There were no differences in NDD rates or vision scores between ZIKV-exposed and unexposed children. Rates of microcephaly at birth , and childhood stunting and wasting did not differ between groups. Our results show that Grenadian ZIKV-exposed children, the majority of whom were without microcephaly, had similar neurodevelopmental outcomes to unexposed controls up to at least an age of 4 years.Maternal infection with Zika virus (ZIKV) is associated with a distinct pattern of birth defects, known as congenital Zika syndrome (CZS). In ZIKV-exposed children without CZS, it is often unclear whether they were protected from in utero infection and neurotropism. Early neurodevelopmental assessment is essential for detecting neurodevelopmental delays (NDDs) and prioritizing at-risk children for early intervention. We compared neurodevelopmental outcomes between ZIKV-exposed and unexposed children at 1, 3 and 4 years to assess exposure-associated NDD risk. A total of 384 mother–child dyads were enrolled during a period of active ZIKV transmission (2016–2017) in Grenada, West Indies. Exposure status was based on laboratory assessment of prenatal and postnatal maternal serum. Neurodevelopment was assessed using the Oxford Neurodevelopment Assessment, the NEPSY The timely achievement of cognitive milestones in the first few years of life is the most important predictor of cognitive outcomes during school age and adolescence . A recenChildren born to women infected with ZIKV during pregnancy have a 5 to 14% risk of congenital Zika syndrome (CZS) . Among tOur objective was to extend the understanding of neurodevelopment in normocephalic ZIKV-exposed children by longitudinally tracking neurodevelopmental outcomes and anthropometrics from birth to 48 months of age in a cohort of ZIKV-exposed children and a parallel group of unexposed controls born during a period of active ZIKV transmission in Grenada, West Indies . We hypoThis ambispective, population-based cohort study followed 388 children born to 384 mothers during a period of active ZIKV transmission in Grenada, West Indies. The children were followed from birth to 4 years of age.Mother–child dyads were enrolled between April 2016 and March 2017 at public health centres throughout Grenada .Prenatal cohort: One hundred and fifty three women were enrolled during pregnancy. Maternal serum was collected at enrolment .Postnatal cohort: Two hundred and thirty one mothers were enrolled post-birth, at which time maternal serum was collected .Data on perinatal outcomes and anthropometric measurements were collected soon after birth. Neurodevelopmental outcomes and anthropometric measurements were collected at 12, 36 and 48 months post-birth. Information on child health and socio-environmental indicators were collected at each time point. Data were collected from medical records as well as via direct interviews with the primary caregiver.Maternal serum samples were initially assessed for flavivirus exposure using indirect IgG capture enzyme-linked immunosorbent assay (ELISA) with pooled dengue virus (DENV) antigen . The samChild ZIKV exposure status (exposed vs. unexposed) was classified according to the results of the maternal serum pGOLD IgG immunoassay (infected vs. uninfected). Children were classified as ZIKV-exposed if they were born to mothers who had positive pGOLD results for ZIKV, with avidity testing showing infection in the past 6 months . Children = 26), 3 (n = 5) and 4 (n = 1) due to <50% completion rate on the measures of neurodevelopment.For the 1, 3 and 4 years assessments, we used the previously published definitions of ZIKV-exposed children and unexposed controls [Neurodevelopmental and vision assessments were administered by local research staff with undergraduate or graduate degrees in Psychology or Public Health who were trained and standardized in the assessments. All assessors were fluent in the local dialect and masked to child exposure status.p < 0.001 for cognitive and motor outcomes, and 0.30, p < 0.04 for language outcomes, with little to no bias on Bland–Altman analysis); satisfactory internal consistency ; and high levels of inter-rater  and test–retest reliability  across all domains [The OX-NDA is a comprehensive, rapid assessment of cognition, motor skills, language and (positive and negative) behaviour for children aged 10–14 months ,17. Its  domains . For eac domains .The OX-NDA is designed for use across socioeconomic groups and populations. Its kit consists of common household items encountered across the world. In Grenada, the OX-NDA was customized for cultural relevance and acceptability using the WHO Mental Health Initiative translation guidelines .The NEPSY-II is a standardized, psychometrically valid neuropsychological assessment for preschoolers, children, and adolescents . It conshttps://www.intergrowth21.org.uk (accessed on 1 March 2023)). Vision in all children was assessed at a working distance of 50 cm.Visual acuity and contrast sensitivity were assessed in the cohort’s children at 1, 3 and 4 years using the Cardiff Tests ,22,23. TWeight and length were measured at 1, 3 and 4 years of age using the WHO Multicentre Growth Reference Study protocols ,25. MeasSerial measurements of occipitofrontal HC at birth and 1 year of age were performed to ensure that none of the children developed late onset microcephaly. Normocephaly was defined as occipitofrontal HC between the 4th and 96th percentile, borderline microcephaly was defined as between 1st and 3rd percentile, and microcephaly was defined as less than 1st percentile, for sex and age in accordance with WHO child growth standards .Information on perinatal and birth outcomes was obtained from hospital records and through a structured clinical interview at the 1-year follow-up visit. Information on child health outcomes, household and socio-environmental characteristics was collected at each follow-up visit  using structured caregiver interviews. These characteristics included measures of food security (USDA Food Security Questionnaire) , maternap < 0.05.Maternal and child data across the follow-up visits were entered into a secure, online database Research Electronic Data Capture (REDCap) . Statistt-tests for continuous variables. Attrition analyses of socio-demographic measures were performed across timepoints between mother–child dyads who completed outcome assessments and those who were lost to follow-up.Participant characteristics, including socio-demographic measures, perinatal factors, and child anthropometrics, were compared between the ZIKV-exposed and unexposed groups using chi-square tests or Fisher’s exact tests for categorical variables, and independent samples t-tests. Cardiff visual acuity and contrast sensitivity scores were compared between groups using independent samples t-tests, and rates of low visual acuity and low contrast sensitivity were compared between groups using Fisher’s exact tests.Rates of neurodevelopmental delay for the OX-NDA cognition, motor and language domains and the NEPSY-II cognition, motor, language, and personal social domains were compared between the ZIKV-exposed and unexposed groups using chi-square tests. Continuous OX-NDA and NEPSY-II scores across all domains were compared between groups using independent samples The study was approved by the Institutional Review Boards of St. George’s University, Grenada, West Indies (IRB#16061) and Stanford University, USA (IRB#s 37004 and 45242), and granted research clearance by the Grenada Ministry of Health. Mothers provided written informed consent for themselves and on behalf of their participating children.n = 149), or their exposure status was indeterminable (n = 5). Of the eligible mother–infant dyads, 113 were classified as ZIKV-infected during pregnancy (mother) and 114 as ZIKV-exposed (child), and 117 were classified as ZIKV uninfected (mother) and 120 as unexposed (child). Of these, 31 ZIKV-exposed children completed neurodevelopmental assessments at 1, 3 and 4 years, and 35, 27 and 28 unexposed children completed these assessments at 1, 3 and 4 years of age, respectively. Despite high rates of attrition , there were no differences in socio-environmental indicators between the children who completed the neurodevelopmental assessments and those who were lost to follow-up.The flowchart with patients enrolled in the study is presented in n = 40); the distribution of male and female children did not differ significantly between the ZIKV-exposed and unexposed groups. The overall risk of perinatal morbidity in the cohort was low: 13% of children were born preterm; 11% had reported complications during birth; and 4.5% required resuscitation at birth. Median APGAR scores at 1 min were 8.00 (2.00–7.00) and 8.00 (4.00–9.00) for ZIKV-exposed and unexposed children, respectively. Median gestational age at birth was identical for both groups . Duration of exclusive breastfeeding and age at weaning did not differ significantly between the two groups. Most mothers and their partners had completed secondary school education. There were no differences in socio-demographic or perinatal factors between ZIKV-exposed and unexposed children . The unexposed group had a higher rate of cognitive delay; however, this difference did not persist at ages of 3 and 4 years.OX-NDA scores at age 1 year, and NEPSY-II scores at ages 3 and 4 years, across domains did not differ between ZIKV-exposed and unexposed children . CognitiThe rates of any and no delay for cognitive, motor and language domains  between ZIKV-exposed and unexposed children at ages 1, 3 and 4 years are presented in The visual acuity and contrast sensitivity scores, and rates of low vision, did not differ between ZIKV-exposed and unexposed children, measured at ages of 3 and 4 years .Weight, length and head circumference were similar between the two groups at birth and at 1 year of age . Rates oAt birth, the rates of microcephaly did not differ between ZIKV-exposed (0.88%) and unexposed (0.83%) children, and microcephaly was reported only in one child in each group. Rates of microcephaly at 1 year of age were higher than those recorded at birth in both groups (22.6% vs. 14.3%); these, however, did not differ significantly between ZIKV-exposed and unexposed children.In this study, weight, length and head circumference were similar between ZIKV-exposed and unexposed children at birth and at 1 year of age, and rates of childhood stunting, wasting, and microcephaly did not differ between groups. We found no evidence of neurodevelopmental delays in cognition, motor, language, behaviour, personal–social and vision outcomes in ZIKV-exposed children at 1, 3 and 4 years of age, relative to a parallel group of socio-demographically similar but unexposed children. Although there was a marginal difference in NDD rates for the cognition domain at 1 year of age, there were higher rates of delay in the unexposed, rather than the ZIKV-exposed group. This difference was no longer apparent at 3 and 4 years of age. Overall, the findings suggest that the absence of NDDs and microcephaly at age 1 year is a positive harbinger of normal neurocognitive development in ZIKV-exposed children. However, we do acknowledge that our study was observational in design and cannot therefore (dis)prove causation.Our findings are consistent with those previously reported for 2-year-old neurodevelopmental outcomes in the same cohort: no differences in 2-year cognitive, motor, language or behaviour scores, or rates of delay were reported between ZIKV-exposed and unexposed children . A populn = 113) only if serology was collected during the prenatal period. Mothers who had serum collected during the postnatal period only were classified as “possibly exposed but unconfirmed” (n = 149) and were not included in further analyses. However, if they tested negative, we did include them in the study as “uninfected”. Second, as our sample size was small due to high rates of attrition (approximately 50% between 1 and 4 year assessments), it is important to consider the likelihood of type II error when interpreting our findings. Nevertheless, our final sample size of 234 and 59, respectively, at the 1- and 4-year follow-ups is larger than and comparable with the 2-year follow-up sizes of approximately n = 60 of many ZIKV-exposed birth cohorts [One major limitation of our study was its reliance on serologic (IgM/IgG) testing for the identification of maternal ZIKV infection during pregnancy. Although nucleic acid amplification tests (NAATs) provide precise evidence on the actual presence of infection during the testing period, many mother–infant pairs were enrolled in the study after delivery; therefore, serology testing was necessary to determine prior ZIKV exposure. We classified mothers as infected during pregnancy  to distinguish ZIKV from DENV exposure, which is common in Grenada. Our study adds to the growing body of literature that ZIKV-exposed children without neurologic manifestations at birth or during infancy do not appear to be at elevated risk for developmental delay during the preschool years [In this study, ZIKV-exposed and unexposed children were similar in socio-demographic, socio-environmental, perinatal and growth characteristics between 0 and 4 years of age, which increases our confidence in findings of no neurodevelopmental difference between the two groups. Additionally, we recruited participants from public health centres in every parish to increase the likelihood that our sample was socio-demographically representative of the larger Grenadian population. Randomized controlled designs are necessary to causally examine the consequences of viral exposure on neurodevelopment but this is often not feasible during pandemics. Prospective and ambispective birth cohort studies offer the next best opportunity to address complex etiological questions about prenatal exposures and neonatal outcomes, even though they are unable to prove (or disprove) causal links. A further strength of our study was the follow-up of ZIKV-exposed children into preschool age, which allowed us to examine whether NDDs manifest as the demand for more complex cognitive information processing increases as children age. There are few cohorts that have followed ZIKV-exposed children beyond 2 years of age ,36. Neveol years .Longitudinal tracking of ZIKV-exposed children alongside a parallel group of socio-demographically similar, unexposed children revealed no major delays in cognition, motor skills, language, vision, behaviour or personal–social skills at 1, 3 and 4 years of age, with no differences in neurodevelopmental scores between the two groups. Additionally, early life factors associated with higher rates of NDDs did not vary systematically between the groups. Considering that we could not confirm fetal ZIKV infection in our sample, it is possible that many of the exposed children were protected in utero from vertical transmission. Nevertheless, further longitudinal follow-up of ZIKV-exposed children, from different populations and geographies, is needed to confirm that these children continue to develop along typical neurodevelopmental trajectories into school age and adolescence.


We assess whether the INTER-ACT postpartum lifestyle intervention influences symptoms of depression and anxiety, sense of coherence and quality of life during the first year after childbirth. A total of 1047 women of the INTER-ACT RCT were randomized into the intervention (n = 542) or control arm (n = 505). The lifestyle intervention consisted of 4 face-to-face coaching sessions, supported by an e-health app. Anthropometric and mental health data were collected at baseline, end of intervention and 6-months follow-up. We applied mixed models to assess whether the evolution over time of depressive symptoms, anxiety, sense of coherence and quality of life differed between the intervention and control arm, taking into account the women’s pre-pregnancy BMI. There was no statistical evidence for a difference in evolution in anxiety or quality of life between intervention and control arm. But an improvement in symptoms of depression and sense of coherence was observed in women who received the intervention, depending on the mother’s pre-pregnancy BMI. Women with normal/overweight pre-pregnancy BMI, reported a decrease in EPDS between baseline and end of intervention, and the decrease was larger in the intervention arm ; intervention arm: -0.71 ). Women with pre-pregnancy obesity showed an increase in EPDS between baseline and end of intervention, but the increase was less pronounced in the intervention arm ; intervention arm: +0.42 (95% CI -0.42 to 1.25)). Women with a normal or obese pre-pregnancy BMI in the intervention arm showed a decrease in sense of coherence between baseline and end of intervention (-0.36) , while women with overweight pre-pregnancy showed an increase in sense of coherence (+1.53)  between baseline and end of intervention. Receiving the INTER-ACT postpartum lifestyle intervention showed improvement in depressive symptoms, in normal weight or overweight women on the short run, as well as improvement in sense of coherence in women with pre-pregnancy overweight only.Trial registration: ClinicalTrials.gov;NCT02989142. Globally, 20% of women experience mental health problems in the first year after childbirth . Almost Research shows that psychological, biological, social, behavioural, and demographic factors can play a role in the development of maternal mental health problems –7. In adThese findings suggest that lifestyle interventions may impact maternal mental health. Many lifestyle interventions have been developed to reduce GWG and subsequently related perinatal complications such as gestational diabetes and pregnancy-induced hypertension , 11. ThoDepressive and/or anxiety symptoms are associated with unhealthy eating patterns , 19, whiUnfortunately, mental health outcomes such as depression and anxiety are hardly evaluated in lifestyle interventions , 17, 20.st, 2nd & 3rd trimester) in women with a history of excessive GWG. The primary aim of INTER-ACT was to reduce pregnancy- and birth related complications at the end of a subsequent pregnancy. This study aims to assess whether the INTER-ACT lifestyle intervention affects maternal mental health outcomes in the form of depressive symptoms, anxiety, SOC and QoL during the first year after childbirth. Our hypothesis is that women who received the INTER-ACT postpartum lifestyle intervention have better mental health outcomes during the first year after childbirth compared to their counterparts who received no intervention.INTER-ACT is a randomized controlled trial (RCT)  in whichThe INTER-ACT study ) is a multicentre RCT to investigate lifestyle and lifestyle interventions after childbirth and during a subsequent pregnancy to reduce pregnancy- and birth related complications. Details of the INTER-ACT methodology are published elsewhere . For curStudy nurses informed and recruited participants 2 to 3 days after childbirth. Inclusion criteria were: excessive GWG according to the 2009 National Academy of Medicine (NAM) guideline , age ≥18https://data.castoredc.com/). Randomization into the intervention or control arm was electronically performed by the biostatistician within the first week after childbirth, using an allocation ratio of 1:1 supported by block randomization  and stratification by hospital. The study personnel announced the randomization directly to the participants during the first study visit (6 weeks after childbirth). Blinding was not possible for participants, research staff and caregivers due the difference in follow-up between the intervention arm  and control arm (only questionnaires and body measurement).Study nurses were midwives employed in the concerned hospital department who volunteered to collaborate in the INTER-ACT study. They were trained by research staff in recruiting and including participants, as well as collecting and reporting data from the medical records. At time of recruitment and inclusion, both participants and study nurses were blinded for randomization. Study nurses entered the data of the recruited participants into the electronic Case Report Form (eCRF) ‘Castor’  focused on a general discussion of the lifestyle components: nutrition, physical activity and mental health. Session 3 (12 weeks after childbirth) offered a specific targeted and in depth coaching on nutrition, eating behaviour and food intake. Session 4 (6 months after childbirth) offered a specific targeted coaching on physical activity, sedentary behaviour and mental health.The mental health component consisted of 2 main topics; stressors and social support. The session (4) aimed to provide insight into specific stressors that have an impact on the participant’s well-being and to increase knowledge around the impact of well-being on general health. We informed participants about feelings of stress and tension related to transition to parenthood and identified and discussed personal stressors.In addition, the session focused on strengthening the participant’s social network by identifying and optimizing the social support they received. Information was provided using the Ask- Tell- Ask method.Motivational interviewing, behavioural change techniques, goal settings, action planning and reinforcement were implemented in the coaching sessions. Additionally, the e-health app supported the coaching sessions by sending motivational messages and informational advice, and participants were able to set and monitor their own lifestyle goals. To stimulate self-monitoring of physical activity and body weight, women were supported to use a received Bluetooth connected weight scale  and activity tracker (Withings GO) which was linked to the e-health app .To increase feasibility for both staff and participants, a deviation of 2 weeks before and 4 weeks after the predetermined visit timepoint was allowed.Pregnancy- and birth related outcomes were extracted from medical records by trained study nurses at the time of recruitment.2). Pre-pregnancy weight was self-reported and weight at childbirth was self-reported or measured by medical personnel on admission at the birth unit. Based on these two weight measurements, total weight gain was calculated and assessed whether women had excessive GWG according to the NAM guidelines [Body mass index (BMI) was calculated as weight (kg)/ height  was surveyed once at baseline.The methodology of the mental health questionnaires was also described in previous research . CharactAs shown in previous research, the Edinburgh Postnatal Depression Scale (EPDS) is appropriate for measuring levels of depression and anxiety after childbirth . A cut-oThe Gotland Male Depression Scale (GMDS) complements the EPDS as it is a valid instrument for measuring non-typical suicidality-related symptoms of depression and using both scales can increase the detection rate of depressive symptoms . Cut-offThe Spielberger State Trait Anxiety Inventory 6-item (sSTAI-6)  is a valThe Sense Of Coherence (SOC) is measured with the 13 item short scale (SOC-13), derived from the original 29-items Orientation to Life Questionnaire . For curQuality of Life (QoL) was assessed using a Linear Analogue Scale (LAS). Participants were asked to score QoL on a scale from 0 to 100, with 0 representing a poor quality of life and 100 an extremely good quality of life. The LAS was one comprehensive score, summarizing physical, psychological, and social aspects.All questionnaires used in this study were self-completed questionnaires in Dutch version. Each participant received by e-mail a personal link to the questionnaire, which was sent from the eCRF. In current analyses, the Cronbach’s alpha was acceptable (α = ≥.70 < .80) for the EDS-3A, to good (α = ≥.80 < .90) for the EPDS, GMDS, sSTAI-6 and SOC at each timepoint.Data were analysed by using Statistical Package for the Social Science (SPSS) version 27.0  and Statistical Analysis System (SAS) version 9.4 .2), pre-pregnancy overweight (BMI 25.0–29.9 kg/m2) and pre-pregnancy obesity (BMI ≥30 kg/m2). Differences in categorical variables were assessed with the (Mantel-Haenszel) chi-square test; differences in continuous variables were assessed with the t-test or Mann-Whitney U test.Differences in mental health outcomes between the intervention and the control arm were investigated for all pre-pregnancy BMI groups together, as well as stratified by pre-pregnancy BMI class: normal pre-pregnancy weight , the randomization arm (intervention vs. control), the pre-pregnancy BMI class  and baseline characteristics that showed imbalance between the two randomization arms ), and QoL at W6 (Week 6)). We also considered a breakpoint at month 6  or obesity (41.6%) compared to women with a normal pre-pregnancy BMI (26.6%) (P = ≤0.001).Despite randomization, there seems to be an imbalance between the intervention- and control arm for method of conception, gestational weight gain in kg and QoL at baseline. More women were more spontaneously pregnant in the control arm (92.1%) compared to the intervention arm . In women with a normal pre-pregnancy BMI, the median GWG was 18kg (IQR 17–20) in the intervention arm compared to 19kg (IQR 17–21) in the control arm(P = 0.035). The median score of QoL at baseline was slightly higher in the control arm  compared with the intervention arm  (P = 0.038). No difference was found anymore between intervention- and control arm regarding method of conception, quality of life and GWG in women with a 6 month measurement (n = 720) or 12 month measurement (n = 507). Details are presented in In the overall group, no significant differences in the prevalence of anxiety, depressive symptoms, SOC or QoL, were shown between the intervention- and control arm, neither at the end of intervention nor after 6 months follow-up.However, in the subgroup of women with a normal pre-pregnancy BMI, depressive symptoms (EPDS ≥10) after 6 months follow-up were statistically significantly less prevalent in the intervention arm compared to the control arm . This difference was not shown in women with pre-pregnancy overweight or pre-pregnancy obesity.In the overall group, no significant differences in numeric mental health scores  were shown at the end of intervention or after 6 months follow-up between the intervention- and control arm.Women with a normal pre-pregnancy BMI who received the INTER-ACT intervention scored one point lower on the GMDS after 6 months follow-up compared to women with normal pre-pregnancy BMI and who received usual care . Results are presented in We assessed the evolution over time of the mental health outcomes with mixed models, considering as explanatory variables the randomization arm (intervention vs control), the pre-pregnancy BMI and baseline characteristics that showed imbalance between the two randomization arms ), and QoL at W6 (Week 6) , S1 FileThere was no statistical evidence for a difference in evolution of the sSTAI-6 between intervention and control arm, nor between the different pre-pregnancy BMI categories. The sSTAI-6 increases in the first year after childbirth, with a steeper increase between baseline and end of intervention ) as compared to the 6 months follow-up ). Higher values of sSTAI-6 were associated to lower QoL at baseline ) and more excessive weight  per 1 kg increase in excessive weight).The evolution in EDS3-A did not seem to differ between intervention and control arm, but differed by pre-pregnancy BMI. Women with pre-pregnancy obesity had an increase between baseline and end of intervention ), followed by a decrease till 6 months follow-up ). While women with a normal/overweight pre-pregnancy BMI showed a decrease in EDS-3A between baseline and end of intervention ) and increase afterwards  between end of intervention and 6 months follow-up). Higher values of EDS3-A were seen in women with lower QoL at baseline  per 10 pts decrease) .The evolution in EPDS differed between the intervention and control arm, depending on whether the woman had pre-pregnancy obesity or not. Women with pre-pregnancy obesity showed an increase in EPDS between baseline and end of intervention, but decrease afterwards: in the control arm+ 0.71  between baseline and end of intervention, and -0.35  till 6 months follow-up; in the intervention arm + 0.42 (95% CI -0.42 to 1.25) between baseline and end of intervention, and– 0.74  till 6 months follow-up. Women with normal/overweight pre-pregnancy BMI, reported a decrease between baseline and end of intervention, followed by an increase till 6 months follow-up: in the control arm -0.42  from baseline till end of intervention and +0.50  till 6 months follow-up; in the intervention arm -0.71  from baseline till end of intervention and +0.10 (-0.26 to 0.47) till 6 months follow-up.Higher values of EPDS were seen in women with lower QoL at baseline (+1.3 (95% CI 1.12 to 1.48) per 10 pts decrease).No statistical evidence was found for an evolution in GMDS during the first year .The evolution of SOC during the first year after childbirth depended on whether or not women received the INTER-ACT intervention, her pre-pregnancy BMI, her QoL at baseline, and the amount of excessive GWG.Women in the intervention arm showed a decrease in SOC over time, but only in women with a normal or obese pre-pregnancy BMI: -0.36  between baseline and end of intervention, -0.20  between end of intervention and 6 months follow-up. In women with overweight pre-pregnancy (in the intervention arm): +1.53  between baseline and end of intervention; stable afterwards  between end of intervention and 6 months follow-up).In the control arm, the values of SOC seemed to be increasing during the first year, again only in women with a normal/obese pre-pregnancy BMI: increase of +0.98  between baseline and end of intervention, stable between end of intervention and 6 months follow-up ). In women with overweight pre-pregnancy in the control arm, there seemed to be a decrease of -1.77  between baseline and end of intervention, followed by an increase of +0.56  between end of intervention and 6 months follow-up.Higher values of SOC were associated to higher QoL at baseline  per 10 pts increase) and less excessive weight  per 1 kg decrease in excessive weight) .There was no statistical evidence for a difference in evolution of QoL between the intervention arm and the control arm. But the evolution in QoL differed by pre-pregnancy BMI: Women with obese pre-pregnancy BMI started with the highest reported QoL ) , but had a decrease in QOL ) between baseline and end of intervention, and increase of +3.06  till 6 months follow-up. Women with overweight pre-pregnancy start also with a higher reported QoL ), but their QoL almost does not change: +0.43  between baseline and end of intervention, and -0.33  between end of intervention and 6 months follow-up. Women with normal pre-pregnancy BMI had an increase +4.46  from baseline till end of intervention, followed by a decrease of -3.35  till 6 months follow-up .To our knowledge, this is the first RCT evaluating the effect of a postpartum lifestyle intervention, including a mental health component on levels of anxiety, depression, SOC and QoL during the first year after childbirth in women with pre-existing excessive GWG. We found that the INTER-ACT lifestyle intervention was associated with an improvement in the number of women with depressive symptoms, or low SOC at 6 months after intervention, but only in normal weight women. Mixed models revealed that both our intervention as well as the pre-pregnancy BMI category and QoL at baseline were associated with levels of depressive symptoms throughout the first year after childbirth. Women with pre-pregnancy obesity showed an increase in EPDS between baseline and end of intervention, but an decrease afterwards. Women with normal/overweight pre-pregnancy BMI showed a significant decrease in depressive symptoms between baseline and end of intervention, followed by an increase till 6 months follow-up. A higher QoL at baseline had a significant positive effect on levels of depression, mainly in women with pre-pregnancy normal weight and overweight. The evolution of SOC depended on pre-pregnancy BMI, the amount of excessive GWG and the QoL at 6 weeks after childbirth. Women with a normal pre-pregnancy BMI reported better levels of SOC, compared to normal weight women of the control arm. Women with pre-pregnancy obesity reported worser levels of SOC if they received the INTER-ACT intervention compared to the control arm. Lower levels of excessive GWG (1kg vs 5kg) and a higher QoL at baseline had a significant positive effect on SOC.Previous studies focusing on lifestyle interventions in the general population showed that women with obesity experience a lack of motivation, and therefore less adherence to treatments , 36. OurAnxiety (sSTAI-6) increased over time. These findings are in line with our previous research . HoweverThe mental health component of the INTER-ACT intervention focused on stressors and social support. Lack of social support is often identified as a major cause of adverse mental health . StudiesThe fact that the INTER-ACT intervention is limited to social support and stressors, and we did not select women based on the presence of mental health problems, may be a reason for the absence of large effects of mental health improvement after receiving the INTER-ACT intervention. Indeed, as shown in Stress and depression appear to be predictors of poor adherence to lifestyle interventions . RegardlThe strengths of this study were the study design (a multicentre RCT with long-term follow-up), the large study group and the analysis of four different mental health outcomes. Nevertheless, there were also some limitations in this study. The mental health questionnaires were completed prior to the coaching session, so the effect of the coaching session at that time point was not yet apparent in the mental health outcomes. A second limitation is that we presume that our control arm may have been triggered by the regular home visits they received as part of the data-collection (anthropometrics). During the measurements conversations on diet, physical activity and mental well-being were not initiated, however, we believe that by home visits and interaction with mothers, a trigger may have occurred that can have an effect on the mental well-being. A third limitation is that our results cannot be fully generalized to the entire population of postpartum women as our sample mainly consisted of working women (92%) who held at least a bachelor’s degree (71%). A fourth limitation is that within the INTER-ACT trial, power analysis was driven solely by the primary outcome: a composite outcome of occurrence of pregnancy- and birth related problems . As a result, there may be a lack of statistical power in current analyses that focus on mental health outcomes, especially in the pre-pregnant obese women. This might limit the statistical evidence of the inter-act intervention on mental health, but can induce as well rather chance findings such as e.g. the significant difference in GMDS between the intervention and control arm at 6 months follow-up in the normal-weight women.The INTER-ACT postpartum lifestyle intervention shows improvement in depressive symptoms and levels of SOC, with differences within pre-pregnancy BMI. Attention to women’s QoL at baseline and pre-pregnancy weight are important key factors for maternal mental health the first year after childbirth. In addition, women in the postpartum period may benefit more from lifestyle interventions if they also include evidence-based psychological approaches, both in terms of addressing mental health as well as addressing the adherence needed to create a long-term effect.S1 Checklist(PDF)Click here for additional data file.S1 File(PDF)Click here for additional data file.S1 Protocol(PDF)Click here for additional data file.


Are there safety differences between mRNA vaccines for COVID-19, and do those differences vary by frailty level?In this cohort study of 6 388 196 older US adults, a 4% lower risk of pulmonary embolism, a 2% lower risk of thromboembolic events, and a 14% lower risk of diagnosed COVID-19 were observed among those who received the mRNA-1273 vaccine compared with the BNT162b2 vaccine. Although both vaccines were safe across frailty subgroups, differences were generally greater in individuals without frailty.These findings suggest that compared with BNT162b2, mRNA-1273 was associated with a lower risk of adverse events, possibly due to improved protection against COVID-19. This cohort study compares the risk of potential adverse events between mRNA vaccines mRNA-1273 and BNT162b2 for COVID-19 among older US adults. Head-to-head safety comparisons of the mRNA vaccines for SARS-CoV-2 are needed for decision making; however, current evidence generalizes poorly to older adults, lacks sufficient adjustment, and inadequately captures events shortly after vaccination. Additionally, no studies to date have explored potential variation in comparative vaccine safety across subgroups with frailty or an increased risk of adverse events, information that would be useful for tailoring clinical decisions.To compare the risk of adverse events between mRNA vaccines for COVID-19 (mRNA-1273 and BNT162b2) overall, by frailty level, and by prior history of the adverse events of interest.This retrospective cohort study was conducted between December 11, 2020, and July 11, 2021, with 28 days of follow-up following the week of vaccination. A novel linked database of community pharmacy and Medicare claims data was used, representing more than 50% of the US Medicare population. Community-dwelling, fee-for-service beneficiaries aged 66 years or older who received mRNA-1273 vs BNT162b2 as their first COVID-19 vaccine were identified. Data analysis began on October 18, 2022.Dose 1 of mRNA-1273 vs BNT162b2 vaccine.Twelve potential adverse events  were assessed individually. Frailty was measured using a claims-based frailty index, with beneficiaries being categorized as nonfrail, prefrail, and frail. The risk of diagnosed COVID-19 was assessed as a secondary outcome. Generalized linear models estimated covariate-adjusted risk ratios (RRs) and risk differences (RDs) with 95% CIs.This study included 6 388 196 eligible individuals who received the mRNA-1273 or BNT162b2 vaccine. Their mean (SD) age was 76.3 (7.5) years, 59.4% were women, and 86.5% were White. A total of 38.1% of individuals were categorized as prefrail and 6.0% as frail. The risk of all outcomes was low in both vaccine groups. In adjusted models, the mRNA-1273 vaccine was associated with a lower risk of pulmonary embolism  and other adverse events in subgroup analyses . The mRNA-1273 vaccine was also associated with a lower risk of diagnosed COVID-19 , a benefit that was attenuated by frailty level .In this cohort study of older US adults, the mRNA-1273 vaccine was associated with a slightly lower risk of several adverse events compared with BNT162b2, possibly due to greater protection against COVID-19. Future research should seek to formally disentangle differences in vaccine safety and effectiveness and consider the role of frailty in assessments of COVID-19 vaccine performance. Further, no studies to date have assessed comparative vaccine safety within and across patient subgroups with increased frailty or history of the diagnoses identified as vaccine-associated adverse events—conditions likely to modify vaccine response and potentially contribute to differences in safety.16Few studies have directly compared the risk of potential adverse events between mRNA vaccines, which differ in their manufacturing, administration, and immune response.19 As previously suggested,13 a more effective vaccine may appear to be safer for some outcomes due to the enhanced and differential prevention of COVID-19. Because of the prevalence of SARS-CoV-2 at the time of early vaccination efforts and observed differences in mRNA vaccine effectiveness,20 additional studies are needed to understand the extent to which differences in adverse events may be attributed to differential early effectiveness.Importantly, several of the potential vaccine-associated adverse events are also sequelae of SARS-CoV-2.To inform public health recommendations and clinical decision making, we used a large population-based cohort of more than 6 million older adults to compare the risk of potential adverse events shortly after the first dose of mRNA-1273 and BNT162b2. We also assessed whether frailty and prior history of the conditions identified as potential vaccine-associated adverse events modified comparative vaccine associations.21 We matched pharmacy customer prescription and vaccination data deterministically to the 100% Medicare enrollment files based on name, address, and date of birth. Approximately 95% of records were successfully matched, creating a cohort of more than 28 million individuals aged 65 years or older. Medicare Parts A and B were used to capture inpatient, outpatient, carrier, skilled nursing, and COVID-19 vaccine claims, and the Common Medicare Environment was used to measure sociodemographics and enrollment. The Minimum Data Set captured nursing home residence. The Brown University Institutional Review Board approved this study and waived informed consent because deidentified secondary data were used. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.We conducted a retrospective cohort study using customer data from 2 large national pharmacy companies linked to Medicare claims between December 11, 2020, and July 11, 2021.The study population comprised community-dwelling Medicare fee-for-service (FFS) beneficiaries aged 66 years or older who received an mRNA vaccine as their first COVID-19 vaccine dose during the study period. The study index date  at which follow-up began was defined as the start  of the week that individuals received their first vaccine dose. The study population was restricted to Medicare FFS beneficiaries to capture relevant covariate information derived from FFS claims.13 individuals with recently diagnosed COVID-19 were excluded to capture those eligible for vaccination.As of the study index date, we sequentially excluded individuals who were aged younger than 66 years, resided in long-term care, were in the hospital, were not continuously enrolled in FFS Medicare for the previous 12 months, had a documented COVID-19 diagnosis in the prior 4 weeks, had invalid vaccine data , or were deceased . We exclCurrent Procedural Terminology codes (0011A for mRNA-1273 and 0001A for BNT162b2) in the Medicare Part B/Carrier File and pharmacy records. To study a vaccine-naive population, we chose to assess the risk of adverse events following the first dose of an mRNA vaccine.Our primary exposure comparison of interest was the receipt of an initial dose of mRNA-1273 vs BNT162b2. Since the per-protocol and intention-to-treat estimands are identical with a single-dose exposure, we estimated both estimands in this study. The week of individuals’ first vaccine dose and vaccine manufacturer were identified using 22 Outcomes were measured using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes from FFS claims in Medicare Parts A and B: acute myocardial infarction, facial nerve palsy , deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis or encephalitis, Guillain-Barre syndrome, hemorrhagic stroke, thrombocytopenia purpura, myocarditis or pericarditis, nonhemorrhagic stroke, pulmonary embolism, and transverse myelitis  during which the first vaccine dose was administered and continued until one of the following events: death, occurrence of an outcome (each assessed separately), or end of follow-up , whichever occurred first. Individuals with a recorded outcome on the index date who thus had 0 days of follow-up were excluded from the analysis of that outcome. We chose a 28-day follow-up period to capture adverse events most likely to be related to the vaccine.23 self-reported race and ethnicity,24 dual eligibility, and billing source of the vaccine claim ) for all individuals. Race and ethnicity was included as a covariate to account for potential differences in vaccine access and likelihood of vaccination and included American Indian or Alaska Native, Asian, Black, Hispanic, White, other , or unknown or missing. History of comorbidities within the past year was captured using FFS claims.25 We measured the number of weeks since an individual’s last COVID-19 diagnosis  with 95% CIs were estimated using generalized linear models . Covariates that were imbalanced (>10% standardized difference28) and/or determined to be clinically relevant were included in a series of models. Adjustment was conducted in stages to show the relative impact of different covariates and increasing adjustment: unadjusted (model 1); region and month of vaccination (model 2); age, sex, race and ethnicity, and frailty (model 3); and models 2 and 3 plus vaccine billing source , time since prior diagnosed COVID-19, and time since prior hospitalization, outpatient visit, and emergency department visit (model 4). For outcomes with a statistically significant association in model 4, population-averaged risk differences (RDs) and 95% CIs were derived from the estimated probabilities.We used standardized differences to evaluate covariate balance between the mRNA-1273 and BNT162b2 vaccine groups.We assessed potential variation in the comparative risk of adverse events across frailty level and prior history of the outcome being assessed , we used multinomial logistic regression to compare the risk of the adverse event alone, diagnosed COVID-19 alone, and the co-occurrence of the adverse event and diagnosed COVID-19.First, since the vaccines were not randomly assigned and potential confounding bias was a concern, we examined the 28-day risk of hip and vertebral fractures as negative control outcomes.P < .05. Data analysis began on October 18, 2022.To provide assurance that unintentional errors in the analysis were not responsible for any findings, the cohort creation and outcome measurements were coded independently and in duplicate. Statistical analyses were conducted using SAS, version 9.4 (SAS Institute Inc), and Stata, version 17 (StataCorp LLC). Statistical significance was defined as We identified 6 388 196 eligible Medicare beneficiaries who received their first dose of an mRNA vaccine; slightly over half (n = 3 390 704) received BNT162b2 . Their mWe observed few differences in baseline characteristics between groups. However, on average, individuals who received BNT162b2 were older , were more likely to be Black , and were more likely to be categorized as frail .The risk of all adverse events was low, with each occurring in less than 1.0% of eligible individuals .The risk of each adverse event was greater among individuals who had a prior history of that condition ; however, full adjustment nullified this association , suggesting sufficient confounding control. Outcomes assessed at 21 days replicated the primary analysis (eTable 10 in P = .01 for interaction). In a multinomial model comparing the risk of pulmonary embolism alone, diagnosed COVID-19 alone, and the co-occurrence of pulmonary embolism and diagnosed COVID-19, mRNA-1273 was associated with a significantly lower risk of COVID-19 alone  and the co-occurrence of pulmonary embolism and COVID-19 , but not pulmonary embolism alone  ; this association was attenuated in individuals categorized as frail  .19 this and potentially other observed differences in adverse events may be the result of early vaccine effectiveness and differential mitigation of COVID-19. Some variation in the comparative risk of adverse events and diagnosed COVID-19 was observed across subgroups, with mRNA-1273 showing generally larger protective associations in individuals categorized as nonfrail.We compared the risk of potential adverse events between the mRNA-1273 and BNT162b2 vaccines in a cohort of more than 6 million older US adults. We observed that the risk of adverse events was very low in both vaccine groups, and the vaccines did not differ in risk for most outcomes in the overall analysis. However, mRNA-1273 was associated with a lower risk of some adverse events, including pulmonary embolism, compared with BNT162b2. Notably, individuals who received mRNA-1273 also had a 14.0% lower risk of diagnosed COVID-19. Because pulmonary embolism is a sequela of COVID-19,14 Among a cohort of US veterans, Dickerman et al13 compared the risk of potential vaccine-associated adverse events over 38 weeks using electronic health record data and sought to account for differential effectiveness by censoring on SARS-CoV-2. Relative to BNT162b2, mRNA-1273 was associated with a reduced risk of several outcomes, including thromboembolic events, myocarditis or pericarditis, and acute myocardial infarction. However, the authors cautioned that differences in SARS-CoV-2 incidence could not be ruled out as a potential explanation of differences in adverse events. We also observed a lower risk of several adverse events among those who received mRNA-1273 vs BNT162b2 in a larger and diverse cohort, over shorter follow-up, with robust confounding control, and across clinical subgroups. We also observed that mRNA-1273 was associated with a reduced risk of diagnosed COVID-19.20To date, a small number of studies have directly compared the safety of the BNT162b2 and mRNA-1273 vaccines and accounted for important clinical differences between groups.19 Differences in adverse events between vaccines may reflect the benefits of vaccination with a more effective product due to superior protection against COVID-19 and its sequelae. Results from our sensitivity analysis support the hypothesis that differences in the risk of pulmonary embolism between the vaccines are related to differential early effectiveness. Regardless of the underlying mechanism, however, the comparative reduction in morbidity associated with mRNA-1273 is notable and may have real benefits at the population level. Nonetheless, studies confirming the extent to which differences in adverse events can be attributed to early effectiveness are needed.Given the overlap in adverse events identified as potentially being associated with mRNA vaccines and those attributable to SARS-CoV-2, differences in safety outcomes between vaccines should be considered alongside early effectiveness.15 the greater immunogenicity associated with mRNA-1273 may have been diminished in individuals categorized as frail, thereby reducing its degree of differential protection against COVID-19 and its sequelae.30Assessments of potential adverse events by frailty level and their prior history of occurrence reinforced the primary analysis and provide evidence of mRNA vaccine safety in real-world and more clinically vulnerable populations. These analyses also preliminarily favor attributing the observed differences in adverse events to early effectiveness rather than safety. The mRNA-1273 vaccine was associated with generally larger reductions in adverse events and diagnosed COVID-19 among individuals categorized as nonfrail. Because frailty is known to attenuate vaccine response,18 we do not anticipate that outcomes would be differentially captured between vaccine groups. Fourth, we cannot confirm whether the observed differences in adverse events are due to a vaccine safety signal or differential effectiveness. Fifth, our use of administrative claims without chart review makes it challenging to determine the timing of adverse events and the temporal sequencing of diagnosed COVID-19. Similarly, since our follow-up period began at the start of the week, it was possible for adverse events to occur prior to the true vaccination date; however, due to the severity of the outcomes assessed, we suspect this sequencing to be rare. Finally, we do not have data on the risks of adverse events under study in an unvaccinated comparator group.First, despite our large sample, several outcomes were too rare to examine with precision. Second, residual confounding remains a possibility and the smaller effect sizes reported herein should be interpreted with some caution. Additionally, early perceptions regarding differences in vaccine performance may have contributed to the nonrandom selection or administration of BNT162b2 and mRNA-1273. However, we adjusted for many factors and the results from the negative control outcome analysis demonstrate robustness. Third, incomplete outcome ascertainment is possible; however, with the potential exception of myocarditis,18 vaccination with any available product should be prioritized. Nonetheless, mRNA-1273 was associated with a slightly lower risk of pulmonary embolism and other adverse events compared with BNT162b2. Because individuals who received mRNA-1273 also had a lower risk of diagnosed COVID-19, the reduced risk of adverse events in this vaccine group may represent the benefits of vaccination with a more effective product. Future research should seek to formally disentangle differences in vaccine safety and effectiveness and consider the role of frailty in assessments of COVID-19 vaccine performance.In this cohort study of older US adults, the risk of adverse events following BNT162b2 and mRNA-1273 administration was low for both mRNA vaccines, affirming their safety overall and in patient subgroups at potentially increased risk of adverse events. Because the risk of adverse events following natural infection exceeds that of either mRNA vaccine,


Obstructive sleep apnea (OSA) severity can vary markedly from night-to-night. However, the impact of night-to-night variability in OSA severity on key cardiovascular outcomes such as hypertension is unknown. Thus, the primary aim of this study is to determine the effects of night-to-night variability in OSA severity on hypertension likelihood. This study uses in-home monitoring of 15,526 adults with ~180 nights per participant with an under-mattress sleep sensor device, plus ~30 repeat blood pressure measures. OSA severity is defined from the mean estimated apnea–hypopnoea index (AHI) over the ~6-month recording period for each participant. Night-to-night variability in severity is determined from the standard deviation of the estimated AHI across recording nights. Uncontrolled hypertension is defined as mean systolic blood pressure ≥140 mmHg and/or mean diastolic blood pressure ≥90 mmHg. Regression analyses are performed adjusted for age, sex, and body mass index. A total of 12,287 participants  are included in the analyses. Participants in the highest night-to-night variability quartile within each OSA severity category, have a 50–70% increase in uncontrolled hypertension likelihood versus the lowest variability quartile, independent of OSA severity. This study demonstrates that high night-to-night variability in OSA severity is a predictor of uncontrolled hypertension, independent of OSA severity. These findings have important implications for the identification of which OSA patients are most at risk of cardiovascular harm. Untreated OSA is associated with a wide range of adverse health and safety consequences including increased risk of hypertension3, cardiovascular disease4, depression5, reduced quality of life6, traffic accidents7, and all-cause mortality4.Obstructive sleep apnea (OSA) is a common clinical sleep disorder characterized by repetitive upper airway collapse during sleep. OSA is estimated to affect approximately one billion people globally9. This has raised concerns regarding OSA misdiagnosis and possible misdirected management and care9. Night-to-night variation in OSA may explain, at least in part, why a single-night diagnosis of OSA shows inconsistent relationships with important health outcomes and responses to treatment12. Indeed, emerging evidence indicates that high night-to-night variability in OSA severity may be an important contributor to cardiovascular diseases such as atrial fibrillation14. Similarly, blood pressure varies widely from day-to-day in some people, and high day-to-day variability in blood pressure is associated with atrial fibrillation, OSA, all-cause mortality, and cardiovascular events, independent of mean blood pressure21. Whether night-to-night changes in OSA severity contribute to blood pressure variability is unknown.Recent evidence indicates that there is considerable night-to-night variation in OSA severity23 and a clinically validated home-blood pressure monitor. We hypothesized that high variability in OSA severity would be a strong predictor of hypertension and blood pressure variability.To investigate the potential clinical importance of night-to-night variation in OSA severity on cardiovascular risk, this study was designed to determine the potential association between night-to-night variability in OSA severity and blood pressure using a validated under-mattress sleep monitorThis study includes data from 12,287 adults monitored over ~180 nights using an under-mattress sleep sensor device accompanied by ~30 repeat blood pressure measurements. Here we use the under-mattress sleep sensor technology to estimate OSA severity  and OSA variability (standard deviation of AHI over the recording period). People in the highest variability quartile within each OSA severity category have a 50–70% increased likelihood of uncontrolled hypertension compared to the lowest variability quartile, regardless of OSA severity. We conclude that high variability in OSA severity is an independent predictor of uncontrolled hypertension and this has major implications for identification of patients most at risk of cardiovascular harm. Furthermore, this study highlights the unique and important insights that multi-night, in-home, non-invasive monitoring of OSA severity can yield.2. However, the proportion of males was slightly higher, and mean BMI and AHI values were ~1 kg/m2 and 3 events/h higher, respectively, in the current study sample  and 1482 (9.5 %) were excluded because they had <28 nights of sleep recordings or an average use of <4 times a week, respectively. A further 346 (2.2%) were excluded due to missing body mass index (BMI) data and 34 (0.2%) as they were <18 or >90 years old. The characteristics of the remaining 12,287 users are summarized in Table p-values < 0.001) for participants with severe and variable OSA compared to controls and those with low night-to-night variability in OSA severity . When OSA severity and variability were combined into one model, the variance inflation factors (a measure of collinearity) for OSA severity and variability were below 5 (2.81 and 2.74), supporting the combination of both metrics into a single model. The likelihood ratio test indicated that a model with both OSA severity and variability provided a superior model fit than a model with OSA severity alone . In this combined model, OSA severity was associated with a 7% increase in uncontrolled hypertension likelihood . Furthermore, OSA variability independent of OSA severity was associated with a 51% increase  in uncontrolled hypertension likelihood.OSA severity  and higher variability in OSA severity  were associated with increased uncontrolled hypertension likelihood in separate models after controlling for age, BMI, and sex. Both associations were nonlinear, and marginal probability plots are shown in Fig. Categorical analysis of OSA severity confirmed that mild, moderate, and severe OSA were associated with increased uncontrolled hypertension likelihood compared to the no OSA group Fig. . Particip = 0.029). Quartile analysis of AHI variability within the OSA severity category also suggested increased hypertension risk for participants with variable AHI, although some results became non-significant likely due to the smaller sample size  participants remained for the sensitivity analysis. Of these, 1170 (21.7%) cases of hypertension were observed. In separate models, high average AHI  and high AHI variability  were associated with an increased risk of hypertension. In the combined model, average AHI was associated with a 14% increase in hypertension risk , and variability in AHI was associated with a 36% increase in hypertension risk . Model fit was superior in the combined model than in the AHI-mean-only model  and a ~0.37 mmHg increases in systolic blood pressure variability  independent of mean AHI. In the combined model, mean AHI was not associated with blood pressure variability. In separate models, mean AHI  and AHI variability  were associated with increased blood pressure variability. The combined model provided a superior model fit compared to a model with mean AHI alone . Quartile analyses also indicated an association between OSA severity categories, OSA variability, and greater blood pressure variability. Severe OSA was associated with ~1 mmHg increase in systolic and ~0.7 mmHg increase in diastolic blood pressure variability compared to no OSA  that may contribute to hypertension risk and blood pressure variability requires further consideration. However, validation studies versus gold standard polysomnography in over 150 participants28. However, the main study findings remained in sensitivity analyses when limited to morning blood pressure entries. Accordingly, circadian influences appear unlikely to have been a major confounder in the current study. Indeed, consistent with previous findings, variability in systolic blood pressure is a significant predictor of death when blood pressure is measured in the morning or evening, or both16. The number of clinical covariates available in this study was also somewhat limited. Thus, the potential impact of uncontrolled confounding behavioral and lifestyle factors 37 and treatment status to influence the current findings remain to be investigated. Like many digital health innovations and consumer-data research, there is a balance between data volume and the ability to capture all clinically relevant variables. Conceptually, these data could also be synchronized via electronic health records databases, and via the development of new digital health tools to automatically capture more diverse aspects of a person’s health. Multimodal inputs to predictive algorithms  have been recently shown to better predict health outcomes compared to single-source approaches across 12 predictive tasks, including 10 distinct chest pathology diagnoses, hospital length-of-stay, and 48 h mortality predictions38. Similarly, the field of sleep medicine may benefit from multi-input clinical data where daytime symptoms, overall clinical history, and multi-sensor recordings could be used to better predict health outcomes and treatment response.Instructions on the timing of blood pressure measurements were not given to participants. Thus, some of the variability in blood pressure may reflect circadian changes across the day39. Thus, it will be important to investigate whether the potential consequences of night-to-night variability in OSA severity are comparable between sexes in a larger cohort with more comparable numbers of women.The decision of the users to purchase a WSA and monitor their blood pressure may represent a selection bias towards those who had preexisting sleep and/or cardiovascular problems. Indeed, users were predominantly male, clearly indicating a sex-specific participation bias. Nonetheless, while no sex differences were detected in the current study in relation to the detected associations with uncontrolled hypertension, the pathophysiology of OSA differs in women versus menDespite these methodological considerations, the identification of strong associations between blood pressure variability, uncontrolled hypertension, and high night-to-night variability in OSA severity provides further support for the unique and important insights that multi-night non-invasive monitoring can yield regarding clinical end-points and potential health risks.Data were acquired retrospectively from 15,526 participants from a consumer-user database of people aged between 18 and 90 years who purchased an under-mattress sleep sensor device WSA and reported blood pressure measurements on at least five separate occasions. Blood pressure measurements were acquired using an FDA-registered Withings blood pressure cuff monitor in the participant’s home, synchronized directly to the Withings database . Data were collected between 1 July 2020 and 30 March 2021. Further inclusion criteria included ≥28 nights of WSA recordings and an average use of ≥4 times per week. All participants provided written consent through the Withings app for their deidentified data to be used for research purposes when signing up for a Withings account and the current study was approved by the Flinders University Human Research Ethics Committee.23. The estimated AHI also has minimal bias with in-laboratory polysomnography-derived AHI when the AHI is considered as a continuous variable22.The WSA is a nearable sleep monitoring device placed under-the-mattress that detects body movements, respiratory rate, heart rate, snoring, and cessation of breathing episodes. These signals are used to estimate the AHI using automated algorithms that show good agreement with in-laboratory polysomnography-derived AHI with high predictive performance to classify mild (89% sensitivity and 75% specificity), moderate-to-severe (88% sensitivity and 88% specificity) and severe OSA (86% sensitivity and 91% specificity)The Withings blood pressure monitor used in conjunction with the WSA comes with an instruction booklet that outlines how to take a blood pressure measurement. The user is instructed to (1) rest for ≥5 min before taking a measurement, (2) be seated in a comfortable position and in a quiet area with legs uncrossed, feet flat on the floor, and back/arm supported (3) not speak during the measurements, and (4) perform the measurement on their left arm. The user has the option of performing a single measurement or taking three consecutive measurements to acquire an average blood pressure value.40 , and OSA variability was defined within each OSA severity category.Hypertension exposure variables were the mean estimated AHI (hereafter referred to as “OSA severity”) and the average standard deviation of estimated AHI (hereafter termed “OSA variability”). OSA severity and variability were calculated for each participant derived from all available nights for each individual. OSA severity categories were defined using standard clinical cut-offs41 across the monitoring period as these thresholds are most commonly applied in previously published papers on the relationship between uncontrolled hypertension and OSA severity35. However, alternate definitions of uncontrolled hypertension were also included in sensitivity analyses. Only participants with five or more independent blood pressure measurements across the assessment period were included in the analysis. Systolic and diastolic blood pressure variability was defined as the standard deviation of the systolic and diastolic blood pressure across all measurements during the recording period.Uncontrolled hypertension was defined as a mean systolic blood pressure ≥140 mmHg or mean diastolic blood pressure ≥90 mmHgAll first-time users of the WSA are prompted to enter their age, sex, height, and weight from which body mass index (BMI) is calculated. These data were either self-reported and manually entered or, in the case of weight, acquired via Withings scales, a device fed directly into the online Withings database.β coefficients) for continuous variables were used to compare the 75th percentile to that of the 25th percentile, using the 25th percentile as the reference.Odds ratio (ORs) and 95% confidence interval (CIs) were determined using logistic-regression models to assess the association between OSA severity, OSA variability, and uncontrolled hypertension. Linear regression was used to assess the association between OSA severity, OSA variability, and blood pressure variability. Arbitrary cut-offs for continuous variables were omitted in favor of restricted cubic spline transformations, which are better suited to non-linearity. Thus, ORs (or 42.OSA severity and variability were first included in separate models (Model 1A and 1B), and then in a combined model (Model 2). All models also included age, BMI, and sex. Likelihood ratios were used to compare predictive performance between models. Collinearity was assessed using variance inflation factors. Interactions between OSA severity and OSA variability and sex were also examined. Although the primary analysis examined OSA severity as a continuous measure, secondary analyses also examined OSA severity categorized according to standard clinical cut-offs and quartiles. Logistic and linear regression was performed in the R programming language, using the rms modeling package43, and was therefore included as a confounder in the third sensitivity analysis. Finally, alternative definitions of hypertension were also investigated, including the home-blood pressure cut-offs of the European/NICE guidelines45 (systolic blood pressure/diastolic blood pressure ≥ 135/85), the AHA guidelines  (≥130/80) and stage 2 hypertension of the NICE guidelines44 (≥150/95).Four sensitivity analyses were conducted to further validate our findings. Firstly, given that blood pressure may vary during the day, we performed a sensitivity analysis where only morning blood pressure, measured between 6 a.m. and 12 p.m., entries were included. Secondly, the analysis was repeated by further adjusting for the number of blood pressure entries to control for potential biases associated with a variable number of blood pressure entries for each participant. Third, total sleep time has been shown to influence AHI certainty46 in R programming language.A potential mediating effect of night-to-night variability in OSA severity in the association between OSA severity and uncontrolled hypertension was investigated using a model depicted in Supplementary Fig. Further information on research design is available in the Supplementary materialREPORTING SUMMARY


P = .02) and history of SLT (P = .04) were significantly associated with better adherence. Glaucoma severity and the announcement of glaucoma progression were not significantly associated with adherence to VF examination. The COVID-19 pandemic had greatly influenced the adherence to VF examination in glaucoma patients. This study demonstrated that patients with the diagnosis of glaucoma suspect and history of SLT were more likely to adhere to VF examinations even during the COVID-19 pandemic.We described the proportion of adherence to the scheduled visual field (VF) examination and the associated factors in glaucoma patients in a tertiary referral center during the Coronavirus disease 2019 (COVID-19) outbreak in Taiwan. Patients with scheduled VF examinations during May 25th to July 12th, 2021, were retrospectively evaluated. Clinical characteristics including type of glaucoma, intraocular pressure (IOP) at the day of arranging VF examinations, prescriptions of anti-glaucoma medications, non-medical glaucoma treatment, length of glaucoma history, mean deviation (MD) of VF defect, and announcement of glaucoma progression were recorded. The associations between the adherence and the clinical factors were analyzed by univariate and multivariate logistic regression. There were 204 patients included, of which 37 patients (18.14%) adhered to VF examinations. A total of 161 patients (78.9%) were diagnosed with open-angle glaucoma (OAG), 27 patients (13.2%) with angle closure glaucoma, and 16 patients (7.8%) with glaucoma suspect. Most of the participants (41.2%) had mild VF defect and had been prescribed with no more than 1 bottle of anti-glaucoma medication. In the multivariate analysis, diagnosis of glaucoma suspect ( It is an optic neuropathy characterized by progressive loss of retinal nerve fiber layer accompanied with irreversible visual field loss. While reduction of intraocular pressure (IOP) has been proven to be a major influencing factor of glaucoma progression,,4 most studies regarding the adherence of glaucoma patients only focused on adherence to anti-glaucoma medications.–7 Adherence to follow-up examinations is crucial in monitoring glaucoma progression. However, there was limited literature discussing the adherence to follow-up visits and related examinations, especially in Asian countries. The American Academy of Ophthalmology recommended at least 2 follow-up visits per year and yearly visual field (VF) test in patients with primary open-angle glaucoma in the preferred practice pattern guidelines. Patients with poor adherence to follow-up examinations were more likely to have severer glaucomatous disease.Glaucoma is one of the leading causes of blindness worldwide. and the impact was greatest among low-income countries.,12 Taiwan was one of the few countries that had initiated restrictions at the very early stage of the outbreak. Before first COVID-19 surge, there was almost 18 months of success in pandemic control in Taiwan, with <1300 cumulative cases until May 2021. Most residents were able to go to work and perform daily economic activities, including concerts, religious festivals and baseball games. After the outbreak in May 2021, an increase of 15,000 cases in 3 months were reported; meanwhile, over 100,000 confirmed cases were announced in the United States during this period. Despite a relatively low infection rate, Central Epidemic Command Center (CECC) in Taiwan raised the epidemic warning level for 2 major cities and strengthened related measures on May 15th, 2021. Many hospitals applied a strict COVID-19 screening policy for hospital visits during this period.The outbreak of Coronavirus disease 2019 (COVID-19) had a major impact on utilization of the healthcare services the VF test still remains a standard role in glaucoma evaluation. With more follow-up examinations in the visual field, the progression speed would be more accurately estimated by the glaucoma progression analysis provided by Humphrey field analyzer . However, there was a prominent reduction of visits in glaucoma clinics and a great portion of scheduled VF examinations were canceled by patients’ will. During this period, all patients had to provide a negative COVID-19 antigen test within 3 days from the scheduled VF examination according to our department regulation. The complicated process of antigen test and additional fee may have weakened the patients’ will to come back to complete the scheduled VF examination. Meanwhile, patients were anxious about getting infected by COVID-19 while visiting the hospital during this period. On the other hand, Pujari R. et al used a questionnaire to investigate the change in glaucoma patient experience during the COVID-19 pandemic, and they found that patients were more uncertain of their glaucoma care and more worried about losing vision from glaucoma. It is interesting and important to know the compliance of the glaucoma patients during this period. However, it is hard to determine the reason for glaucoma patients’ follow-ups, whether for glaucoma itself or for other reasons. The visual field examination is one of the most representative glaucoma examinations. Therefore, we aimed to analyze the impact of COVID-19 outbreak to the adherence to the scheduled VF examination during this short period and evaluated the possible associated factors regarding their adherence in a tertiary glaucoma referral center in New Taipei City in Taiwan.Although optical coherence tomography (OCT) provides a reliable and objective technique in glaucoma follow-up to measure peripapillary retinal nerve fiber layer and macular ganglion cell-inner plexiform layer thickness,A retrospective chart review study was conducted in Far Eastern Memorial Hospital (FEMH). The study protocol was approved by the Ethics Committee of the institution (No:110278-E) and the study adhered to the tenets of the Declaration of Helsinki. The list of patients diagnosed with glaucoma and glaucoma suspect, who had scheduled VF examinations between May 17th, 2021, and July 12th, 2021 was investigated. Participants who had severe visual field defect  in the initial exam, were not eligible for event-based guided progression analysis and were defined as “severe VF defect.” Those participants who had only received <2 VF examinations were not eligible for event-based progression analysis, thus were classified as “insufficient examinations.”At FEMH, patients diagnosed with glaucoma were advised to have routine VF examinations every 3 to 6 months in adherence to American Academy of Ophthalmology preferred practice pattern guidelines.(9) During the study period, all patients had to provide a negative COVID antigen test within 3 days from the scheduled VF examination according to our department regulation. Those who adhered to this policy and received scheduled VF examination in the study period were defined as “adherence” and those who refused or delayed their VF examination over the study period were defined as “non-adherence.” Baseline demographic data and clinical characteristics were collected from the medical charts including type of glaucoma, duration of glaucoma, bottles of anti-glaucoma medications prescribed, IOP at the day of arranging VF examination, mean deviation (MD) of VF defect, and non-medical glaucoma treatment history including trabeculectomy and selective laser trabeculoplasty (SLT). VF tests were performed with a Humphrey field analyzer  running the standard Swedish interactive threshold algorithm 30–2 program. The results were classified into 3 groups: mild defect (above −6 dB), moderate defect (−6 to −12 dB), and severe defect (<−12 dB). Duration of glaucoma was classified into 3 groups, which was <1 year, 1 to 5 years, and over 5 years. VF progression was defined by event-based analysis. Possible progression was announced when there were at least 3 locations that showed significant variability compared to baseline tests and repeated in the same points in at least 2 consecutive follow-up tests. Likely progression was announced when there were at least 3 locations that showed significant variability compared to baseline tests and repeated in the same points in at least 3 consecutive follow-up tests. “Possible progression” and “likely progression” in the latest VF examination before the scheduled VF examination in the study period were defined as VF progression in our analysis.Exclusion criteria were patients aged below 20 years or those with 1 eye legally blind. If bilateral eyes were glaucomatous, only the worse eye was analyzed in this study.P value < .25 were included in multivariable regression. A value of P < .05 was considered statistically significant in multivariable analysis.Statistical analysis was performed using SPSS 22.0 software . Descriptive statistics such as the number and percentage for categorical data and the mean ± standard deviation for continuous data were used to present data distributions. Binary logistic regression was implemented to evaluate the association between each clinical characteristics and adherence to VF examination, controlling for age and gender. All variables associated with adherence in the univariable analysis with During the study period, 205 patients with glaucoma had scheduled visual field examinations. One patient was excluded because he had one legally blind eye. Thirty-seven patients 18.14%) were classified into the adherence group, while 167 (81.86%) patients were classified into the non-adherence group. The mean age of participants was 54.22 ± 13.99 years. Of the 204 participants, 78.9% were diagnosed with open angle glaucoma (OAG), 13.2% were diagnosed with angle closure glaucoma, and 7.84% were diagnosed with glaucoma suspect. The majority  of participants had been diagnosed with glaucoma for more than 1 year. Over half of the participants  had been prescribed with no more than 1 bottle of anti-glaucoma medication. The mean IOP was 14.63 ± 3.90 mm Hg, and 95.6% of IOP was under 21 mm Hg. 5.4% of participants underwent trabeculectomy, while 16.7% underwent SLT. Around half of participants  had mild VF defect (MD > −6 dB). 18.1% of participants had possible or likely progression in visual field progression analysis. The demographic data and clinical characteristics of study participants were listed in Tables 8.14% werP = .12), glaucoma progression (P = .05), and history of SLT (P = .2). In multivariable analysis, diagnosis of glaucoma suspect , and history of SLT  were significantly associated with greater adherence. Status of glaucoma progression was not significantly associated with adherence in multivariable analysis  for above clinical characteristics were shown in Table  The pandemic has profoundly affected every social and medical field, even harmed the overall corneal transplant activity across Italy, with a reduction of nearly 60% as compared to the same period of 2019. Previous studies also reported impact on the adherence to lipid-lowering medications and biologics and reported that about 30 to 40 percent of patients failed to refill these medications after the first outbreak of COVID-19. Dramatic decrease of long-acting injectable antipsychotics prescriptions during this period was also reported. Researchers had proposed some theories for the adverse impact of COVID-19 pandemic on the adherence to medications. First, restrictive measures including limited physical distancing brought inconvenience when going out. Second, the elderly patients, who were more likely to have chronic conditions, were advised by every social media to stay at home. Also, mobilization of healthcare professionals to the COVID-19 frontline limited the accessibility of healthcare services. Reduced hospitalizations for chronic disease including heart failure and chronic obstructive pulmonary disease were also observed during COVID-19 pandemic. However, data about the reduction in ophthalmic examinations because of the lockdown restrictions were limited. This study in a tertiary referral center provides a comprehensive and in-depth overview of the impact of COVID-19 pandemic on the adherence to VF examinations, which was one of the most representative examinations in glaucoma patients. To the best of our knowledge, there was no study evaluating the impact of COVID-19 pandemic on glaucoma in the aspect of follow-up examinations instead of glaucoma treatment.COVID-19-related drop in volume of eye surgical procedures were reported. In one questionnaire-based study discussing the impact of COVID-19 in patients with glaucoma in South India, longer distance to hospital, using more than one anti-glaucoma medication, lack of awareness about glaucoma, and psychological affections were significantly associated with poor medication adherence. A more recent study revealed significant reduction of adherence rate of ocular hypotensive medication from 86.6% to 68% after COVID-19 pandemic outbreak in the United States. Their study provided more detailed insight on psychological effect on adherence in the COVID-19 pandemic. Lower psychometric measures of resilience, which resulted in lower levels of planful problem solving, was associated with poorer adherence. As far as we know, the factors we evaluated in our study were never discussed in previous studies, that we found the diagnosis of glaucoma suspect and history of SLT treatment were significantly associated with better adherence. It was interesting to find that the severity of glaucoma and the announcement of glaucoma progression were not significantly associated with the adherence to VF examination.The COVID-19 outbreak in May 2021 in Taiwan resulted in major lockdown for almost 90 days. Meanwhile, FEMH adopted strict COVID-19 screening policies for all inpatient and outpatient departments. Patients who were scheduled for hospitalization or examinations in enclosed spaces with inadequate ventilation for over 15 minutes, including magnetic resonance imaging, hemodialysis and VF examinations…etc, were requested to take COVID-19 antigen test within 3 days. Although the screening policies were strict, which made the environment in the hospital were relative safer than the outside stores, the VF examination adherent rate was still very low. A total of 204 patients were enrolled, only 37 patients (18.14%) completed the VF examination. The fear of COVID-19 pandemic and inaccessibility of hospital-visit might result in the low adherence rate of VF examinations during this period. A systematic review revealed reduction by one third of healthcare utilization during COVID-19 pandemic.,28 However, few studies had evaluated the association between the adherence to follow-up examinations and VF progression status. Ung et al revealed that more severe VF loss and using more IOP-lowering medications were significant factors associated with poor follow-up visit adherence. In the Philadelphia glaucoma detection and treatment project, male gender, final diagnosis of glaucoma, and anti-glaucoma medications prescription were associated with greater adherence to follow-up examinations. This project was conducted before the COVID-19 pandemic and was performed in underserved urban communities. In our study, the severity of glaucoma and the announcement of glaucoma progression were not significantly associated with the adherence to VF examination. Two reasons might account for these findings. First, glaucoma was a chronic disease and if it was progressive, it was generally slowly progressive. Therefore, there would not be a sudden change in the severity of glaucoma, and patients with even severe glaucoma would not have better adherence to follow-up examination. Second, the glaucoma progression in this study was defined by the glaucoma progression analysis, which was usually too sensitive to be detected by the patients. These might explain the poor associations between the announcement of glaucoma progression and adherence to VF examination.It has been well recognized that poor adherence to anti-glaucoma mediation, which usually refers to not regular using anti-glaucoma mediation, was associated with faster VF progression.–31 IOP-lowering medications remained the first-line treatment for OAG in Taiwan. In FEMH, surgical and SLT treatment were only suggested to the patients with VF progression and unsatisfied IOP control or those intolerant to anti-glaucoma medication. However, when their IOP was controlled within low teens under topical medication, some patients hesitated and refused to receive further filtering surgery with the fear of surgical complications. They would rather choose SLT for further IOP control. Therefore, the awareness of unstable glaucoma control in patients who underwent SLT treatment might contribute to better adherence to VF examinations even during the period of COVID-19 pandemic. On the other hand, the eagerness to know if disease progression got controlled after the SLT treatment is the other reason for the higher adherence of VF examination in this group. On the contrary, history of trabeculectomy was not significantly associated with the adherence in our study. These patients usually had more severe VF defect and relatively poor visual acuity. However, they usually had more stable IOP after trabeculectomy and lower demand of anti-glaucoma medications after the trabeculectomy. This might result in careless attitude upon glaucoma follow-up examinations. Also, there were only 11 patients (5.4%) who underwent trabeculectomy in this study. The small sample size might have resulted in insufficient statistical power.A history of SLT treatment was significantly associated with better adherence in our study. To the best of our knowledge, there was no literature studying the association of the adherence to glaucoma examination and history of the SLT treatment. Although previous studies suggested SLT can be an effective primary treatment in OAG eyes,P = .02) in the multivariable analysis. The eagerness to know whether one has glaucoma or not might result in less impact of COVID-19 pandemic on hospital utilization for patients with suspected glaucoma.Diagnosis of glaucoma suspect was associated with better adherence to the VF examination in this study, compared to those who had confirmed diagnosis of glaucoma. Patients with glaucoma suspect were either referred from primary clinic for glaucoma evaluation or confirmation. The VF examination was crucial for glaucoma evaluation and deciding whether to commence anti-glaucoma medications. Moreover, VF examinations for patients were important for monitoring progression. Under National Health Insurance in Taiwan, it was easy to refill the anti-glaucoma medications at local pharmacies or local ophthalmological clinics. There was no crucial need of hospital visits, especially the tertiary teaching hospital only for refilling the medications during the COVID-19 pandemic. The other reason was that VF examination was not commonly available in local clinics. Therefore, even there were only 16 patients (7.8%) in the group of glaucoma suspect, we found significant association with better adherence to VF examination (Our study has its limitations, including its retrospective design and relatively small sample size. Moreover, our study included patients from glaucoma suspect to advanced glaucoma. There were 2 circumstances not appropriate for analysis of VF progression, which were patients with insufficient examinations in the glaucoma suspect group, and those with severe VF defect in the advanced glaucoma group. The 2 populations accounted for 30% of the participants. The diversity of the status of VF progression may limit the statistic power. However, our study reflected the real-world data during the COVID-19 pandemic. Lastly, the outbreak of COVID-19 pandemic and the policy of the government was different in every country. This study was a single center study in Taiwan and the results may not directly apply to other countries. On the other hand, the special circumstances in this period with relatively low COVID-19 infection rate and tightened restrictions provided us a unique investigation of adherence to VF examination in the glaucoma patients. Further studies investigating delays in patient appointments of visual field examination with impacts on glaucomatous progression will further elucidate the real impacts that COVID-19 has brought to the glaucoma patients.In conclusion, our study demonstrated the low adherence of scheduled VF examination in patients with glaucoma and glaucoma suspect during the COVID-19 pandemic. Patients with diagnosis of glaucoma suspect instead of glaucoma and history of SLT treatment were associated with greater adherence. Poor adherence to VF examinations may result in delay of diagnosing and detecting disease progression. The findings of our study may shed light on the importance of adherence to VF examination and awareness the adverse impacts of disease monitoring during COVID-19 pandemic.Conceptualization: Pei-Yao Chang, Yu-Han Wang.Data curation: Yu-Han Wang.Formal analysis: Yu-Han Wang, Jiun-Yi Wang.Investigation: Yu-Han Wang.Methodology: Pei-Yao Chang, Yu-Han Wang.Project administration: Pei-Yao Chang, Yu-Han Wang.Resources: Yu-Han Wang.Software: Yu-Han Wang.Supervision: Pei-Yao Chang, Yu-Han Wang, Jia-Kang Wang.Validation: Yu-Han Wang.Visualization: Yu-Han Wang, Jiun-Yi Wang.Writing – original draft: Yu-Han Wang.Writing – review & editing: Pei-Yao Chang.


The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is more infectious than the previous variants but less severe; more patients are being followed up without hospitalization. Identification of patients with severe disease symptoms as early as possible and prompt initiation of treatment are crucial. A case of a 19-year-old man with mild COVID-19 is described in this report. He died of a secondary infection with Fusobacterium necrophorum bacteremia and a progressive hemorrhagic disorder. The diagnosis was made based on the clinical course and needle necropsy results. In non-severe COVID-19 patients, rapid deterioration of the disease symptoms requiring emergency treatment should lead to suspicion of additional fatal infections with similar clinical symptoms. The clinical symptoms of COVID-19 differ among the variants [We report an unusual case of a mildly ill COVID-19 patient, without a high risk of serious illness, who died soon after admission due to a Fusobacterium necrophorum infection. This experience suggests that even for patients with mild COVID-19 without risk factors, there is a need to remain alert for additional serious bacterial infections, and prompt intervention should be initiated before their condition worsens.A 19-year-old man was diagnosed with COVID-19 by a reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2, a day after the onset of fever. He had no past medical history of illness and had already been administered two doses of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2). He was followed up at home because of a mild illness with no risk of progressing to severe COVID-19. However, his clinical symptoms gradually deteriorated, with a sore throat, fever (with a body temperature of over 40°C), and chills. Five days after onset, he presented with impaired consciousness and was transferred to a nearby acute-care hospital. He was intubated, and norepinephrine was administered owing to severely impaired consciousness and hypotension. A whole-body computed tomography (CT) scan at the hospital revealed neither any signs of pneumonia nor any other findings as the source of the fever. The patient was transferred to our tertiary care center because intensive care was required.On arriving at our hospital, a physical examination revealed a consciousness disturbance with a Glasgow Coma Scale (GCS) of E1VTM4. The heart rate was 180 beats per minute, and the blood pressure was 94/69 mmHg under continuous infusion of 0.1 µg/kg/min of norepinephrine. Initial blood examination revealed severe inflammation, acute kidney injury (AKI), and severe coagulopathy. Arterial blood gas analysis revealed metabolic acidosis . The sequential organ failure assessment score was 13 . The DIC score established by the Japanese Association for Acute Medicine -the critAfter these treatments, an additional CT scan of the head was performed, which revealed diffuse cerebral edema and intracranial hemorrhage in the brainstem extending to the fourth ventricle Figure .The patient died of increased intracranial pressure due to a brain hemorrhage, two days after admission. The two initial sets of blood bacterial cultures were found to be positive for F. necrophorum.Post-mortem needle biopsies of the kidney, lung, and bone marrow revealed glomerular neutrophils, interstitial neutrophils in the alveolar septum, and hypercellular bone marrow, respectively Figure .There were no convincing features of thrombotic angiopathy or hemophagocytic syndrome. Considering the clinical course and the needle necropsy results, the patient was finally diagnosed with DIC and septic shock due to F. necrophorum bacteremia secondary to COVID-19.This case provides us with an important message: when non-severe COVID-19 patients without any risk factors present with rapid deterioration of the disease symptoms requiring emergency treatment, suspicion must be raised for additional fatal infections that are associated with COVID-19 infection, exemplified by mucormycosis and pulmonary aspergillosis ,4.According to a survey by the National Institute of Infectious Diseases in Japan, 96.6% of COVID-19 cases in Japan during February 2022 were caused by the Omicron variant; the present case occurred during this period . The OmiFever and sore throat are closely associated with upper airway infection caused by flu viruses, Group A Streptococcus, and F. necrophorum . Among tThe diagnosis of F. necrophorum was delayed till the end because the symptoms of SARS-CoV-2 (Omicron variant) infection are almost the same as those for F. necrophorum. A throat swab was not sent for culture sensitivity. COVID-19 medication was not administered; only antipyretics were administered. Therefore, the administration of appropriate antibiotics was delayed. Careful diagnosis is necessary so as not to miss lethal bacterial infections that overlap with COVID-19 symptoms, as was the case in this report.Here, we report a fatal case of severe F. necrophorum infection secondary to mild COVID-19. Our case emphasizes the importance of diagnosing overlapping severe bacterial infections with similar clinical symptoms as COVID-19 during the treatment of patients with COVID-19, even though the patient may not have any risk factors. This would help in the initiation of prompt intervention before the patient’s condition deteriorates.