Statistical inference in matched case-control studies of recurrent events.

BACKGROUND: The concurrent sampling design was developed for case-control studies of recurrent events. It involves matching for time. Standard conditional logistic-regression (CLR) analysis ignores the dependence among recurrent events. Existing methods for clustered observations for CLR do not fit the complex data structure arising from the concurrent sampling design. METHODS: We propose to break the matches, apply unconditional logistic regression with adjustment for time in quintiles and residual time within each quintile, and use a robust standard error for observations clustered within persons. We conducted extensive simulation to evaluate this approach and compared it with methods based on CLR. We analysed data from a study of childhood pneumonia to illustrate the methods. RESULTS: The proposed method and CLR methods gave very similar point estimates of association and showed little bias. The proposed method produced confidence intervals that achieved the target level of coverage probability, whereas the CLR methods did not, except when disease incidence was low. CONCLUSIONS: The proposed method is suitable for the analysis of case-control studies with recurrent events

Semiannual Versus Annual Influenza Vaccination in Older Adults in the Tropics: An Observer-blind, Active-comparator-controlled, Randomized Superiority Trial.

BACKGROUND: Antibody titres and vaccine effectiveness decline within 6 months after influenza vaccination in older adults. Biannual vaccination may be necessary to provide year-round protection in the tropics, where influenza circulates throughout the year. METHODS: Tropical Influenza Control Strategies (TROPICS1) was a single-center, 1:1 randomized, observer-blinded, active-comparator-controlled, superiority study in 200 community-resident adults aged ≥65 years. Participants received a standard-dose trivalent inactivated influenza vaccination (IIV3) at enrollment, and either tetanus-diphtheria-pertussis vaccination or IIV3 6 months later. The primary outcome was the proportion of participants with haemagglutination-inhibition (HI) geometric mean titre (GMT) ≥1:40 1 month after the second vaccination (month 7). Secondary outcomes included GMTs to month 12, the incidence of influenza-like illness (ILI), and adverse reactions after vaccination. RESULTS: At month 7, the proportion of participants with an HI tire ≥1:40 against A/H1N1 increased by 21.4% (95% confidence interval [CI] 8.6-33.4) in the semiannual vaccination group. This proportion was not significantly higher for A/H3N2 (4.3, 95% CI -1.1-10.8) or B (2.1, 95% CI -2.0-7.3). Semiannual vaccination significantly increased GMTs against A/H1N1 and A/H3N2, but not B, at month 7. Participants receiving a repeat vaccination of IIV3 reported a significantly lower incidence of ILI in the 6 months after the second vaccination (relative vaccine effectiveness 57.1%, 95% CI 0.6-81.5). The frequency of adverse events was similar after the first and second influenza vaccinations. CONCLUSIONS: Semiannual influenza vaccination in older residents of tropical countries has the potential to improve serological measures of protection against infection. Alternative vaccination strategies should also be studied. CLINICAL TRIALS REGISTRATION: NCT02655874

Efficacy of Femarelle for the treatment of climacteric syndrome in postmenopausal women: An open label trial

AbstractObjectiveTo assess the effects of 2 months of treatment with Femarelle for climacteric syndrome in Taiwanese postmenopausal women.Materials and methodsA multi-center, open-label trial of 260 postmenopausal women, age ≥ 45 years with vasomotor symptoms. Women were enrolled after obtaining a detailed medical history and a thorough physical examination. They then received Femarelle (640 mg/d) twice daily for 8 weeks. The primary outcome was the changes in the frequency and severity of hot flushes from baseline to 4 weeks (1 month) and 8 weeks (2 months). Changes of general climacteric syndrome were assessed using a modified climacteric scale designed by Greene.ResultsThe frequency and severity of hot flushes were significantly improved with Femarelle use (p < 0.001). After 8 weeks of treatment, the percentage of women with various climacteric syndromes was reduced (from 100% to 20.9% for hot flushes, from 97.7% to 87.9% for psychological symptoms, from 93.8% to 78.8% for somatic symptoms, and from 87.8% to 74.9% for sexual symptoms). General climacteric syndrome scores also significantly decreased, from 20.8 ± 0.7 at the time of enrollment to 12.9 ± 0.7 after 8 weeks of Femarelle treatment (p < 0.0001). Participants experienced improvement of various climacteric symptoms and signs after 8 weeks of treatment (75.1% for hot flushes, 68.7% for psychological symptoms, 70.6% for somatic symptoms, and 69.0% for sexual problems respectively). After 4 weeks and 8 weeks of treatment with Femarelle, patients showed statistically significant improvement in climacteric symptoms (p < 0.0001). Three women (1.2%) withdrew from the study after 4 weeks of treatment due to adverse effects.ConclusionFemarelle significantly improved climacteric symptoms in Taiwanese postmenopausal women. However, further evaluation is needed regarding the safety of long-term consumption

Changes in the global hospitalisation burden of respiratory syncytial virus in young children during the COVID-19 pandemic: a systematic analysis

Background The coronavirus disease 2019 (COVID-19) pandemic was reported to have impacted RSV epidemiology and could have important implications for RSV prevention and control strategies. We aimed to understand the RSV-associated acute lower respiratory infection (ALRI) hospitalisation burden in children younger than five years during the COVID-19 pandemic period and the possible changes in RSV epidemiology from a global perspective.Methods We conducted a systematic literature search for studies published between January 1, 2020 and June 30, 2022, from MEDLINE (Ovid), Embase (Ovid), Global Health (Ovid), Web of Science, WHO COVID-19 database, CINAHL, LILACS, OpenGrey, CNKI, WanFang and ChongqingVIP. We included unpublished RSV epidemiology data shared by international collaborators. Eligible studies reported data for RSV-associated ALRI hospital admission rates or at least one of the following severity measures: the proportion of RSV cases that needed supplemental oxygen, mechanical ventilation or intensive care unit admission, and in-hospital case fatality ratio. A generalised linear mixed-effects model was used for data synthesis to understand the changes in the incidence, age distribution and severity of RSV-associated ALRI hospitalisations in children under five years during the COVID-19 pandemic, compared to the year 2019. Findings We included 61 studies, 14 studies from published literature and 47 unpublished datasets. Most studies (51/61) were from the high-income region, followed by the upper-middle-income region (9/61); only one study was from the lower-middle-income region, and no studies were from the low-income region. Compared to 2019, all income regions saw substantial decreases in RSV-associated ALRI hospitalisation rate across all age groups in 2020; the number of RSV-associated ALRI hospitalisations in children aged 0–&lt;60 months decreased by approximately 80% (325,000 to 66,000), 14% (581,000 to 501,000) and 42% (1,378,000 to 795,000) for high-income, upper-middle-income and lower-middle-income countries, respectively. RSV hospitalisation rate started to rise in 2021, and by March 2022, the annualised rate returned to a level comparable to 2019 (6·0/1000, 95% uncertainty interval [UI] 5·4–6·8 by March 2022 vs 5·0/1000, 3·6–6·8 in 2019) in high-income countries while remaining lower in middle-income countries. Across all time periods and income regions, RSV-associated ALRI hospitalisation rates peaked in infants aged 0–&lt;3 months and declined with increasing age. Compared to the pre-pandemic period, there was a significantly increased proportion of RSV-associated ALRI hospitalisations in those aged 12–&lt;24 months in high-income and upper-middle-income regions (ORs ranged from 1·30 [1·07–1·59] to 2·05 [1·66–2·54]). No consistent changes in disease severity were observed. Interpretation Our study documented a significant reduction in RSV-associated ALRI hospitalisation burden in children under five years during the first year of the COVID-19 pandemic. A rebound to pre-pandemic levels in RSV-associated ALRI hospitalisation rate was observed in the high-income region by March 2022 but not in the middle-income region, suggesting a more persistent negative impact of the COVID-19 pandemic on health-care systems and health-care access in middle-income regions. RSV surveillance needs to be established (or re-established) to monitor the changes in RSV epidemiology, particularly in low- and lower-middle-income countries.Funding EU Innovative Medicines Initiative Preparing for RSV Immunisation and Surveillance in Europe (PROMISE); Bill &amp; Melinda Gates Foundation; World Health Organization. <br/

Epidemiological risk factors for adult dengue in Singapore: an 8-year nested test negative case control study

10.1186/s12879-016-1662-4BMC Infectious Diseases16132

"I wouldn't really believe statistics" - Challenges with influenza vaccine acceptance among healthcare workers in Singapore.

BACKGROUND: Influenza vaccine acceptance among healthcare workers (HCWs) is a worldwide problem, but relatively little research has focussed on Asia, including Singapore. Despite widespread access and recommendations from public health authorities, influenza vaccine uptake remains suboptimal among HCWs. METHODS: Our qualitative study used focus group discussions to identify and explain factors limiting influenza vaccine acceptance among HCWs in Singapore. A total of 73 doctors, nurses, allied health and ancillary staff across three public hospitals were included. RESULTS: Challenges identified include a fear of contracting influenza from vaccination exacerbated by negative anecdotes regarding vaccine safety and efficacy, distrust of published efficacy data, uncertainty regarding relevance of existing data for Singapore, reluctance to introduce chemicals or overmedicate, pain from injection, low risk attributed to influenza and limited awareness of influenza transmission with a preference for alternatives in patient protection. Differences in attitudes were observed across vocational groups. Lack of overt promotion by hospital leadership in some institutions, perceived vaccine hesitancy among doctors, access, and work culture that implicitly encourages working through illness were further barriers. CONCLUSION: Our findings highlight a combination of misperceptions about influenza vaccination and cognitive biases at the individual level, and challenges at the institutional level limiting uptake. Findings indicate an urgent need to provide targeted education and communication. Rather than providing more data, we recommend a widely-disseminated, locally-compiled synthesis addressing specific concerns of hesitant HCWs. Tailoring interventions to specific vocational groups should be considered. Institutional norms and culture may have a powerful influence in setting default behaviours: more effort is needed in improving influenza vaccine promotion and priority at some institutions, integrating vaccine-related communication with other infection control communication and addressing influenza vaccine hesitancy among doctors as a priority. Finally, further study of strategies to address cognitive biases affecting influenza vaccine acceptance in Singapore is desirable

Comparing the immunogenicity of AS03-adjuvanted 2009 pandemic H1N1 vaccine with clinical protection in priority risk groups in England.

In England, during pandemic 2009 H1N1, vaccine efficacy and immunogenicity population studies in priority groups were rolled out in parallel to evaluate the pandemic vaccination programme. This provided a unique opportunity to compare immunogenicity and clinical protection in the same population and thus provide insights into the correlates of protection for the pandemic H1N1 2009 vaccine in risk groups. While clinical protection from AS03-adjuvanted pandemic 2009 H1N1 vaccine was high in those aged <25 years and pregnant women, effectiveness in older adults with chronic conditions has been found to be surprisingly poor. Here we present results from the immunogenicity study derived from the same population. Individuals from priority groups eligible for pandemic vaccination attending participating general practices were recruited. Pre and post-vaccination blood samples were collected and HI antibody testing to assess immune response to vaccination performed. The final cohort consisted of 610 individuals: 60 healthy children aged <5 years; 32 healthy pregnant women; 518 individuals from risk groups. Seroconversion rate in healthy children aged <5 years (87%, 95% CI: 75% to 94%) was higher than that of risk groups combined (65%, 95% CI: 61% to 69%) (p<0.001). Multivariable analysis of risk groups showed that the size of response in those who did seroconvert was lower in those who received the 2009/10 seasonal TIV (Fold effect: 0.52, 0.35 to 0.78). Predicted immunological boosting from higher pre-vaccine titres after 2009 pandemic H1N1 vaccination only occurred in children (seroconversion rate = 92%) and not in individuals aged 10 to 39 from risk groups (seroconversion rate = 74%). The lack of clinical protection identified in the same population in older adults from risk groups could be attributed to these lower seroresponses. Current immunogenicity licensing criteria for pandemic influenza vaccine may not correlate with clinical protection in individuals with chronic disease or immunocompromised

Acceptance and uptake of influenza vaccines in Asia: a systematic review

In Asia, the public health burden of influenza is significant despite the existence of efficacious influenza vaccines. Annual seasonal influenza vaccination can reduce the incidence of influenza significantly, yet influenza vaccination coverage remains low in this part of the world. As a densely populated region with varying climatic zones and a larger proportion of developing countries compared to the West, Asia is at increased risk of influenza. To provide a more comprehensive and nuanced understanding of the Asian region, the key objective of this systematic review is to examine the determinants of vaccination uptake in Asia, beyond that of existing studies that have largely been western-centric. We carried out a systematic review of peer-reviewed scientific research, examining the key determinants, acceptance and uptake of influenza vaccinations across Asia. A comprehensive search strategy was defined to capture studies that met the inclusion criteria of articles published in English, from 2008 to 2018, focusing on adult populations within Asia. A total of 83 relevant studies were appraised in this review. Analyses of the extant data confirmed that vaccination rates within Asia are low, and that most countries lack scientific research on vaccination behaviours. Studies were categorised into four different population groups: healthcare workers, high risk groups, general population and uniform groups. The motivators and deterrents for vaccine uptake varied according to population groups and characteristics. Both general populations and healthcare workers were concerned with vaccine safety and efficacy, and recommendations from health authorities were influential in vaccine uptake within the other populations. The findings suggest that further research is needed within a broader range of Asian countries to garner greater in-depth knowledge of vaccination behaviours in the region. In particular, influenza vaccination programs within Asia should focus on improving engagement more effectively, through greater relatability and transparency of data when educating the public.Ministry of Health (MOH)This research is supported by the Singapore Ministry of Health's Communicable Diseases Public Health Research Grant MOH/CDPHRG/0017/2015