%) with a SINS between 13-18, as compared to 55 (41.4%) SINS 0-6, 71(53.4%) SINS 7-12 and 7 (5.2%) SINS 13-18 in the radiotherapy alone group. At baseline, the total SINS and the presence of mechanical pain was significantly associated with the SOSGOQ pain domain (r = -0.519, P < 0.001) and the NRS pain score (r = 0.445, P < 0.001) for all patients. The presence of mechanical pain demonstrated to be moderately associated with a positive change in PROs at 12 weeks post-treatment. Spinal instability, as defined by the SINS, was significantly correlated with PROs at baseline and change in PROs post-treatment. Mechanical pain, as a single SINS component, showed the highest correlations with PROs.

Study Pre-protocol for “BronchStart - The Impact of the COVID-19 Pandemic on the Timing, Age and Severity of Respiratory Syncytial Virus (RSV) Emergency Presentations; a Multi-Centre Prospective Observational Cohort Study”

Background: Bronchiolitis (most frequently caused by respiratory syncytial virus; RSV) is a common winter disease predominantly affecting children under one year of age. It is a common reason for presentations to an emergency department (ED) and frequently results in hospital admission, contributing to paediatric units approaching or exceeding capacity each winter. During the SARS-CoV-2 pandemic, the circulation of RSV was dramatically reduced in the United Kingdom and Ireland. Evidence from the Southern Hemisphere and other European countries suggests that as social distancing restrictions for SARS-CoV-2 are relaxed, RSV infection returns, causing delayed or even summer epidemics, with different age distributions. Study question: The ability to track, anticipate and respond to a surge in RSV cases is critical for planning acute care delivery. There is an urgent need to understand the onset of RSV spread at the earliest opportunity. This will influence service planning, to inform clinicians whether the population at risk is a wider age range than normal, and whether there are changes in disease severity. This information is also needed to inform decision on the timing of passive immunisation of children at higher risk of hospitalisation, intensive care admission or death with RSV infection, which is a public health priority. Methods and likely impact: This multi-centre prospective observational cohort study will use a well-established research network (Paediatric Emergency Research in the UK and Ireland, PERUKI) to report in real time cases of RSV infection in children aged under two years, through the collection of essential, but non-identifying patient information. Forty-five centres will gather initial data on age, index of multiple deprivation quintile, clinical features on presentation, and co-morbidities. Each case will be followed up at seven days to identify treatment, viral diagnosis and outcome. Information be released on a weekly basis and used to support clinical decision making.

How representative is a point-of-care randomized trial? Clinical outcomes of patients excluded from a point-of-care randomized controlled trial evaluating antibiotic duration for Gram-negative bacteraemia: a multicentre prospective observational cohort study

ObjectivesPatients included in randomized controlled trials (RCT) are poorly representative of the general population. We compared outcomes of patients excluded from the PIRATE trial, a point-of-care RCT evaluating antibiotic durations for Gram-negative bacteraemia, with those of enrolled patients. MethodsA prospective observational cohort study, ‘EPCO’ (Excluded Patients' Clinical Outcomes) included patients excluded from the PIRATE trial. As in PIRATE, whose patients were randomized to 7-day, 14-day, or C-reactive-protein (CRP)-guided antibiotic durations, EPCO's primary outcome was occurrence of clinical success at 30 days. We also compared baseline characteristics, outcome rates and treatment-effect estimates. ResultsIn all, 405 patients were included in EPCO and compared with the 503 PIRATE patients. Reasons for exclusion were mainly medical (317/405; 78%), the most frequent being complicated infection. Excluded patients had more co-morbidities (Charlson median 3 versus 1, p < 0.001). Bacteraemia was more often health-care-associated (26% versus 9%, p < 0.001). The 30-day success rate was significantly lower among EPCO patients (299/396; 76% versus 469/493; 95%, p < 0.001), but the success rate was not significantly different for those excluded for non-medical reasons (68/75; 91%, p 0.09). There was no significant difference in failure rates of EPCO patients according to their treatment duration (difference 7 days versus 14 days: p 0.75; 7 days versus CRP-correspondent: p 1.00; 14 days versus CRP-correspondent: p 1.00). ConclusionAlthough point-of-care-randomized trials are more inclusive and representative than traditional RCTs, they are still likely to select patients with lower failure risk. Shorter antibiotic durations were not associated with failure in either included or excluded patients, supporting the generalizability of the PIRATE trial's findings.

Prevalence and early-life risk factors of school-age allergic multimorbidity: The EuroPrevall-iFAAM birth cohort.

BackgroundCoexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan‐European, population‐based birth cohort study have been lacking. This study compares the prevalence and early‐life risk factors of these diseases in European primary school children.MethodsIn the prospective multicentre observational EuroPrevall‐iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC‐based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence of at least two of these.ResultsFrom 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family‐allergy‐score, odds ratio (OR) 1.50 (95% CI 1.32–1.70) per standard deviation; early‐life allergy symptoms, OR 2.72 (2.34–3.16) for each symptom; and caesarean birth, OR 1.35 (1.04–1.76). Female gender, OR 0.72 (0.58–0.90); older siblings, OR 0.79 (0.63–0.99); and day care, OR 0.81 (0.63–1.06) were protective factors.ConclusionAllergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early‐life factors are modifiable and may be considered for prevention strategies.

Diagnostic accuracy of prehospital serum S100B and GFAP in patients with mild traumatic brain injury: a prospective observational multicenter cohort study \u2013 \u201cthe PreTBI I study\u201d

BackgroundThe biomarker serum S100 calcium-binding protein B (S100B) is used in in-hospital triage of adults with mild traumatic brain injury to rule out intracranial lesions. The biomarker glial fibrillary acidic protein (GFAP) is suggested as a potential diagnostic biomarker for traumatic brain injury. The aim of this study was to investigate the diagnostic accuracy of early prehospital S100B and GFAP measurements to rule out intracranial lesions in adult patients with mild traumatic brain injury.MethodsPrehospital and in-hospital blood samples were drawn from 566 adult patients with mild traumatic brain injury (Glasgow Coma Scale Score 14–15). The index test was S100B and GFAP concentrations. The reference standard was endpoint adjudication of the traumatic intracranial lesion based on medical records. The primary outcome was prehospital sensitivity of S100B in relation to the traumatic intracranial lesion.ResultsTraumatic intracranial lesions were found in 32/566 (5.6%) patients. The sensitivity of S100B > 0.10 μg/L was 100% (95%CI: 89.1;100.0) in prehospital samples and 100% (95% CI 89.1;100.0) in in-hospital samples. The specificity was 15.4% (95%CI: 12.4;18.7) in prehospital samples and 31.5% (27.5;35.6) in in-hospital samples. GFAP was only detected in less than 2% of cases with the assay used.ConclusionEarly prehospital and in-hospital S100B levels < 0.10 μg/L safely rules out traumatic intracranial lesions in adult patients with mild traumatic brain injury, but specificity is lower with early prehospital sampling than with in-hospital sampling. The very limited cases with values detectable with our assay do not allow conclusions to be draw regarding the diagnostic accuracy of GFAP.Trial registrationClinicalTrials.gov identifier: NCT02867137.

Study Pre-protocol for "BronchStart - The Impact of the COVID-19 Pandemic on the Timing, Age and Severity of Respiratory Syncytial Virus (RSV) Emergency Presentations; a Multi-Centre Prospective Observational Cohort Study".

Background: Bronchiolitis (most frequently caused by respiratory syncytial virus; RSV) is a common winter disease predominantly affecting children under one year of age. It is a common reason for presentations to an emergency department (ED) and frequently results in hospital admission, contributing to paediatric units approaching or exceeding capacity each winter. During the SARS-CoV-2 pandemic, the circulation of RSV was dramatically reduced in the United Kingdom and Ireland. Evidence from the Southern Hemisphere and other European countries suggests that as social distancing restrictions for SARS-CoV-2 are relaxed, RSV infection returns, causing delayed or even summer epidemics, with different age distributions. Study question: The ability to track, anticipate and respond to a surge in RSV cases is critical for planning acute care delivery. There is an urgent need to understand the onset of RSV spread at the earliest opportunity. This will influence service planning, to inform clinicians whether the population at risk is a wider age range than normal, and whether there are changes in disease severity. This information is also needed to inform decision on the timing of passive immunisation of children at higher risk of hospitalisation, intensive care admission or death with RSV infection, which is a public health priority. Methods and likely impact: This multi-centre prospective observational cohort study will use a well-established research network (Paediatric Emergency Research in the UK and Ireland, PERUKI) to report in real time cases of RSV infection in children aged under two years, through the collection of essential, but non-identifying patient information. Forty-five centres will gather initial data on age, index of multiple deprivation quintile, clinical features on presentation, and co-morbidities. Each case will be followed up at seven days to identify treatment, viral diagnosis and outcome. Information be released on a weekly basis and used to support clinical decision making.

Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK

SummaryBackgroundMortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital.MethodsIn this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260.FindingsBetween March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8–32·7) in March 9 to April 26, 2020, to 16·4% (15·0–17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65–0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94–0·95) of the reduction in in-hospital mortality.InterpretationThe reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain.FundingNational Institute for Health Research and the Medical Research Council.

Associations of continuous glucose monitoring-assessed glucose variability with intima-media thickness and ultrasonic tissue characteristics of the carotid arteries: a cross-sectional analysis in patients with type 2 diabetes

BackgroundThe association between glucose variability and the progression of atherosclerosis is not completely understood. We aimed to evaluate the associations of glucose variability with the progression of atherosclerosis in the early stages.MethodsWe conducted a cross-sectional analysis to investigate the associations of glucose variability, assessed by continuous glucose monitoring, with intima-media thickness (IMT) and gray-scale median (GSM) of the carotid arteries, which are different indicators for the progression of atherosclerosis. We used baseline data from a hospital-based multicenter prospective observational cohort study among Japanese patients with type 2 diabetes without a history of cardiovascular diseases aged between 30 and 80 years. Continuous glucose monitoring was performed by Freestyle Libre Pro, and glucose levels obtained every 15 min for a maximum of eight days were used to calculate the metrics of glucose variability. IMT and GSM were evaluated by ultrasonography, and the former indicates thickening of intima-media complex in the carotid artery wall, while the latter indicates tissue characteristics.ResultsAmong 600 study participants (age: 64.9 ± 9.2 (mean ± SD) years; 63.2%: men; HbA1c: 7.0 ± 0.8%), participants with a larger intra- and inter-day glucose variability had a lower GSM and most of these associations were statistically significant. No trend based on glucose variability was shown regarding IMT. Standard deviation of glucose (regression coefficient, β = − 5.822; 95% CI − 8.875 to − 2.768, P < 0.001), glucose coefficient of variation (β = − 0.418; − 0.685 to − 0.151, P = 0.002), mean amplitude of glycemic excursion (β = − 1.689; − 2.567 to − 0.811, P < 0.001), mean of daily differences (β = − 6.500; − 9.758 to − 3.241, P < 0.001), and interquartile range (β = − 4.289; − 6.964 to − 1.614, P = 0.002) had a statistically significant association with mean-GSM after adjustment for conventional cardiovascular risk factors, including HbA1c. No metrics of glucose variability had a statistically significant association with IMT.ConclusionsContinuous glucose monitoring-assessed glucose variability was associated with the tissue characteristics of the carotid artery wall in type 2 diabetes patients without cardiovascular diseases.

Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study)

BackgroundThe clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting.MethodsThis multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation.ResultsOne hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both p < .001). NRS, MPI, HIT-6 and MIDAS scores significantly decreased (p < .001). Ten patients (6.1%) dropped out for inefficacy and classified as non-responders. Patients with ≥50%RRs, i.e. responders, were 76.5% in the HFEM and 63.5% in the CM group at V6. Among CM patients, the V6 responders presented a lower body mass index (p = .018) and had failed a lower number of preventive treatments (p = .013) than non-responders. At V6, 77.2% of CM patients converted to EM, and 82.0% ceased MO. Adverse events, none serious, were reported in up to 10.3% of patients during evaluation times.ConclusionsGalcanezumab in real life was safe, well tolerated and seemed more effective than in RCTs. Normal weight and a low number of failed preventives were positively associated with galcanezumab effectiveness in CM patients.Trial registrationClinicalTrials.govNCT04803513.

Predicting Lymph Node Metastasis in Non-small Cell Lung Cancer: Prospective External and Temporal Validation of the HAL and HOMER Models

Two models, the Help with the Assessment of Adenopathy in Lung cancer (HAL) and Help with Oncologic Mediastinal Evaluation for Radiation (HOMER), were recently developed to estimate the probability of nodal disease in patients with non-small cell lung cancer (NSCLC) as determined by endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). The objective of this study was to prospectively externally validate both models at multiple centers. Are the HAL and HOMER models valid across multiple centers? This multicenter prospective observational cohort study enrolled consecutive patients with PET-CT clinical-radiographic stages T1-3, N0-3, M0 NSCLC undergoing EBUS-TBNA staging. HOMER was used to predict the probability of N0 vsN1 vsN2 or N3 (N2|3) disease, and HAL was used to predict the probability of N2|3 (vs N0 or N1) disease. Model discrimination was assessed using the area under the receiver operating characteristics curve (ROC-AUC), and calibration was assessed using the Brier score, calibration plots, and the Hosmer-Lemeshow test. Thirteen centers enrolled 1,799 patients. HAL and HOMER demonstrated good discrimination: HAL ROC-AUC= 0.873 (95%CI, 0.856-0.891) and HOMER ROC-AUC= 0.837 (95%CI, 0.814-0.859) for predicting N1 disease or higher (N1|2|3) and 0.876 (95%CI, 0.855-0.897) for predicting N2|3 disease. Brier scores were 0.117 and 0.349, respectively. Calibration plots demonstrated good calibration for both models. For HAL, the difference between forecast and observed probability of N2|3 disease was+0.012; for HOMER, the difference for N1|2|3 was-0.018 and for N2|3 was+0.002. The Hosmer-Lemeshow test was significant for both models (P= .034 and .002), indicating a small but statistically significant calibration error. HAL and HOMER demonstrated good discrimination and calibration in multiple centers. Although calibration error was present, the magnitude of the error is small, such that the models are informative.

Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study

ObjectivesLittle is known about how additional second-line drug resistance emerges during multidrug-resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the recommended 2-year MDR-TB treatment. MethodsIndividuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. ResultsOf the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51–4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03–5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22–7.21) were independent risk factors associated with the development of additional second-line drug resistance. ConclusionsA large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.