Within the prison environment, where strict surveillance and prompt decision-taking are essential to maintain security, poor sleep may be hazardous to correctional officers. This study aims to estimate the prevalence of and identify factors associated with severe sleep disorders in correctional officers.An exploratory cross-sectional study comprised all correctional officers in a prison complex in Salvador city, Brazil. Information about sleep quality, sociodemographic and occupational aspects, lifestyle habits, and common mental disorders (self-reporting questionnaire-20 score ≥7 points) were collected via a self-administered questionnaire. Severe sleep disorder was defined as a score ≥31 points according to the mini sleep questionnaire. The measure of association used was the prevalence ratio (PR). Prevalence ratios were estimated by using a Cox multivariate regression model. The final adjusted model only included the variables that presented a prevalence ratio ≥1.20.The prevalence of severe sleep disorders in the 374 correctional officers was 55.3%, and was strongly  associated with number of stressful activities at work , number of attack and threat events against the correctional officers over the last 12 months , common mental disorders , and non-White skin color .This study found high prevalence of severe sleep disorders in correctional officers, associated with impairment of their mental health, skin color, and, particularly, with situations of stress and violence at work. These factors must be taken into account when planning and providing health care to these workers. A review about the psychological distress and work stress of correctional officers identified 40 articles, with 22 focused on stress, 12 on burnout, and eight on psychic suffering. Sixteen publications came from the United States of America; four studies came from Latin America, all of them from Brazil2. In July 30, 2017, the Brazilian penitentiary system had 1,507 prisons, 706,619 prisoners, and 80,350 correctional officers3. The functioning of this system is hampered by inadequate public policies, corruption, shortage of material and human resources, overcrowding, and violence4.In the prison system context, correctional officers are exposed to several sources of stress, including a closed coercitive work enviroment, the need to deal with violence and perform ardous tasks, constant vigilance about order and security, difficult work schedules, and obedience to hierarquical relationships5.Correctional officers present a high prevalence of diabetes, cardiovascular diseases, stroke, arterial hypertension, metabolic disorders, obesity, increased risk of physical injuries, burnout, depression, anxiety, suicide, infectious diseases, and sleep disorders6. In occupational environments, sleep deficiency affects worker productivity, and health and safety, and leads to high economic burdens. Problems related to insufficient sleep hours have been related to the loss of estimated 717 billion dollars in 2020 in five countries 7.Insufficient sleep can affect many aspects of individual health, causing daytime sleepiness; emotional problems; cognitive impairment; effects on body weight; changes in circadian rhythm, glucose metabolism, and inflammatory response; and negative impacts on the cardiovascular, reproductive, and immunological systems. In the community context, sleep deprivation increases the probability of occupational and traffic accidents, decreases sociability, and performance and productivity at work8. The prison environment is dangerous and interactional. Correctional officers must be able to defuse tension and maintain calm among prisoners, requiring to only use necessary amounts of force to maintain safety without abusing prisoners. Correctional officers sleep disorders can lead to mistakes, irritation, and excessive responses to problems, resulting in abuse or unnecessary harm to prisoners.In the prison environment, where strict surveillance and prompt decision-taking are essential for maintaining security, sleep deprivation and consequent fatigue can threaten correctional officers’ life, since it impairs their ability to evaluate risks5. A nationwide, representative study among correctional officers in France reported a 41.8% prevalence of sleep disorders, evaluated by a specific questionnaire1.Correctional officers are frequently affected by sleep disorders. A study with 355 prison workers from the State of Washington, USA, reported high prevalence of (27.6%), and insomnia (44.8%), according to the Pittsburg sleep quality indexThe objective of this study is to estimate the prevalence of and identify factors associated with severe sleep disorders among correctional officers in a Brazilian prison complex.A cross sectional exploratory study including all 571 correctional officers assigned to the public State Penitentiary Complex in the city of Salvador, Brazil. All correctional officers studied were employees of the State Justice Department, selected by an open competition exam that includes physical and psychological evaluation of their aptitute for the profession. These employees have full labor rights assured, including sick leave.The correctional officers were approached during working time and participated voluntarily in the study. After explaining the objectives, participants signed an informed consent form. All information relating to the participants was confidential. The study was approved by the ethics committee in research on human beings of the Medical School of Bahia for opinion number 2.464.066 and amendment 2.824.557, and carried out in accordance with the Helsinki declaration.Data collection occurred between September and December 2018. Correctional officers were excluded from the study if were on sick leave (17); on a ninety-day sabbatical (15); who retired during data collection (6); where there was a lack of information about the unit they were assigned to (30); who had been substituted by another correctional officer during a whole month (37); who had been transferred to another work station or were working for the union (15); or who deviated from their prescribed work position (4), resulting in 447 eligible individuals. Of these, 46 were excluded because they refused to participate in the study after three consecutive invitations, and 27 because they provided incomplete answers to the study questionnaire. In the end, the study population comprised 374 individuals, corresponding to 83.7% of all eligible officers.A self-administered questionnaire containing sociodemographic and occupational information, lifestyle habits, common mental disorders, and sleep quality was handed over to the correctional officer that took 20-30 minutes to complete it.9. The Brazilian MSQ contains ten questions on sleep-related aspects, such as difficulty falling asleep, mid-sleep awakening, use of hypnotic medication, excessive daytime sleepiness, feeling tired on waking up in the morning, snoring, waking up too early, headaches on awakening, falling asleep during the day, and excessive movements during sleep. The answers are provided in Likert-type scales varying from 1 (never) to 7 . The total sum of scores provides an estimate of sleep quality, classified as: good sleep quality (10-24 points); mild sleep disorders (25-27 points); moderate sleep disorders (28-30 points); and severe sleep disorders (≥31 points)10. The study outcome variable (severe sleep disorders) was dichotomized using a cutoff of ≥31 points.Subjective sleep quality was assessed by the mini sleep questionnaire (MSQ), translated into Brazilian Portuguese11. A study of Brazilian undergraduate students reported the MSQ to be a good tool for assessing sleep disorders, with adequate reliability  and test-retest reliablity10.A study with 1,830 undergraduate students assessed the psychometric properties and reliability of the MSQ Italian version, and recommended it as a useful screening tool for insomnia and hypersomnia. Cronbach’s alpha was 0.77The following occupational characteristics were investigated: time worked as correctional officer, prison unitiy ; Closed Prison Unit, for prisoners in the closed prison regime; and the Pretrial Unit, for custody of pretrial inmates), working position, contact with prisoners, training for the current post, shift work, having another job, membership of a union or other professional association, witnessed prisoner escape, carries firearm on duty, has discharged firearm on duty, has been threatened by crime factions.The correctional officers were asked about nine stressful activities at their work: prisoner admission; opening prison gate; closing prison gate; visiting hours; cell search; prisoner search; prisoner counting; escorting prisoner during indoor activities; and escorting prisoner during outdoor activities. These questions were answered as 0 = No or 1 = Yes. A new ordinal variable was built, by grouping the number of stressful activities as; 0-1; 2-4; 5-7; and 8-9.12. Common mental disorders were evaluated by the self-reporting questionnaire (SRQ-20), applying a ≥5 cutoff point for men and ≥7 for women13.The attack or threat events against the correctional officer over the last 12 months were evaluated by three questions addressing violence perpetrated by prisoner; by relative, companion, or neighbor; or by the correctional officer’s chief or colleague, answered on a no/yes basis. A new variable was built to represent the total number of attack or threat events, coded as 0, 1, 2, and 3. Information was collected about age (23-59/60-72 years), sex , skin color (White/Non-White) civil status (married or stable partnership/other), having children (yes/no), schooling (higher education or graduatio/high school), weekly practice of physical activity (one or more days per week/none), regular leisure activities (yes/no), smoking . Alcoholism was detected by using CAGE questionnaire, applying a ≥2 positive answers cutoff point15. Variables were inserted in the Cox model by using the ENTER method. Following the initial selection, the four remaining independent variables as well as shift work variable were again included in the final Cox regression model, in order to calculate their respective prevalence ratios. Although arbitrarily defined as a benchmark, the adjusted PR>1.20 evaluates effect size, instead of statistical significance. According to Rothman (2014)16, epidemiological studies should focus on the effect size (the magnitude of the associations), instead of statistical testing.In bivariate analysis, prevalence ratio (PR) was calculated for severe sleep disorders according to the strata of independent variables. The variables for entry in the Cox regression model were then selected on the basis the magnitude of the association (PR >1.20), and according to theoretical plausibility and the epidemiological evidence in the literature. This evidence led to the inclusion of the shift work variable in the multivariable models. Shift work is associated with a high prevalence of sleep disorders17. In this case, the follow-up time should be set as 1 for all participants, as a strategy to obtain PR point estimates19. Further, Cox regression has the advantage to allow estimates of prevalence ratios instead of prevalence odds ratios17.Cox regression is generally used to analyze longitudinal studies in which the response is the number of episodes of an event over a given time. However, Cox regression is an adequate technique to analyze cross-sectional studies21.Since it was a census study, sampling procedures techniques were not used. Using statistical inference tests or calculating confidence intervals were therefore not appropriateStatistical Package of Social Science) version 22.0.Data was processed and analyzed using SPSS  among the 374 correctional officers was 55.3%. The prevalence of moderate sleep disorders, mild sleep disorders, and good sleep were 11.0%, 10.7%, and 23.0%, respectively.Bivariate analysis revealed that prevalence of severe sleep disorders was strongly (PR>1.20) higher among correctional officers who belonged to the younger age group (23 to 59 years), declared their skin color to be non-White, did not practice physical activities, did not practice regular leisure activities, were smokers, present common mental disorders , work inThe prevalence of severe sleep disorders was >1.20 and rose in proportion  to the number of attacks or threats against the correctional officer over the last 12 months and among those who were threatened by criminal factions .The prevalence of severe sleep disorders was strongly (PR>1.20) associated with the stressful acitivies visiting hours, cell search, prisoner counting, and escorting prisoners during indoors activities. The prevalence of severe sleep disorders was >1.20 and increased  according to the number of stressful activities at work  .All 11 variables presenting PR>1.20 and the variable shift work were selected to compose a model analyzed by Cox regression. Four variables were still strongly (PR>1.20) associated with the dependent variable, after this first run. In the final model, the prevalence ratios adjusted by the multivariate model revealed that severe sleep disorders were strongly associated (PR≥1.20) with number of stressful activities at work , number of attack and threat events against the correctional officers over the last 12 months , common mental disorders (RP=2.24), and non-White skin color (RP =1.37). Shift work was not strongly associated with the outcome (RP=1.08) .The 27 individuals excluded from the study because did not provide valid answers to all questions of the study. These 27 correctional officers had lower prevalence of severe sleep disorders than the 374 individuals who had a complete set of information . These 27 individuals were similar to the 374 individuals effectively investigated in relation to the following characteristics: male , age group 23-59 years (88.9% versus 84.7%), non-White skin color (85.2% versus 93.0%), higher education/graduation schooling (66.7% versus 63.1%), and common mental disorders (27.5% versus 25.9).22.This study found a high prevalence of severe sleep disorders among correctional officers: 55.3%. This high prevalence justifies the use of prevalence ratio as the association measure and the Cox regression model in this study. The use of prevalence odds ratio obtained by the logistic regression model would overestimate the association measure23. Among lecturers from Feira de Santana State University, Brazil, the prevalence of poor sleep quality was quite high, 61.3%, using MSQ≥28 cutoff point24, but, nevertheless, was lower than that found in our study, using the same ≥28 cutoff point: 66.3%. A population-based study in the city of Campinas, Brazil, assessed the sleep quality of with 1,998 people aged 20 or above, posing the single question: “How do you evaluate the quality of your sleep?”. The answers were expressed as: excellent/very good, good, regular, bad, or very bad. The combined percentage of “bad” and “very bad” responses was 29.1% (95% CI: 26.5-31.7)25. Studies using other questionnaires to measure sleep disorders found lower prevalences: 41.8% in France1 and 44.8% for insomnia and 27.6% for sleep apnea in the USA5.To the best of our knowledge, there are no comparable studies about sleep disorders among Brazilian correctional officers. However, studies have measured the frequency of sleep disorders in other Brazilian populations. In a random sample of the general population from the city of Presidente Prudente, Brazil, the prevalence of sleep disorders was 46.7% (95% CI: 43.1-50.2), using an MSQ≥25 cutoff pointThe results of this study final model confirmed that the prevalence of severe sleep disorders was strongly associated with four factors: number of stressful activities at work, number of attack and threat events against the correctional officers over the last 12 months, common mental disorders, and non-White skin color.26. These situations of tension and violence can act as stressors in the correctional officers’ daily working lives, and worsen their sleep quality. In a qualitative research about work conditions and their impact on health, correctional officers reported that sickness was due to moments of tension experienced in the prison, causing fear, insecurity, and dissatisfaction27.This study found a positive gradient  in the adjusted prevalence ratios of severe sleep disorders linked to a higher number of attack or threat against correctional officers over the last 12 months increased. Further, higher prevalences of severe sleep disorders were strongly associated with the number of stressful activities at work. Work is considered a strong societal determinant of sleep quality28. Correctional officers’ close contact with members of criminal factions affects their health, especially their mental health, and contributes to poor sleep quality. Bivariate analysis revealed a 32% higher prevalence among correctional officers who had been attacked or threatened by faction members. Attacks and threats perpetrated by prisoners linked to criminal factions have certainly contributed to the variable “number of attack or threat events against the correctional officer over the last 12 months” which, for its part, was strongly associated with severe sleep disorders.Brazilian prisons face steady growth in the number of criminal factions and difficulties in controlling them inside prisons1. A study carried out in 1999, with a sample of 311 correctional officers from the State Penitentiary Complex of Salvador, using SRQ-20 with the 7/8 cutoff point, reported a 30.7% prevalence of common mental disorders, strongly associated to multiple adverse working conditions29. The SRQ-20 cutoff >7 used in the 1999 survey for both sexes has certainly underestimated the prevalence of common mental disorders. Furthermore, the proportion of female correctional officers in the institution has increased in the period 1999-2018 from 8.0% to 16.6%.Poor working conditions and specific features of their occupation may have contributed to the strong association (RP=2.43) between common mental disorders and severe sleep disorders found in this study. Correctional officers present a high prevalence of mental health problems30 than Afro-American and Latinos, and higher rates of long and short sleep32 than their Afro-American counterparts.The adjusted prevalence of severe sleep disorders was 37% higher among officers declaring their skin color to be non-White compared to the White. Adults from race/ethnicity White presented better sleep quality32.The adjusted prevalence of severe sleep disorders among correctional officers who worked shifts was only 15% higher than among those who did not. In this penitentiary complex, work schedules are organized in 24-hour shifts followed by a 72-hour rest. However, double shifts are frequent, mainly due to shift changes or substitutions between correctional officers. Shift work can be harmful to the sleep quality of correctional officers, particularly when associated with long working hours33, because of its possible association with severe sleep disorders. Due to its cross sectional design, this study has only limited capacity to establish causality. Except for skin color, all other independent variables that were found associated with severe sleep disorders could have had a reverse causality relationship with this dependent variable. Furthermore, sleep is hard to measure, because of its subjective nature34. Studies use several instruments to assess sleep and only a few of them have used the mini sleep questionnaire, limiting the comparison of results. The small number of studies about sleep quality among correctional officers also prevent comparison. Future studies, using more acurate methods to assess sleep, such as actigraphy and polysomnography, can throw new light on this issue.Selection bias is one notable study limitation, since only 83.7% of the eligible population was investigated. However, the 27 correctional officers excluded because of incomplete data presented characteristics similar to those found among the 374 individuals effectively investigated. Another limitation of this study was the lack of an obesity measureIn conclusion, this study found a high prevalence of severe sleep disorders among correctional officers, associated with stress and violence at work, common mental disorders, and skin color. These factors must be taken into account in future actions aiming to provide health care to these workers. Hopefully, stress and violence at work are possible to be modified. In order to improve correctional officers sleep quality, the prison complex management and the occupational health service personnel should consider improving the workplace environment and physical and psychosocial working conditions.


Only a few studies have performed comprehensive comparisons between hospitalized patients from different waves of COVID-19. Thus, we aimed to compare the clinical characteristics and laboratory data of patients admitted to the western part of Denmark during the first and second waves of COVID-19 in 2020. Furthermore, we aimed to identify risk factors for critical COVID-19 disease and to describe the available information on the sources of infection.We performed a retrospective study of medical records from 311 consecutive hospitalized patients, 157 patients from wave 1 and 154 patients from wave 2. The period from March 7 to June 30, 2020, was considered wave 1, and the period from July 1st to December 31, 2020, was considered wave 2. Data are presented as the total study population, as a comparison between waves 1 and 2, and as a comparison between patients with and without critical COVID-19 disease (nonsurvivors and patients admitted to the intensive care unit (ICU)).Patients admitted during the first COVID-19 wave experienced a more severe course of disease than patients admitted during wave 2. Admissions to the ICU and fatal disease were significantly higher among patients admitted during wave 1 compared to wave 2. The percentage of patients infected at hospital decreased in wave 2 compared to wave 1, whereas more patients were infected at home during wave 2. We found no significant differences in sociodemographics, lifestyle information, or laboratory data in the comparison of patients from waves 1 and 2. However, age, sex, smoking status, comorbidities, fever, and dyspnea were identified as risk factors for critical COVID-19 disease. Furthermore, we observed significantly increased levels of C-reactive protein and creatinine, and lower hemoglobin levels among patients with critical disease.At admission, patients were more severely ill during wave 1 than during wave 2, and the outcomes were worse during wave 1. We confirmed previously identified risk factors for critical COVID-19 disease. In addition, we found that most COVID-19 infections were acquired at home. Coronavirus disease 2019 (COVID-19) is a global pandemic with more than 236 million confirmed cases worldwide as of October 10, 2021 . The firThus, the primary aim of this study was to compare and identify differences in the demographic, clinical, and laboratory characteristics of patients hospitalized in the western part of Denmark during the first and second wave periods of COVID-19 in 2020. Furthermore, we aimed to identify risk factors for critical COVID-19 disease and describe the given information on the sources of infection 14 days prior to infection.This retrospective study included consecutive hospitalized patients regardless of the duration of hospitalization. The study was conducted at the Regional Hospital West Jutland (RHWJ).To be included in the study, patients tested positive at least once with a SARS-COV-2 polymerase chain reaction (PCR) result. All patients were either inhabitants or stayed in the geographical area served by the hospital at the time of hospitalization. Included patients were admitted from March 7 to December 31, 2020. None of the patients had received a vaccination for COVID-19 prior to admission.Electronic medical records from inpatients with a positive SARS-COV-2 PCR result were obtained and reviewed. In total, five trained reviewers participated in the review process of the medical records. All medical records were reviewed independently and cross-checked by a second reviewer.We obtained information on demographical data, lifestyle information, comorbidities, vital signs at admission, disease symptoms, treatments, initial laboratory data, and clinical outcomes from the medical records. Furthermore, the medical records were reviewed to obtain information on the sources of infection, e.g., (1) infection at home, (2) infection by a person outside home, (3) infection at hospital, (4) infection at an institution, or (5) infection by an unknown source.The initial laboratory data from the hospital presentation included C-reactive protein (CRP), lactate dehydrogenase, lymphocyte counts, leucocyte counts, thrombocyte counts, hemoglobin, alanine aminotransferase, bilirubin, alkaline phosphatase, creatinine, potassium, and sodium.We defined the two wave periods of the COVID-19 outbreak in Denmark in 2020 as follows: the first period from March 7 to June 30, 2020, and the second period from July 1st to December 31, 2020.long hospitalizations if the duration of the admission was eight days or longer. Comorbidity was defined as the presence of at least one underlying medical condition. A total of 13 comorbidities were included the study: Asthma, stroke or transient ischemic attack, coronary heart disease/ischemic heart disease, psychiatric disorder, diabetes mellitus, hypertension, chronic bronchitis and chronic obstructive pulmonary disease, cancer, rheumatoid arthritis and connective tissue diseases, neurological diseases, osteoarthritis, metabolic diseases, nephrological and urological diseases. Cancer was defined to include all types of cancer. Neurological diseases included epilepsy, sclerosis, neuralgias, and parkinson's disease. Metabolic diseases included hyperthyroidism and hypothyroidism. Nephrological and urological diseases included all diseases in the kidneys and the urinary tract. Initial laboratory data were defined as the first available laboratory test result at hospital presentation. Recorded symptoms  denote if the patient had experienced any of the symptoms at least once during their COVID-19 infection.Nonsurvivors and patients admitted to the intensive care unit (ICU) were classified as having critical disease. Fatal disease was defined as death during admission or death within 30 days after the diagnosis. The length of hospitalization was defined as the actual number of days admitted to the hospital. Hospital admissions were defined as Data were managed using electronic data capture tools (REDCap) hosted in the Central Denmark Region , 18.Data analyses were mainly descriptive. Continuous variables are presented as medians and interquartile ranges (IQRs). Categorical variables are presented as counts (N) and percentages. The Mann–Whitney U test (Wilcoxon rank-sum test) was used for comparisons between continuous variables, and the chi-squared test or Fisher´s exact test was used to compare differences in categorical variables. Missing data was not imputed. A p-value below 0.05 was considered significant. All analyses were performed using Stata 17.In total, 311 COVID-19 patients were admitted to the hospital. One hundred fifty-seven patients were admitted during the first wave and 154 were admitted during the second wave. The distribution of daily admitted patients from March 7 to December 31, 2020, is illustrated in Fig. Approximately 80% of all patients had at least one comorbidity, and more than half of all patients had multiple comorbidities. The most common comorbidity was hypertension. Further analyses showed that patients with at least one comorbidity were older than those with no comorbidity  versus 44 years (IQR: 31–57 years)).No differences in age, sex, smoking, and body mass index (BMI) were observed between the patients hospitalized in RHWJ in wave 1 compared to wave 2. However, we observed differences in the frequencies between the specific comorbidities, e.g., more patients with metabolic disease and cancer were observed during the first COVID-19 wave than during the second wave.The median age increased significantly among patients with critical COVID-19 disease. Furthermore, significantly more males and present or previous smokers were observed among patients with critical disease. Patients with critical disease were also more likely to suffer from one or more comorbidities.The vital signs at admission and initial laboratory tests are shown in detail in Table 9 IQR:0.69–1.41) was below the normal range (1.3–3.5 × 109/l).In the total study population, we observed elevated levels of inflammatory markers. The median levels of CRP (39 IQR:12.35–95) and lactate dehydrogenase (236 IQR:194–315) were above the normal ranges . Furthermore, the median lymphocyte count  versus 83 µmol/l (IQR: 76–124)).Details on treatment and outcomes, in addition to symptoms during infection are shown in Table The proportion of patients with critical disease during the second wave was smaller than during the first wave (5.84% vs. 28.66%). Only six patients were admitted to the ICU during the second wave compared to 25 patients during the first wave. Similarly, significantly more patients died during admission or within 30 days after their diagnosis during wave 1 than during wave 2. The median time from onset of disease symptoms to hospital admission and the median length of hospitalization were shorter during the second wave. Furthermore, the number of patients receiving mechanical ventilation and the median number of days with oxygen supplementation were significantly lower during the second wave. Significantly more patients experienced fever, dyspnea, and cough during wave 1 compared to wave 2 whereas fewer patients experienced nausea.Patients with critical disease were admitted faster and for a longer time than patients without critical disease. For patients with critical disease, the median time from onset of symptoms to admission was two days (IQR: 1–7), and the median length of hospitalization was 18 days (IQR: 9–27). Most patients with critical disease received oxygen supplementation and 44% underwent mechanical ventilation. Dyspnea and fever were also highly prevalent among patients with critical disease and present in more than 80% of the patients.Details on the sources of infection are presented in Table The sources of infection were known for approximately 40% of all patients in the present study. The sources of infection were known for 46% of the patients in wave 2 and 32% of the patients in wave 1. In general, most infections were acquired at home. We observed a difference in the sources of infection between waves 1 and 2. During the first wave approximately 10% were infected at the hospital compared to 1% during the second wave. In contrast, more patients were infected at home during the second wave.In the comparison of the clinical presentation of hospitalized patients admitted during the first and second waves of COVID-19 in the western part of Denmark, we found a milder course of disease during the second wave period from July to December 2020 compared to the first wave period from March to June 2020. Fewer patients experienced critical disease during wave 2. Furthermore, patients admitted during wave 2 were hospitalized and received oxygen supplementation for a shorter time than patients from wave 1. In addition, fewer patients received mechanical ventilation and experienced symptoms such as fever, cough, and dyspnea. Despite a milder course of disease, patients hospitalized in wave 2 were admitted significantly sooner after the onset of symptoms than those hospitalized in wave 1. Patients admitted during wave 2 were mostly infected with COVID-19 at home, and only a few were infected at the hospital. We found no significant differences in sociodemographics, lifestyle information, or laboratory data in the comparison of patients admitted during the first and second waves of COVID-19 in 2020.Recent studies have compared the characteristics of hospitalized patients from different waves of COVID-19 , 19–22. et al. reported a shorter period from disease onset to admission during the second wave, and Jalali et al. reported a decreased percentage of individuals admitted to the ICU during the second wave [In agreement with our study, studies from Spain, Japan, and Iran indicated a milder course of disease during the second wave period , 3, 20. ond wave .et al. also reported a higher CRP level among patients with a critical or fatal disease and a higher level of CRP during the first COVID-19 wave [Although not statistically significant, we observed a tendency toward higher CRP and creatinine levels among patients admitted in wave 1 than in wave 2. This finding is in line with higher CRP and creatinine levels among patients with a critical disease since more patients from wave 1 experienced critical disease. In comparison, Mollinedo-Gajate -19 wave . To our Likely explanations for a milder course of disease during the second wave compared to the first wave of COVID-19 are numerous. First, vulnerable and elderly persons were more likely to be exposed to the virus at the beginning of the pandemic compared to wave 2. Different restrictions, prohibitions, and orders were applied in Denmark from mid-March 2020 to control the spread of the disease and to protect vulnerable and elderly persons. Thus, we assume that a larger percentage of the population was at risk of critical disease during the first wave of COVID-19. Second, the initial treatment of COVID-19 was mostly symptomatic, however, as the clinical management was refined over time, this could possibly have improved the outcome for those hospitalized later during the pandemic. Refined clinical management could likewise have resulted in a reduced length of hospitalization in wave 2 compared to wave 1. Third, potential changes in SARS-CoV-2 genomic variations from wave 1 to wave 2 could have influenced the disease severity among patients, as SARS-CoV-2 genomic variations have been associated with the mortality rate of COVID-19 . FinallyInterestingly, patients were admitted sooner in wave 2 than in wave 1, increasing the likelihood of timely treatment. Potentially, this could have decreased the number of individuals experiencing critical disease.Most studies investigating risk factors for COVID-19 were conducted during the beginning of the pandemic , 24–26. In the beginning of the pandemic, the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was high in the service area of the RHWJ compared to the rest of Denmark . Data on2 and a population of approximately 286,000 inhabitants, our study population is representative of the most severely affected COVID-19 individuals in the western part of Denmark in 2020. The Danish healthcare system is universal, publicly funded, and based on the principles of free and equal access to healthcare, including tests, for all citizens. A key strength of this study was that all patients were included consecutively and followed from admission to discharge. Furthermore, all patients were included in the study before the Danish population was offered vaccination against COVID-19. Overall, these factors help eliminate selection bias.By inclusion of all hospitalized COVID-19 patients in a geographical area comprising 5000 kmThe present study has some limitations due to the study design and number of cases. We performed a single-center study, which affects the external validity. Furthermore, the retrospective study design affects the available data, especially the documentation of sources of infection. The present study did not include individual information on the pharmalogical treatment. In general COVID-19 patients at RHWJ were treated using thromboprophylaxis. During wave 2 the pharmacological treatment also comprised remdesivir, dexamethasone, and tocilizumab. Thus patient outcomes may have been affected by differences in the pharmacological treatment. Wave periods of the pandemic have evolved at different times on continents/countries during the pandemic . In the Our study is a new comprehensive investigation comparing demographical, clinical, and laboratory characteristics in addition to sources of infection between two COVID-19 waves in 2020. The results bring new knowledge to the field and confirm and qualify previous findings. In conclusion, the course of disease was worse among patients hospitalized in wave 1 than in wave 2. The length of hospitalization was significantly longer in wave 1 and more patients experienced critical disease. However, we observed no significant differences in baseline or laboratory characteristics among patients admitted in wave 1 compared to wave 2. Presumably, the health conditions of patients upon admission and treatment during admission were better in wave 2 compared to wave 1. In general, a large percentage of patients were infected with COVID-19 at home, and most hospital-acquired COVID-19 infections were observed during the first wave. In agreement with other studies including patients from wave 1, we identified higher age, male sex, smoking, comorbidities, fever and dyspnea as risk factors for critical COVID-19 disease. Furthermore, we observed significantly increased levels of CRP and creatinine, and lower hemoglobin levels among patients with critical disease.Further studies investigating the laboratory characteristics of COVID-19 patients and sources of infection are warranted. In addition, future studies comparing risk factors for critical diasease in different waves of COVID-19 could be interesting.


Kearns Sayre Syndrome (KSS) is a rare mitochondrial disease characterized by a primary dysfunction of the mitochondrial respiratory chain. Cardiac involvement is a poor prognostic factor of KSS. Pregnancy and delivery in a KSS patient with cardiac involvement is uncommon, and strategies for the supervision and management of this group remain unclear. Herein, we report and discuss pregnancy and delivery complicated with acute cardiopulmonary failure in a woman with KSS. Mitochondrial disease (MD) refers to a clinically heterogeneous group of disorders that arise from dysfunction of the mitochondrial respiratory chain due to a genetic abnormality in nuclear or mitochondrial DNA (mtDNA). The conservative estimate for the prevalence of MD is 11.5:100,000 . Kearns A 35-year-old woman developed bilateral ptosis and PEO at age 14. Progressive muscle weakness and fatigue were noted from age 16. The diagnosis of KSS was confirmed at age 29 by the above symptoms and subsequent laboratory findings, and the process is summarized in including the pancreas, thyroid, parathyroid, and ovary, demonstrated no associated endocrine dysfunction. Her medications included multivitamins, idebenone, and coenzyme Q10. Her condition showed no serious progression since the beginning of supportive therapy. She had no new occurrence of other symptoms, such as dysphagia, hearing loss, syncope, or dyspnoea.The patient had a first and natural pregnancy at age 35. A systematic cardiac assessment was performed 2 months before her pregnancy, while an electrocardiogram (ECG) showed a preexisting complete right bundle branch block (RBBB) and left anterior fascicular block (LAFB) . Echocar2), bilateral palpebral ptosis, external ophthalmoplegia, and proximal muscle weakness. Tendon reflexes of limbs had disappeared. The oedema of the lower extremity was up to the level of the knee. Laboratory results showed normal levels of hemoglobin, brain natriuretic peptide (BNP), D-dimer, and lactic acid. Arterial blood gas analysis showed no obvious hypoxemia, pH, bicarbonate, and PCO2 were within normal limits. Cardiac assessment presented no obvious ECG changes compared with the previous results. At the same time, a reduced LVEF (50%) and mild dilation of the left ventricle were found by echocardiography. She was in NYHA class III. After a comprehensive evaluation of her condition by a multidisciplinary team, a cesarean section (CS) under combined spinal-epidural anesthesia was performed at 38+6 weeks. A 3.65 kg male infant was delivered with Apgar scores of 10-10 at 1 and 5 minutes after delivery. The surgery was uneventful, and the intraoperative blood loss was ~200 ml.The patient was referred to our hospital at 38+3 weeks with complaints of lower extremity oedema and progressive dyspnoea after routine activity. Physical examination revealed a good nutritional status  was 56 mmHg, and carbon dioxide pressure (PaCO2) was 87 mmHg. The BNP value reached 1234 pg/ml. ECG showed a new first-degree atrioventricular (AV) block with preexisting RBBB and LAFB. Echocardiography showed decreasing systolic function of the left ventricle (LVEF was 30%)   and pulmOver more than 5 years of outpatient follow-up, the patient was in a stable condition except for a slight progression of muscle weakness and ophthalmoplegia. The increased glucose level gradually returned to normal within 2 months after delivery and without recurrence. Compared with the previous results at discharge, echocardiography performed 6 months before the paper was submitted showed no remarkable changes except for a slightly reduced LVEF (48%). Her son is now more than 5 years old, and regular physical examination showed normal growth and development.de novo mutational events occurring either in an oocyte or in the early stage of embryonic development. Thus, the majority of cases with KSS are sporadic, while only 4% of KSS cases can acquire this genetic abnormality by maternal inheritance (KSS is a rare form of MD and is predominantly caused by mtDNA rearrangement. The pathogenic mtDNA changes mainly presented a 4.9 kb “common deletion” range from nucleotide positions 8,470 to 13,446, including several important functional genes, including MT-ATP8, MT-ATP6, MT-CO3, MT-ND3, MT-ND4 L, MT-ND4, and MT-ND5(Cardiac involvement, as a major prognostic factor of KSS, can take many forms, namely, cardiac conduction abnormalities and cardiomyopathy. As a part of the diagnostic criteria, cardiac conduction disorders occur in 84% of KSS patients . The mosSeveral retrospective studies of pregnancies in MD found that pregnancies are well tolerated, for the most part, and complications are very similar to those in the general population except for a higher incidence of early pregnancy loss, gestational diabetes mellitus, intrauterine growth retardation, and postpartum hemorrhage , 15. HowIn conclusion, to assess the pregnancy-related risk in female patients with KSS who are pregnant or wish to become pregnant, a detailed imaging assessment should be performed to identify the presence and degree of cardiac involvement. Further studies are required in KSS with cardiac involvement to explore optimal methods to predict the potential risk of adverse cardiac prognosis during pregnancy.The patient has no doubts about our treatment. She hopes this report will incentivize more investigations to elucidate the pathophysiological changes of KSS during the course of pregnancy and delivery, especially among cases with cardiac involvement. She thinks this rare but high-risk pregnancy group should get more attention.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


IntroductionOsteoarthritis (OA) of the knee is a common degenerative disease, relatively more prevalent among middle-aged people. It is one of the major reasons for walking-related disability. Recently, early knee OA has been seen as an imperative concern in many younger patients who struggle with the disabling effect of pain and management is extremely speckled. Degenerative changes such as loss of cartilage, subchondral bone changes, synovial inflammation, and meniscal degeneration are seen in OA. Symptoms are relieved by therapeutic strategies such as lifestyle behaviour changes, exercise, and oral and injectable medications. Intra-articular delivery of drugs acts as a direct effect on the target tissue, which grossly reduces side effects and is commonly preferred nowadays. The current study is a comparative assessment of the functional outcomes associated with various treatment modalities in osteoarthritis of the knee, i.e., arthroscopic debridement, arthroscopic debridement with microfracture, platelet-rich plasma (PRP) injection, and hyaluronic acid.MethodsA retrospective observational hospital-based study was conducted among 139 cases of osteoarthritis. Patients aged between 40-60 years with diagnosed Kellgren- Lawrence grade 1 and 2 OA knee, who underwent arthroscopic debridement, arthroscopic debridement with microfracture, PRP injection, or hyaluronic acid in our institute were included.Results2. At the time of diagnosis of OA, the mean visual analogue scale for pain (VAS) and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were 7.26 +0.7 and 55.30 + 2.21 respectively. Out of the total, 88 (63.3%) were females and 51 (36.7%) were males. Right-sided OA knee was seen in the majority of study participants. Of the total, 93 (66.9%) patients had grade 2 and only 46 (33.1%) had grade 1 OA. A statistically significant difference was found between the mean VAS and WOMAC score at the time of diagnosis, three weeks, three months, as well as at six months of therapy. In the hyaluronic acid treatment, no significant difference was found in mean VAS and WOMAC scores.The mean age was 52.83 + 6.8 years. The mean BMI was 27.45 + 1.6 kg/mConclusionVarious treatments are available for early-diagnosed OA. According to the findings of this study, overall improvement was seen in VAS and WOMAC scores at the follow-up after six months of specific treatment. In a period over six months, arthroscopic debridement with micro-fracture was more effective and safe when compared with other modalities of treatment for early OA knee. Also, injection of PRP was superior to other methods for VAS pain reduction, and WOMAC-pain and WOMAC-stiffness scores improved at one month. Osteoarthritis (OA) of the knee is a common degenerative disease, relatively more prevalent among middle-aged people. It is one of the major reasons for walking-related disability. Recently, early knee OA (Kellgren-Lawrence (KL) grade 1 and 2) is becoming an imperative concern in many younger patients who struggle with the disabling effect of pain, and management is extremely speckled. Degenerative changes such as loss of cartilage, subchondral bone changes, synovial inflammation, and meniscal degeneration are seen in OA. These changes are early identified with the help of MRI and ultrasound as well as extensive use of arthroscopy in which there is direct visualization of the whole area of the affected joint and also of the cartilage, menisci, synovial membrane, ligaments, and fat pad [Globally, it is the leading cause of chronic disability in patients older than 70 years and has been deputed as a ‘prior disease’ by the WHO. OA is considered one of the most disabling diseases in developing countries like India . AccordiEven though symptomatic knee OA differs greatly in affected individuals, ruling out early knee OA is critical for evading or delaying the progression to a severe stage of the disease. When patients present with early OA at a younger age, it becomes a serious challenge for orthopaedics consultants, because of a combination of high functional and motility demands and restricted management options .In the management of OA, symptoms are relieved by therapeutic strategies such as lifestyle behaviour changes, exercise, and oral and injectable medications . Oral meIntra-articular injectable drugs are most commonly used nowadays because of their direct effect on the target tissues and reduced adverse effects as it's delivered directly. The majority of injectable medications are corticosteroids (CS), hyaluronic acid (HA), polynucleotides, oxygen-ozone therapy, platelet-rich plasma (PRP), and mesenchymal stem cells (MSCs). CS and HA are mentioned as the best treatments in a few studies for early OA knee .Newer drugs like PRP and MSCs have limited literature regarding their safety and efficacy. These medications play a beneficial role in reducing local inflammation and promoting cartilage and synovial anabolism by releasing a series of growth factors and immune-modulatory molecules . PRP, whThis retrospective study included 139 patients who were diagnosed with OA knee and underwent surgical treatment such as arthroscopic debridement (n=38) and arthroscopic debridement with microfracture (n=32) and conservative management such as PEP injection (n=39) and HA (n=30), who visited the Department of Orthopaedics in RL Jalappa Hospital, Kolar, Karnataka, India, from August 2018 to August 2022. Data collection was performed after obtaining ethical approval from the Institutional Ethics Committee of Sri Devaraj Urs Medical College, Kolar, Karnataka, India . Patients aged 40-60 years with diagnosed KL grade 1 and 2 OA knee who underwent arthroscopic debridement, arthroscopic debridement with microfracture, PRP injection, or HA in our institute were included. The exclusion criteria were patients with previous lower extremity surgery, previous knee trauma, poor diabetic control with glycated haemoglobin (HBA1c) of more than 8%, rheumatoid arthritis, bilateral OA knee, gout, and peripheral neuropathy.Patient data were collected from the clinical follow-up notes. The following data were taken from clinical notes: general physical examination, knee joint examination , grade of OA of the knee , routine investigation, treatment modalities (arthroscopic debridement/arthroscopic debridement with microfracture/PRP injection/HA), complications, and outcomes based on a scoring system  and Western Ontario and McMaster Universities Arthritis Index (WOMAC)).Data were entered into an Microsoft Excel sheet  and analyzed using IBM SPSS Statistics for Windows, Version 24.0 . Continuous variables were summarized using mean with SD. Categorical variables such as sex and KL grading were summarised using frequency and percentages. Functional outcomes measured in terms of VAS and WOMAC scores for pain, stiffness, and physical function were described using mean and SD. A comparison of outcomes between the four study groups  was done by using one-way ANOVA test. p-value less than 0.05 was considered statistically significantA total of 139 patients were included in the study, of which 38 underwent arthroscopic debridement, 32 underwent arthroscopic debridement with microfracture, 39 were treated with PEP injection, and 30 were treated with HA. Of the 139 patients, only 69 had a history of comorbidity; 39 (56.5%) had a history of diabetes and 30 (43.4%) had a history of hypertension  were females and 51 (36.7%) were males in the study, while in a study conducted by Scher et al. [In the present study, the mean age was 52.83 + 6.8 years. Similar age group patients were involved in the study conducted by Li et al.  and Kon r et al.  and Sihvr et al. , more feIn our study, the majority of study participants were affected on the right side of the knee joint. In total, 93 (66.9%) patients had grade 2 and only 46 (33.1%) had grade 1 OA. Similar findings were seen in studies done by Di Matteo et al.  and WangStatistically significant difference was found in this study between the mean VAS and mean WOMAC scores at the time of diagnosis, three weeks, three months, as well as at six months, except in HA treatment, where no significant difference was found between mean VAS and WOMAC scores. Similar findings were seen in the studies by Beaufils et al. , GuenounIn a study conducted by Sun et al., mean VAS scores were improved by 21.9 mm, 25.8 mm, and 20.4 mm from baseline at the one, three, and six-month follow-ups in the only on-type injection group, whereas the VAS scores improved by 18.1 mm, 28.1 mm, and 31.8 mm from baseline in the combined-injection group . The betThe study of Szwedowski et al. stated that the mechanism of actions in the joint to optimize and standardize PRP formulations, identify the most suitable biomarkers for assessing treatment efficacy, and reveal the underlying mechanisms are the major challenges in knee OA treatment with PRP intra-articular injections that are involved in OA pathophysiology . Also, dEverts et al. conducted a study in which the full potential of PRP technology, the concept of individualized treatment protocols based on bioformulation options, and platelet dosing, angiogenesis, and antimicrobial and painkilling effects of PRP relevant to orthopaedic surgery have been addressed . In the In a study by Bowman et al., HA injection provided good pain relief and functional outcomes and was considered the best conservative line for hip OA . A randoIn the study by Katz et al., they state that the popularity of arthroscopic knee surgery rose quickly because of advanced technologies . Also, tThe current study has certain limitations. The study is retrospective, with a low sample size and shorter follow-up, and only the records that were available were used. Another limitation of this study was that the influence of systemic diseases such as diabetes and hypertension on degenerative conditions of joints was not accounted for.Various treatments are available for early diagnosed OA. In this study, overall improvement was seen in VAS and WOMAC scores at the follow-up after six months of specific treatment. In the period over six months, when compared with other modalities of treatment for early OA knee, arthroscopic debridement with microfracture was found to be more effective and safe. Also, injection of PRP was superior to other methods for VAS pain reduction, and WOMAC-pain and WOMAC-stiffness scores improved at one month.


Vaccination is the most effective intervention to prevent influenza. Adults at risk of complications are among the targets of the vaccination campaigns and can be vaccinated with different types of quadrivalent influenza vaccines (QIVs). In the light of assessing the relative immunogenicity and efficacy of different QIVs, a systematic review was performed. Randomized controlled trials conducted in adults aged 18–64 years until 30 March 2021 were searched through three databases . Twenty-four RCTs were eventually included. After data extraction, a network meta-analysis was not applicable due to the lack of common comparators. However, in the presence of at least two studies, single meta-analyses were performed to evaluate immunogenicity and efficacy; on the contrary, data from single studies were considered. Seroconversion rate for H1N1 was higher for standard QIVs, while for the remaining strains it was higher for low-dose adjuvanted QIVs. For seroprotection rate, the recombinant vaccine recorded the highest values for H3N2, while for the other strains, the cell-based QIVs achieved better results. In general, standard and cell-based QIVs showed an overall good immunogenicity profile. Nevertheless, as a relative comparative analysis was not possible, further research would be deserved. Influenza is a major cause of disease burden globally . WorldwiTwo influenza A subtypes (A/H1N1 and A/H3N2), and two antigenically and genetically distinct B lineages (B/Victoria and B/Yamagata) are the current seasonal influenza strains circulating since 1985. Both influenza A subtypes and both B lineages co-circulate, and their frequency distribution varies widely by season and geographic region .Influenza vaccination is the most effective intervention available to prevent influenza infection and its complications and represents a major public health initiative .The Advisory Committee on Immunization Practices (ACIP) recommends influenza vaccination to all people aged 6 months and older, without any contraindications .As influenza viruses rapidly mutate, and the prophylactic effects of vaccination wane over time, vaccine formulations are updated each year in compliance with the World Health Organization (WHO) and Committee for Medicinal Products for Human Use (CHMP) recommendations (in the EU) ,5.Up to 2012, influenza vaccines have been produced to protect against three different seasonal influenza viruses, namely A/H3N2, pandemic A/H1N1, and one out of the two influenza B lineages .The first quadrivalent influenza vaccines (QIVs) were licensed in the US in 2012 ,8. CurreEven if it is challenging to compare the immunogenicity and efficacy of different types of influenza vaccines , there aTogether with children aged 6 months–5 years, pregnant women, and the elderly, the adult population also represents a target group of influenza vaccination [In adulthood, inactivated QIVs have already been compared with inactivated trivalent influenza vaccines (TIVs) with respect to immunogenicity and safety . NeverthThe systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses 2020 (PRISMA 2020) guidelines  and regiA comprehensive literature search was carried out from databases’ inception up to 30th March 2021. Medline, Scopus and Cochrane Central Register of Controlled Trials databases were used to identify all the original articles investigating the immunogenicity or the efficacy of any QIV in people aged from 18 to 64 years. The medical subject headings (MeSH) and key words used for the search are reported in the Evaluated any QIV compared to placebo or TIV or another QIV in adults aged 18–64 years;Adopted a randomized controlled trial (RCT) study design that compared two or more groups, one of which receiving any QIV as intervention;Issued results on immunogenicity, in terms of seroconversion (SCR) or seroprotection rate (SPR), and efficacy, in terms of laboratory-confirmed influenza.Two authors  screened the articles on the basis of titles and abstracts first, using Rayyan. Any double publication of a study was recorded and thereafter removed. Full texts of potential eligible papers were then obtained and checked for final inclusion according to the inclusion and exclusion criteria. Articles were included if they met the following criteria:The SCR was defined as the percentage of participants with either a pre-vaccination HI titer <10 and a post-vaccination HI titer ≥40, or a pre-vaccination HI titer ≥10 and a 4-fold increase in hemagglutination inhibition (HI) antibodies titer after vaccination. The SPR was defined as the percentage of participants with a HI titer ≥40. If the same study was reported in several publications, we selected the most recent publication. Reviews and meta-analyses were excluded. Disagreements were resolved by discussion or in consultation with a third author (CdW or MC).For each included study, two authors  independently carried out data extraction and quality assessment. From each included study, the following information was extracted: first author’s last name, year of publication, trial status, country, study population, population characteristics , participants in the experimental and control arms (number and characteristics), type of intervention, type of control, study endpoints with definition, and results for each endpoint stratified by influenza strains . Data on immunogenicity and efficacy, referring only to adult populations, were extracted from per protocol populations. For studies with missing or incomplete information, authors were contacted. If attempts to contact authors were not successful, such studies were excluded from the quantitative analyses. If raw data were not available, they were calculated from the percentages reported in the study.The study quality was assessed through the Cochrane Risk of Bias Tool (RoB-Tool 2)  by two aThe NMA was carried out using the Markov Chain Monte Carlo engine WinBUGS free software if the assumption of transitivity was satisfied . In the Results were reported as percentage with 95% confidence intervals (95% CI); the width and potential overlaps of 95%CI were considered to elaborate on the comparisons among QIVs.2) method [2 was <25%, and the fixed-effect model was then applied. In case of moderate (25–50%) and high heterogeneity (>50%), the random-effect model was used.Meta-analyses were performed using StatsDirect statistics software version 3, and a fixed- or random-effect model was used to pool data based on the assessment of heterogeneity. Heterogeneity was measured using Cochran-Q test and inconsistency index (I) method ,20. An i) method . Low hetFrom the literature search through Medline (n = 518), Scopus (n = 1090) and Cochrane (n = 757) databases, and after removing duplicates n = 930), we identified 1435 records for title and abstract screening . Among t, we idenAmongst the included studies, all RCTs have been completed. Eleven studies 45.8%) were published between 2011 and 2016 ,30,31,32.8% were As far as the intervention was concerned, 14 studies (58.3%) assessed the standard-dose egg-based QIVs ,41,43,44The control arm received the analogous TIV except for two studies on recombinant QIVs that compared it with the standard-dose egg-based QIVs ,35, and All the studies evaluated the SCR. The serological outcome was determined by HI assay at 21–28 days after vaccination. The SPR was evaluated in most studies, excluding Dunkle et al.   and reported by only two studies ,45. The Nineteen studies (79.2%) had a low risk of bias ,41,43,45The assumption of transitivity was not satisfied and the NMA was not applicable.As far as the meta-analysis of immunogenicity and efficacy endpoint was concerned, 14 studies on the standard-dose egg-based QIV, and 2 on the cell-based QIV were considered for both SCR and SPR. For the latter, two studies on the live attenuated QIV were also considered for meta-analysis. For other QIVs, data extracted from single studies were reported . The comThe SCR for strains A/H1N1 ranged from 5% for live attenuated QIVs to 65% for standard-dose egg-based QIVs, whereas values for A/H3N2 ranged from 5% for live attenuated QIVs to 66% for low-dose adjuvanted QIVs; for B/Yamagata strain, SCR ranged from 9% for live attenuated QIVs to 79% for low-dose adjuvanted QIVs; eventually, for B/Victoria strain, SCR ranged from 10% for live attenuated QIVs to 65% for low-dose adjuvanted QIVs. Looking at the 95%CI, it can be observed that standard-dose egg-based, low-dose adjuvanted, cell-based, recombinant and intradermal QIVs showed similar SCRs with respect to both A strains, apart from cell-based QIVs with respect to H3N2 that showed a lower immunogenicity. With respect to B lineages, results are less conclusive, but it appears that overall low dose adjuvanted QIVs showed a better profile with respect to B Yamagata.Regarding SPR, values ranged from 25% to 98% for A/H1N1, respectively, for live attenuated and cell-based QIVs, and from 26% to 100% for A/H3N2, respectively, for live attenuated and recombinant QIVs. As for B lineage, the lowest values of SPR were observed for recombinant QIV and plant-derived QIV, namely 68% for B/Yamagata and 41% for B/Victoria. The highest values were attained by the cell-based QIVs (99% for B/Yamagata and 98% for B/Victoria). Looking at the 95%CIs, cell-based and recombinant QIVs showed similar SPR with respect to A/H1N1. Low-dose adjuvanted QIVs added to them regarding A/H3N2. With respect to B lineages, low-dose adjuvanted and cell-based QIVs showed similar results. Additionally, the standard-dose egg-based QIVs showed similar results as compared to them with respect to B/Yamagata.With respect to laboratory-confirmed influenza, for plant-derived QIVs, the attack rate in the vaccine group was 4.5% (215/4812), and in the placebo group it was 7.3% (251/4812), with an absolute vaccine efficacy of 38.8% (95%CI 17.9–48.7) to prevent influenza caused by any strain and of 35.1% (95% CI 17.9–48.7) to prevent influenza caused by vaccine-matched strain. Regarding the recombinant QIV, in the 50–64-year-old subgroup, the attack rate was 1.7% for the recombinant QIV group, and 2.9% for the standard QIV control group, leading to a relative vaccine efficacy of 42% (95% CI 15–61).Influenza continues to be a major public health problem worldwide, and current influenza vaccines remain a valuable public health tool to counter it.In this regard, the CDC estimated that influenza vaccination averted 60,500 deaths in the United States between the 2010–2011 and 2019–2020 seasons .In Europe, it is estimated that seasonal influenza vaccination prevents an annual average of 1.6–2.1 million cases of influenza, 45,300 to 65,600 hospitalizations, and 25,200 to 37,200 deaths .QIVs have currently replaced TIVs in several countries, but national immunization advisory technical groups do not generally make specific recommendations for the preferential use of one over other. Nevertheless, the assessment of their relative immunogenicity and efficacy could be useful to inform decisions.Our systematic review and meta-analysis collated together immunogenicity and efficacy data of different QIVs. The analysis of data issued by included RCTs basically showed that QIVs have different immunogenicity. In particular, differences can be observed among QIVs in terms of SCR and SPR against the same vaccine strain, but also within the same QIV, with respect to different endpoints and vaccine strains.In general, live attenuated QIVs did not show good immunogenicity, whereas standard-dose egg-based QIVs showed better SCR, and cell-based QIVs showed better SPR for all four strains. In addition, the recombinant QIV induced high SPR for A/H3N2. Actually, the development of vaccines based on recombinant protein and viruses grown on cell lines has been pursued to overcome the problem of mismatch between vaccine and circulating strains, which mostly regards H3N2 strains  and is dIt is known that SCR and SPR are considered by regulatory agencies to decide upon market authorization of influenza vaccines. In fact, the relationship between HI antibody titer and clinical protection has been well-established. In healthy adults, a serum HI titer ≥40 is associated with a >50% reduction in influenza infection or disease and is considered as a surrogate correlate of protection ,50. ThisAccording to the results of our systematic review, and considering that an HI titer ≥40 is considered the best available parameter for predicting protection from influenza infection, it can be said that the cell-based QIVs showed the best immunogenicity profile even though other QIVs, with the exception of the live attenuated, also achieved high SPR with some differences across strains. However, considerations should be given to the criticalities of the evaluation of immunogenicity, such as the low sensitivity to B strains and the high degree of interlaboratory variability . FurtherAs a matter of fact, since 2017, new CHMP guidelines recommended the measurement of neutralizing antibodies in addition to the HI titer and encouraged the assessment of broader immune responses through anti-neuraminidase antibodies, antibody kinetics, and cell-mediated immunity . This isBeyond the assessment of immunogenicity, efficacy and effectiveness data on laboratory-confirmed influenza and influenza-related clinical endpoints could further provide evidence for the relative comparison of QIVs. In this regard, a recent retrospective study assessed the relative effectiveness of cell-based QIVs, compared to the standard egg-based QIVs, among people aged 4–64 years in the United States during the 2019–2020 influenza season. Results showed that cell-based QIVs were significantly more effective than standard-dose egg-based QIVs in preventing influenza-related and respiratory-related hospitalizations/emergency room visits .In discussing the results of our systematic review, several limitations should be taken in consideration. The most important is represented by the potential heterogeneity among studies due to different influenza seasons and different participants’ history before vaccination. Another relevant aspect is that all the included studies were conducted in the Northern Hemisphere, and this might limit the generalizability of results. Furthermore, even though HI antibody responses were commonly assessed at 21 days post-vaccination, in a few studies, they were assessed at 28–30 days post-vaccination.Among the strengths of our systematic review, the following could be included: the search was performed on the most relevant databases, and the selection of studies and data extraction was performed by taking appropriate measures to prevent potential errors. Therefore, selection bias can be ruled out. Furthermore, included studies were mostly at a low risk of bias, and this enables us to consider their results robust.To the best of our knowledge, this is the first study that collates immunogenicity data of the different QIVs that are either in use or under study for the immunization of the adult population. Although a relative comparison among QIVs was not possible, the assessment of SCR and SPR and their 95%CI provides an overview of their respective potentiality in adulthood.


Cerebral palsy (CP) in children constitutes a set of movement and body posture disorders caused by brain injury, which in turn is associated with a series of intestinal, respiratory, and malnutrition conditions. Twenty-four children were selected and included for the present study and subdivided into two groups: (1) children who included modern kefir (containing 12 probiotic species) in their diet; and (2) control group (not including kefir in their diet). The group supplemented with modern kefir received a beverage with multi probiotic species and the control group received commercial yogurt  for 7 weeks. Anthropometric variables, resting energy expenditure, presence, and diagnosis of functional digestive disorders (FDD), frequency of respiratory problems, presence of elevated C-reactive protein, differential count of leukocytes were evaluated. A significant increase in weight and height was found in the kefir group at the final time point. In addition, kefir intake promoted a significant reduction in functional constipation and stool hardness and increased the absolute value of blood lymphocytes. Since the fermented milk beverage modern kefir improves constipation, which is the most important FDD in children with CP and the nutritional and immune status, it could be considered an important strategy to improve health in these children. Cerebral palsy (CP) is a posture and movement disorder that results from damage to the immature brain or abnormal brain development. According to a recent report from the Center for Disease Control and Prevention (CDC) , it is eThe CP is associated with various conditions such as malnutrition ,5, alterDifferent symptomatic manifestations of gastrointestinal disorders are present in children with CP. Besides, laboratory studies have confirmed that those children show different grades of inflammation, characterized by leukocytosis (an excess of leukocytes in the blood), elevated erythrocyte sedimentation rate, high blood levels of C-reactive protein (CRP) (a marker of an acute phase of inflammation), hypoalbuminemia, and anemia  ,14.In a study by Colson et al.  an incidMalnutrition is common in CP and its prevalence is more common in spastic CP . This colive microorganisms that, when administered in adequate amounts, confer health benefits to the host” [Probiotics are “he host” . Probiothe host” . Clinicahe host” ,21,22. The host” ,24,25.Bifidobacterium, Lactococcus, Leuconostoc, and Lactobacillus, as well as yeasts from Saccharomyces, containing an average range of up to 50 probiotic species [Bifidobacterium, Lactobacillus, and Streptococcus, but without yeasts [8 colony-forming unit (CFU) of each probiotic species during the fermentation process [Traditional kefir, also called milk kefir, is based on the fermentation of milk by kefir grains and includes several microorganisms. It is basically composed of a large variety of probiotic microorganisms, mainly bacteria from genera  species ,27,28. A species ,30,31. At yeasts ,33,34. It yeasts . Both trThe modern kefir of the Sello Rojo brand (Mexico), is a fermented dairy drink from the inoculation of 14 probiotic species isolated from traditional kefir . Based oad libitum) due to some comorbidities were included; however, those whose parents did not agree to participate or were on an antibiotic treatment were eliminated. Those subjects whose parents decided to withdraw from the study or did not meet the scheduled evaluation dates were eliminated. The sample size was calculated using the Lachenbruch formula for the calculation of the sample of “Difference of two proportions” with a confidence level of 90% and a power of 80%, with a 30% adjustment for losses using the free Win Epi calculator. A simple random probabilistic sampling (randomized) was applied, using the STATS 2.0 software. The “Random Number Generator” subprogram was used to automatically generate patient numbers. Participants were randomly assigned to control (n = 12) or model kefir (n = 12) groups. A double-blind randomized clinical trial was conducted on 24 children between 4 and 8 years of age with moderate severe spastic CP from the Rehabilitation Center Telethon (CRIT) in Aguascalientes, Mexico, who attended in the 2020–2021 period . ChildreStreptococcus thermophilus, and Lactobacillus bulgaricus. In addition, acesulfame-K (5 mg/100 mL) was included as sweetener. Nutritional composition of modern kefir was: 5.9 g of protein, 0.9 g of fat, 220 mg of calcium, 10.8 g of carbohydrates, 104 mg of sodium and 0.6 g of lactase per 240 mL . The 12 probiotic species contained in modern kefirwere: (1) Bifidobacterium infantis, (2) Bifidobacterium lactis, (3) Lactobacillus acidophilus, (4) Lactobacillus delbrueckii spp. lactis, (5) Lactobacillus fermentum, (6) Lactobacillus paracasei, (7) Lactobacillus rhamnosus, (8) Lactococcus lactis spp. cremoris, (9) Lactococcus lactis spp. lactis, (10) Lactococcus lactis spp. lactis biovar. diacetylactis, (11) Leuconostoc mesenteroides, (12) Leuconostoc pseudomesenteroides. Sucralose (7.2 mg/100 g) was included as a sweetener. Participant of both groups were administered orally 250 mL of the corresponding beverage per day.Commercial yogurt  was administered to the control group (yogurt group) and modern kefir  to the experimental group (kefir group) for 49 days (7 weeks). The different evaluations were carried out at time zero and at week (W) number 7 of the treatment. Nutritional composition of the commercial yogurt was: 5.9 g of protein, 0.8 g of fat, 210 mg of calcium, 10.8 g of carbohydrates and 89 mg of sodium per 240 mL . It also contained two probiotic species: At the end of the study, a survey on the perception of effects and satisfaction of the product was applied to parents or guardians of children and was validated through a concordance test (test retest). A Likert scale survey was used to obtain responses such as: 1, particularly good; 2, good; 3, regular; 4, bad; 5, particularly bad.Height was obtained under the Stevenson et al.  segmentaResting energy expenditure (REE) was measured through the indirect calorimetry technique with a CardioCoach calorimeter , using the petit mask for children. Subjects were evaluated for 15 min in a reclining chair.A digital survey was applied before (W0) and after (W7) treatment administration using the FDD questionnaire under the Rome IV Criteria  for pareOther digital survey was applied under the criteria of the program “Integrated attention to prevalent childhood diseases” to know the frequency of respiratory problems for periods ranging from weekly to monthly.The perception of the beneficial digestive and respiratory effects after applying the treatments was evaluated through a digital survey applied to parents or guardians of children, in which a Liker scale mentioned 5 items: 1, particularly good; 2, good; 3, regular; 4, bad; 5, particularly bad.For differential  count of leucocytes, five mL of blood was drawn by venipuncture and collected in tubes with EDTA . Two hundred μL of each blood sample were evaluated in an automated hematologic analyzer Orphée Mythic 18 . Clinical abnormalities in white cells, such as leukocytosis, lymphocytosis, leukopenia, or lymphocytopenia, were diagnosed using the 2018 Spanish pediatric hematology guidelines .To the qualitative (negative or positive) determination of CRP, 1 mL of undiluted serum was analyzed by latex agglutination plate test . A negative result indicates that the CRP serum level was lower than 6 mg/L  and a positive result that it was higher than 6 mg/L (inflammatory condition).t-test was used for independent samples and related samples. For the correlation of the variables of presence or absence of FDD and the perception of beneficial effects of the parents after treatment, a Pearson’s R was used, where R = 0.4–0.9. Differences were considered statistically significant when p < 0.05. Statistical analysis was performed using the SPSS software . Comparisons among groups were made with the chi-square test to compare non-parametric type variables with respect to baseline and final time between independent samples, McNemar test for analyzing dichotomous variables, the Wilcoxon test for ordinal variables, and Mann Whitney U test for related samples. Meanwhile, to analyze parametric variables a Student’s From the 24 patients that were included in this study, just 19 completed the treatments. The average age was 6.05 years, and 36.8% were female and 63.2% male. The level of classification of gross motor function was group 4 in 100% of the population, while the distribution based on the degree of hypertonia according to the Asworth scale was: 21.1% were classified as grade 3 (moderate), 36.8% as grade 4 (severe) and 68.4% as grade 3–4 (moderate severe). No significant differences were found between the variables age, weight, height, BMI, and REE at the beginning of the study, as shown in t-test among the independent samples of the groups “before” and “after” the study. However, when the Student’s t-test from related samples (that compared data before (W0) and after (W7) the treatment) showed that not only the height of kefir group increased significantly (p = 0.003) but also the weight (p = 0.027) as is shown in p = 0.003, Spearman r).Regarding the anthropometric parameters and the needs of energy expenditure at rest or REE, no statistically responses were found using the Student’s p < 0.01, Pearson r).Regarding the results for the weight, we also found a significant negative correlation among the diagnostic Asworth hypertonic grade and the weight and BMI, which means that the higher the hypertonia is related to a lower body weight (r = 0.6) or BMI (r = 0.8) (n = 10) from those 45.45% presented as a unique disorder (not accompanied by another FDD), followed by functional dyspepsia , which in most cases was accompanied by other FDDs, such as aerophagia , and pain syndrome in epigastrium  combined with functional constipation. One of the children presented functional abdominal migraine and other IBS, accompanied by constipation. Finally, functional abdominal pain was diagnosed in other participant as a sole disorder. Interestingly, there was a decrease in the presence of FDDs detected after the intervention with modern kefir. In addition, it was observed a notable reduction in constipation, going from 90.9% to just 9.1%, and those children that had some other FDD, no longer was present after 7 weeks of kefir intake.n = 6) presented constipation at the beginning of the study but the proportion was reduced to 12.5% (n = 1) after the treatment with kefir . Specifically, there was a reduction in severity of the hardness of the stool .On the other hand, when it was compared the perception of the included children’s parents at the end of the study, regarding the gastrointestinal benefits of the kefir addition in diets, 63.6% of them perceived the kefir treatment as particularly good but no one of the in the yogurt group perceived the treatment as particularly good, the 25% of kefir group qualified it as good and 37.5% as regular. However, the difference between groups using the Mann Whitney U test at the end of the study was not significant . However, 45.5% of the parents of the patients treated in the kefir group referred to the product as particularly good vs. 12.5% of the control group.On the other hand, when comparing the effect that the treatment had according to the perception of improvement in the presence of respiratory problems between the two treated groups, the difference was not significant , with no differences between the absolute values of these cells in the patients of both groups before starting treatment . The absolute number of monocytes and granulocytes was similar when comparing the values obtained before (W0) and after (W7) the treatments between the groups.On the other hand, there were no significant differences in the absolute values of monocytes, granulocytes, and lymphocytes of the patients in each group before and after treatment with yogurt or kefir . InteresRegarding the total count of lymphocytes in kefir group, although there was not significant change between W0 and W7, it is worthy to mention the case of a child that presented less than 2000 lymphocytes/μL  at W0, p < 0.005; Spearman r)In relation to serum CPR analysis, it was found a positive result  in one child of the kefir population at W1 and W7, while all children in the yogurt group were negative. It has been reported CRP values above 17.1 mg/dL are associated with IBD . HoweverUnexpected side effects were found in the commercial yogurt group, an exacerbation of gastroesophageal reflux was observed in a controlled patient who presented cyclic vomiting syndrome at the end of the study, as well as the appearance of two cases of dyspepsia. In the kefir group, one case of exacerbation of constipation was reported at the end of the study. No subjects excluded due to severity or respiratory complications were reported during the study.Regarding the hematological markers not included in present study, after the blood analysis it was found the presence of hypochromic anemia before and after treatments in both kefir (54.7%) and yogurt (87.5%) groups, as well as granulocytopenia at 36% in kefir and 25% in yogurt group.Bifidobacterium infantis, Streptococcus thermophilus, and Bifidobacterium lactis [Lactobacillus reuteri DSM 17938, and Agave inulin as a prebiotic). Moreover, it has been described that weight is lower in ambulatory children with a higher degree of athetosis, which is caused to energy expenditure due to this alteration in muscle tone [Our results are similar to those reported in previous studies that have described poor weight gain and growth in children with CP ,41,42,43m lactis ,25. Garcm lactis  found nocle tone . HoweverRegarding the REE, a relationship between the weight gain and the increase in REE has been reported in children with spastic quadriparesis CP in a malnutrition state who underwent in-hospital nutritional treatment , while aBifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus bulgaris, and Streptococcus thermophilus (a formulation currently available as Vivomixx in Europe and Visbiome in the US and very similar to the modern kefir formulation), on dyspepsia, IBS, functional abdominal pain, flatulence, bloating, among others. Interestingly, our results show that the few cases of dyspepsia, aerophagia, irritable bowel, functional abdominal pain and migraine, as well as several of these FDDs grouped into functional constipation that were diagnosed in children with CP at the beginning of the study, did not appear at the end of the modern kefir treatment, which corroborates that the supplementation with various combinations of probiotic bacteria contributes to the reduction in symptoms of various FDDs. In this same sense, it has also been described that traditional kefir helps to eradicate conditions such as dyspepsia and irritable bowel [About the effect of kefir on FDDs, there is no similar type of study in children with disabilities, due to the fact that the diagnostic criteria and the version of the measurement instrument in Latin American Spanish of the Roma Foundation have been recently updated. However, different studies have suggested or reported the efficacy of the use of probiotics in the treatment of FDD in children, such is the case of IBS, functional dyspepsia, abdominal pain and migraine, mostly in controlled clinical trials using a single strain or combination with prebiotics ,49,50,51le bowel . On the le bowel . Althougle bowel .L. reuteri DSM 17938 (1 × 108 UFC) combined with inulin as a prebiotic [Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus lactis, Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium infantis, (with 3 × 1010 cfu per envelope) [L. paracasei Lpc-37, B. lactis Bl-04, L. acidophilus La-14, and L. plantarum Lp-115 [Particularly, in children with CP and chronic constipation, it has been reported that different probiotics contribute significantly to the reduction in this FDD, mainly with the strain rebiotic . Howeverrebiotic , using anvelope) , or throm Lp-115 . On the 7938 1 × 8 UFC comm Lp-115 . Howeverlactobacillus genus: L. acidophilus, L. rhamnosus, L. fermentum, L. plantarum, Lactobacillus delbrueckii spp. Lactis, as well as bifidobacteria, Lactococcus lactis spp. cremoris, and Streptococcus thermophilus [Regarding respiratory infections, the use of traditional kefir has shown significant effects in reducing the frequency of respiratory problems and complications, even against SARS-CoV2 . In our mophilus . Thus, tBifidobacteria, improving gut barrier function, and attenuate bacterial/endotoxin translocation [Different works have reported an association between kefir intake and lymphocyte number. Himada et al.  showed alocation . WhetherFinally, we found clinical evidence of hypochromic anemia and granulocytopenia in a high percentage of the participating children with CP. Iron deficiencies and anemia have been reported in children with CP ,69,70, sIn children with infantile CP, the addition in diets of a dairy-fermented drink called modern kefir, which contains 12 probiotics species might be a strategy not only for gaining body weight but also for reducing some digestive disorders, particularly the functional constipation, as well as inducing a positive regulation of the immune status that includes an increase in the total number of lymphocytes. These positive effects might contribute in the short or medium term to a better quality of life of children with CP. The administration of modern kefir might also be considered as a potential treatment in other conditions with immune or intestinal dysfunction.