Search

Aim: Our aim was to examine how fever duration affected the ability of biomarkers to diagnose community-acquired pneumonia (CAP)., Methods: This was a retrospective cohort study of children aged 2-18 years who attended the emergency department at Schneider Children's Medical Centre of Israel with CAP from June 2015 to May 2020. The children underwent biomarker measurements and chest radiographs and optimal biomarker thresholds were identified. Biomarker predictions of x-ray positive CAP were analysed, using receiver operating characteristic curves and area under the curve calculations., Results: We screened 3346 children, 509 met the inclusion criteria and 363 of those had x-ray positive CAP. White blood counts of >15 000/mm 3 and absolute neutrophil counts of >11 200/mm 3 showed significant discriminatory power on day 2 of a fever. A neutrophil to lymphocyte ratio (NLR) of >4.5 displayed significant discriminatory power from days 2-5 and peaked on day 4. C-reactive protein of 6.23 mg/dL was discriminatory on day 4., Conclusion: Fever duration affected how effectively biomarkers diagnosed x-ray positive CAP and all were unreliable on day 1. The NLR showed the most consistent reliability and may be suitable for clinical decision-making. Fever duration should be considered to optimise diagnostic accuracy., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Public reluctance to receive COVID-19 vaccination is associated with safety concerns. By contrast, the seasonal influenza vaccine has been administered for decades with a solid safety record and a high level of public acceptance. We compare the safety profile of the BNT162b2 COVID-19 booster vaccine to that of the seasonal influenza vaccine., Methods: We study a prospective cohort of 5079 participants in Israel and a retrospective cohort of 250,000 members of MHS selected randomly. We examine reactions to BNT162b2 mRNA COVID-19 booster and to influenza vaccinations. All prospective cohort participants wore a smartwatch and completed a daily digital questionnaire. We compare pre-vaccination and post-vaccination smartwatch heart-rate data, and a stress measure based on heart-rate variability. We also examine adverse events from electronic health records., Results: In the prospective cohort, 1905 participants receive the COVID-19 booster vaccine; 899 receive influenza vaccination. Focusing on those who receive both vaccines yields a total of 689 participants in the prospective cohort and 31,297 members in the retrospective cohort. Individuals reporting a more severe reaction after influenza vaccination tend to likewise report a more severe reaction after COVID-19 vaccination. In paired analysis, the increase in both heart rate and stress measure for each participant is higher for COVID-19 than for influenza in the first 2 days after vaccination. No elevated risk of hospitalization due to adverse events is found following either vaccine. Except for Bell's palsy after influenza vaccination, no elevated risk of adverse events is found., Conclusions: The more pronounced side effects after COVID-19 vaccination may explain the greater concern associated with it. Nevertheless, our comprehensive analysis supports the safety profile of both vaccines., (© 2024. The Author(s).)

Background: Pediatric Post-COVID-Condition (PPCC) clinics treat children despite limited scientific substantiation. By exploring real-life management of children diagnosed with PPCC, the International Post-COVID-Condition in Children Collaboration (IP4C) aimed to provide guidance for future PPCC care., Methods: We performed a cross-sectional international, multicenter study on used PPCC definitions; the organization of PPCC care programs and patients characteristics. We compared aggregated data from PPCC cohorts and identified priorities to improve PPCC care., Results: Ten PPCC care programs and six COVID-19 follow-up research cohorts participated. Aggregated data from 584 PPCC patients was analyzed. The most common symptoms included fatigue (71%), headache (55%), concentration difficulties (53%), and brain fog (48%). Severe limitations in daily life were reported in 31% of patients. Most PPCC care programs organized in-person visits with multidisciplinary teams. Diagnostic testing for respiratory and cardiac morbidity was most frequently performed and seldom abnormal. Treatment was often limited to physical therapy and psychological support., Conclusions: We found substantial heterogeneity in both the diagnostics and management of PPCC, possibly explained by scarce scientific evidence and lack of standardized care. We present a list of components which future guidelines should address, and outline priorities concerning PPCC care pathways, research and international collaboration., Impact: Pediatric Post-COVID Condition (PPCC) Care programs have been initiated in many countries. Children with PPCC in different countries are affected by similar symptoms, limiting many to participate in daily life. There is substantial heterogeneity in diagnostic testing. Access to specific diagnostic tests is required to identify some long-term COVID-19 sequelae. Treatments provided were limited to physical therapy and psychological support. This study emphasizes the need for evidence-based diagnostics and treatment of PPCC. The International Post-COVID Collaboration for Children (IP4C) provides guidance for guideline development and introduces a framework of priorities for PPCC care and research, to improve PPCC outcomes., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Limited knowledge exists regarding behavioral and biomarker shifts during the period from respiratory infection exposure to testing decisions (the diagnostic decision period), a key phase affecting transmission dynamics and public health strategy development. This study aims to examine the changes in behavior and biomarkers during the diagnostic decision period for COVID-19, influenza, and group A streptococcus (GAS)., Methods: We analyzed data from a two-year prospective cohort study involving 4795 participants in Israel, incorporating smartwatch data, self-reported symptoms, and medical records. Our analysis focused on three critical phases: the digital incubation period (from exposure to physiological anomalies detected by smartwatches), the symptomatic incubation period (from exposure to onset of symptoms), and the diagnostic decision period for influenza, COVID-19, and GAS., Findings: The delay between initial symptom reporting and testing was 39 [95% confidence interval (CI): 34-45] hours for influenza, 53 [95% CI: 49-58] hours for COVID-19, and 38 [95% CI: 32-46] hours for GAS, with 73 [95% CI: 67-78] hours from anomalies in heart measures to symptom onset for influenza, 23 [95% CI: 18-27] hours for COVID-19, and 62 [95% CI: 54-68] hours for GAS. Analyzing the entire course of infection of each individual, the greatest changes in heart rates were detected 67.6 [95% CI: 62.8-72.5] hours prior to testing for influenza, 64.1 [95% CI: 61.4-66.7] hours prior for COVID-19, and 58.2 [95% CI: 52.1-64.2] hours prior for GAS. In contrast, the greatest reduction in physical activities and social contacts occurred after testing., Interpretation: These findings highlight the delayed response of patients in seeking medical attention and reducing social contacts and demonstrate the transformative potential of smartwatches for identifying infection and enabling timely public health interventions., Funding: This work was supported by the European Research Council, project #949850, the Israel Science Foundation (ISF), grant No. 3409/19, within the Israel Precision Medicine Partnership program, and a Koret Foundation gift for Smart Cities and Digital Living., Competing Interests: All authors declare no competing interests., (© 2024 The Author(s).)

During the COVID-19 pandemic wearing face masks was mandatory. Nowadays, face masks are still encouraged indoors, especially in hospitals. People climbing stairs with masks describe unpredictable dyspnea. In this study, healthy adults climbed 5 floors with and without a mask. Various cardio-respiratory parameters were measured, including O 2 -saturation (O 2 -Sat) and end-tidal CO 2 (EtCO 2 ), at baseline and on the top floor. Subjective indexes, such as Borg's scale, were evaluated. Thirty-two volunteers (16 males), median age 39 years (IQR 32.5-43), median BMI = 23.6 (IQR 21.5-25.1), with good fitness levels, participated. Comparing baseline to end-activity, median (IQR): O 2 -Sat change was -1.0% (-2-0) without mask, versus -3.0% (-4-0) with mask, p = 0.003; EtCO 2 + 7.0 (+3.3-+9) without mask, versus +8.0 (+6-+12) with mask, p = 0.0001. Hypercarbia was seen in 5 (15.6%) participants without mask, median = 48 mmHg (IQR 47.5-51), and in 11 (34%) participants with mask, median = 50 mmHg (IQR 47-54), p < 0.001. Desaturation (O 2 -Sat < 95%) was seen in 5 (15.6%) participants without mask, median = 94% (IQR 93%-94%), and in 10 (31%) participants with mask, median = 91.5% (IQR 90%-93%), p = 0.06. Regression analysis demonstrated that only male sex was significantly associated with abnormal EtCO 2 (OR = 26.4, 95% CI = 1.9-366.4, p = 0.005). Ascent duration increased from median (IQR) of 94 s (86-100) without mask to 98 s (89-107) with mask, p < 0.001. Borg's scale of perceived exertion (range 0-10) increased from median (IQR) of 3.0 (2.5-3.87) without mask to 4.0 (3.0-4.37) with mask, p < 0.001. To conclude, during routine daily activities, such as stair-climbing, face masks cause dyspnea, and have measurable influences on ventilation, including true desaturation and hypercapnia, especially in males., (© 2024 IOP Publishing Ltd.)

Vaccines stand out as one of the most effective tools in our arsenal for reducing morbidity and mortality. Nonetheless, public hesitancy towards vaccination often stems from concerns about potential side effects, which can vary from person to person. As of now, there are no automated systems available to proactively warn against potential side effects or gauge their severity following vaccination. We have developed machine learning (ML) models designed to predict and detect the severity of post-vaccination side effects. Our study involved 2111 participants who had received at least one dose of either a COVID-19 or influenza vaccine. Each participant was equipped with a Garmin Vivosmart 4 smartwatch and was required to complete a daily self-reported questionnaire regarding local and systemic reactions through a dedicated mobile application. Our XGBoost models yielded an area under the receiver operating characteristic curve (AUROC) of 0.69 and 0.74 in predicting and detecting moderate to severe side effects, respectively. These predictions were primarily based on variables such as vaccine type (influenza vs. COVID-19), the individual's history of side effects from previous vaccines, and specific data collected from the smartwatches prior to vaccine administration, including resting heart rate, heart rate, and heart rate variability. In conclusion, our findings suggest that wearable devices can provide an objective and continuous method for predicting and monitoring moderate to severe vaccine side effects. This technology has the potential to improve clinical trials by automating the classification of vaccine severity., (© 2024. The Author(s).)

Background: Studies on post-COVID-19 condition (PCC) in adults have shown deterioration in pulmonary function tests (PFTs), mainly a diffusion limitation. Among the pediatric population, data are scarce. Aim: To characterize PFTs in children with PCC, including changes over time. Methods: A prospective longitudinal study of children with defined PCC and respiratory complaints who were referred to a designated multidisciplinary clinic from 11/2020 to 12/2022. Results: Altogether, 184 children with a mean age of 12.4 years (SD 4.06) were included. A mild obstructive pattern was demonstrated in 19/170 (11%) at presentation, as indicated by spirometry and/or positive exercise challenge test and/or reversibility post bronchodilators, only three had a previous diagnosis of asthma. Lung volumes and diffusion were normal in all but one patient (1/134, 0.7%). Exhaled nitric oxide levels were elevated in 32/144 (22%). A total of 33 children who had repeated PFTs had normal or near-normal PFTs on follow-up testing, including seven (21.2%) who had mild obstructive PFTs at presentation. Multivariate analysis identified older age [OR 1.36 (95% CI:1.07-1.75)], specific imaging findings (prominent bronchovascular markings (OR 43.28 (95% CI: 4.50-416.49)), and hyperinflation (OR 28.42, 95% CI: 2.18-370.84)] as significant predictors of an obstructive pattern on PFTs. Conclusions: In children with PCC and respiratory symptoms, the most common impairment was a mild obstructive pattern; most were without a history of asthma. Improvement was witnessed in long-term follow-up. In contrast to the adult population, no diffusion limitation was found. Empirical periodic inhaler therapy may be considered in children with factors associated with PFT abnormalities.

Background: COVID-19 continues to be a major health threat, particularly among at-risk groups, including individuals aged 60 years or older and people with particular medical conditions. Nevertheless, the absence of sufficient vaccine safety information is one of the key contributors to vaccine refusal. We aimed to assess the short-term safety profile of the BNT162b2 mRNA COVID-19 vaccine booster doses., Methods: In this self-controlled case series study, we used a database of members of the largest health-care organisation in Israel. We analysed the medical records of individuals at risk of COVID-19 complications who had received two doses of the monovalent BNT162b2 mRNA COVID-19 vaccine (tozinameran, Pfizer-BioNTech) as their primary course of vaccination and then also received BNT162b2 mRNA COVID-19 vaccine boosters between July 30, 2021, and Nov 28, 2022, as a monovalent first or second booster, or as a bivalent first, second, or third booster, or a combination of these. We included individuals who had active membership of the health-care organisation and who were alive (excluding COVID-19 deaths) throughout the entire study period. We excluded individuals who, during the study period, were either not active Clalit Health Services members or died of non-COVID-19 causes, and those who were infected with COVID-19 during the 7-day period after vaccination. Individuals' at-risk status was assessed on the day before the baseline period started. The primary outcome was non-COVID-19 hospitalisation for 29 adverse events that might be associated with vaccination. For each adverse event, we compared the risk difference of hospitalisation during a 28-day pre-vaccination baseline period versus during a 28-day post-vaccination period, using a non-parametric percentile bootstrap method., Findings: Of the 3 574 243 members of the health-care organisation, 1 073 110 received a first monovalent booster, 394 251 received a second monovalent booster, and 123 084 received a bivalent first, second, or third booster. Overall, we found no indication of an elevated risk of non-COVID-19 hospitalisation following administration of any of the booster vaccines (risk difference in events per 100 000 individuals: first monovalent booster -37·1 [95% CI -49·8 to -24·2]; second monovalent booster -37·8 [-62·2 to -13·2]; and bivalent booster -18·7 [-53·6 to 15·4]). Except for extremely rare elevated risks after the first monovalent booster-of myocarditis (risk difference 0·7 events per 100 000 individuals [95% CI 0·3-1·3]), seizures (2·2 [0·4-4·1]), and thrombocytopenia (2·6 [0·7-4·7])-we found no safety signals in other adverse events, including ischaemic stroke., Interpretation: This study provides the necessary vaccine safety assurances for at-risk populations to receive timed roll-out booster vaccinations. These assurances could reduce vaccine hesitancy and increase the number of at-risk individuals who opt to become vaccinated, and thereby prevent the severe outcomes associated with COVID-19., Funding: Israel Science Foundation and Israel Precision Medicine Partnership programme., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Lung function deterioration in cystic fibrosis (CF) is typically measured by a decline in the forced expiratory volume in one second (FEV 1 %), which is thought to be a late marker of lung disease. Dynamic hyperinflation (DH) is seen in obstructive lung diseases while exercising. Our aim was to assess whether DH could predict pulmonary deterioration in CF; a secondary measure was the peak VO 2 ., Methods: A retrospective study was conducted of people with CF who performed cardiopulmonary exercise tests (CPETs) during 2012-2018. The tests were classified as those demonstrating DH non-DH. Demographic, genetic, and clinical data until 12.2022 were extracted from patient charts., Results: A total of 33 patients aged 10-61 years performed 41 valid CPETs with valid DH measurements; sixteen (39%) demonstrated DH. At the time of the CPETs, there was no difference in the FEV 1 % measurements between the DH and non-DH groups (median 83.5% vs. 87.6%, respectively; p = 0.174). The FEV 1 % trend over 4 years showed a decline in the DH group compared to the non-DH group ( p = 0.009). A correlation was found between DH and the lung clearance index (LCI), as well as the FEV 1 % (r = 0.36 and p = 0.019 and r = -0.55 and p = 0.004, respectively). Intravenous (IV) antibiotic courses during the 4 years after the CPETs were significantly more frequent in the DH group ( p = 0.046). The peak VO 2 also correlated with the FEV 1 % and LCI (r = 0.36 and p = 0.02 and r = -0.46 and p = 0.014, respectively) as well as with the IV antibiotic courses (r = -0.46 and p = 0.014)., Conclusions: In our cohort, the DH and peak VO 2 were both associated with lung function deterioration and more frequent pulmonary exacerbations. DH may serve as a marker to predict pulmonary deterioration in people with CF.

Background: In vitro studies have demonstrated rescue of CFTR function with Elexacaftor/Tezacaftor/Ivacaftor (ETI) in several mutations other than F508del. However, clinical efficacy was not tested in vivo in people with CF (pwCF) carrying mutations other than F508del. We report effects of treatment with ETI in pwCF with non-F508del mutations., Methods: We retrospectively analyzed pwCF with non-F508del mutations who received treatment with ETI. We evaluated sweat chloride, nutritional status, spirometry, antibiotic treatment, and pulmonary exacerbations (PEx), at baseline and 3-6 months after commencing treatment with ETI., Results: We included 16 pwCF, including eight without previous use of CFTR modulators. Median time on treatment was 5.3 (range, 1.8-7.7) months. Compared to baseline, in the "naïve" group sweat chloride concentration was reduced from 113.0 (98-129) to 64.0 (32-97) mEq/L (n=7; median (IQR), p=0.018), and rate of pulmonary exacerbations declined from a median of 1.5 (IQR 1, 2.75) in the previous year to 0 (0,0) (p= 0.019) with a significant decline in annualized days with antibiotics (oral + parenteral) per year: 36 (17.5; 42) in the year before to 0 (0,0) (median (IQR), p= 0.027). Mean FEV 1 % changed from 66.3±25 to 72.4±29 % (mean ± SD, p=0.058). In the group of patients previously treated with Ivacaftor or Tezacaftor/Ivacaftor, we didn't observe significant improvements in any of the parameters., Conclusions: We demonstrate the clinical efficacy of ETI in pwCF carrying CFTR processing non-F508del mutations which are predicted to respond by in vitro studies. Our results support routine clinical use of ETI in this patient group., Competing Interests: Declaration of Competing Interest MS Received research grants from GSK, Novartis, Trudell Medical International; travel grants- Novartis, Actelion, Boeringer Ingelheim, GSK, Rafa. Speaker's fees- Boeringer Ingelheim, GSK, Astra Zeneca, Teva, Novartis, Kamada. Advisory fees- GSK, Boeringer Ingelheim, Horizon pharma, Vertex pharmaceuticals. DP Received Educational grant: "Circle of care" from Vertex. GL received independent Medical Grant for Investigator-Initiated Study from Vertex, outside of the submitted work., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Modern wars have a catastrophic effect on the wellbeing of civilians. However, the nature of this effect remains unclear, with most insights gleaned from subjective, retrospective studies., Methods: We prospectively monitored 954 Israelis (>40 years) from two weeks before the May 2021 Israel-Gaza war until four weeks after the ceasefire using smartwatches and a dedicated mobile application with daily questionnaires on wellbeing. This war severely affected civilians on both sides, where over 4300 rockets and missiles were launched towards Israeli cities, and 1500 aerial, land, and sea strikes were launched towards 16,500 targets in the Gaza Strip., Results: We identify considerable changes in all the examined wellbeing indicators during missile attacks and throughout the war, including spikes in heart rate levels, excessive screen-on time, and a reduction in sleep duration and quality. These changes, however, fade shortly after the war, with all affected measures returning to baseline in nearly all the participants. Greater changes are observed in individuals living closer to the battlefield, women, and younger individuals., Conclusions: The demonstrated ability to monitor objective and subjective wellbeing indicators during crises in real-time is pivotal for the early detection of and prompt assistance to populations in need., (© 2023. The Author(s).)

Background: The effectiveness of the second BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 booster vaccine dose (ie, fourth inoculation) is well established, but its safety has yet to be fully understood. The absence of sufficient vaccine safety information is one of the key contributors to vaccine hesitancy. In this study, we aimed to evaluate the safety profile of the second BNT162b2 mRNA COVID-19 booster vaccine using data from a retrospective cohort and a prospective cohort., Methods: To evaluate the safety profile of the second booster vaccine, we analysed its short-term effects and compared them to those of the first booster by using data from, first, a retrospective cohort of 250 000 random members of the second-largest health-care organisation in Israel (Maccabi Healthcare Services) and, second, a prospective cohort (the PerMed study) of 4698 participants from all across Israel. Individuals who were aged 18 years or older who received the second BNT162b2 mRNA COVID-19 vaccine booster during the vaccination campaign, from Dec 30, 2021, to July 22, 2022, were eligible for inclusion in the retrospective cohort analysis. To be included in the PerMed study, participants needed to be 18 years or older, members of Maccabi Healthcare Services at the time of enrolment, using their own smartphone, and be able to give informed consent by themselves. Participants from the prospective cohort received smartwatches, downloaded a dedicated mobile application, and granted access to their medical records. The smartwatches continuously monitored several physiological measures, including heart rate. For analysis of the prospective cohort data, we used the Kruskal-Wallis test to compare heart rate levels observed before and after vaccination. The mobile application collected daily self-reported questionnaires on local and systemic reactions. Medical records of the retrospective cohort were accessed to examine the occurrence of 25 potential adverse events, and we evaluated the risk differences between 42 days in the periods before and after vaccination in a pairwise method using non-parametric percentile bootstrap., Findings: The retrospective cohort included 94 169 participants who received the first booster and 17 814 who received the second booster. Comparing the 42 days before and after vaccination, the second booster was not associated with any of the 25 adverse events investigated, including myocardial infarction (risk difference, 2·25 events per 10 000 individuals [95% CI -3·93 to 8·98]) and Bell's Palsy (-1·68 events [-5·61 to 2·25]). None of the individuals was diagnosed with myocarditis or pericarditis following vaccination with the second booster. The prospective cohort included 1785 participants who received the first booster and 699 who received the second booster. We found no significant differences after inoculation with the first booster compared with the second booster (heart rate: day 2 [p=0·3], day 6 [p=0·89]; extent of self-reported reactions [p=0·06]). We found a significant increase in mean heart rate relative to that observed during the week before vaccination (baseline) levels during the first 3 days following the second booster (p<0·0001), peaking on day 2 (mean difference of 1·61 bpm [1·07 to 2·16] compared with baseline). Mean heart rate values returned to baseline levels by day 6 (-0·055 bpm [-0·56 to 0·45] compared with baseline)., Interpretation: Both our retrospective and prospective analyses support the safety of the second booster, with our findings reflecting physicians' diagnoses, patients' objective physiological measures, and patients' subjective reactions. We believe this study provides safety assurances to the global population who are eligible to receive an additional COVID-19 booster inoculation. These assurances can help increase the number of high-risk individuals who opt to receive this booster vaccine and thereby prevent severe outcomes associated with COVID-19., Funding: European Research Council (ERC)., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)