Vaccine-induced and hybrid immunity to SARS-CoV-2 after three or four doses of BNT162b2 - results from 22 months follow-up of a healthcare workers cohort, Israel, 2020-2022.

OBJECTIVES: SARS-CoV-2 remains a global health concern 3 years after its emergence. Safe and effective vaccines mitigate the pandemic impact, but the optimal schedule remains unclear, especially in a context where a high proportion of the population is infected. METHODS: We periodically measured anti-spike SARS-CoV-2 immunoglobulin (Ig)G titers using a quantitative assay in an Israeli healthcare worker cohort who all received at least two BNT162b2 doses and either received further doses and/or were subsequently infected up to 22 months after dose two, and compared geometric mean concentrations according to number of doses received and infection status using analysis of variance. RESULTS: Among the 993 included participants, infection after dose two led to higher geometric mean concentration IgG titers than a third dose (4285 vs 2845 arbitrary unit/ml 1-2 months after infection/vaccination, P = 0.03). In 16-18 months after dose two, those infected and those who received three or four vaccine doses all had IgG geometric mean concentration levels above 500 arbitrary unit/ml with no significant differences among groups (P = 0.6). IgG levels plateaued 16-22 months after dose two. CONCLUSION: Three BNT162b2 doses provide long-term immunogenicity comparable to breakthrough infection after dose two. Dose four transiently increases IgG levels and may be especially important for providing additional protection to vulnerable individuals during periods of increased transmission risk.

Magistral Compounding with 3D Printing: A Promising Way to Achieve Personalized Medicine.

BACKGROUND: Magistral compounding has always been an integral part of pharmacy practice. The increasing demand worldwide for personalized drug treatments might be accommodated by an increase in magistral compounding. The new, flexible technology of 3D medicine printing could advance this process even further. However, the issue of how 3D medicine printing can be implemented within the existing magistral compounding infrastructure has not been explored. AIMS: To investigate how 3D printing can be integrated into the existing compounding system by taking regulatory, economic, and profession-oriented aspects into account. METHODS: Semi-structured interviews were conducted with relevant Dutch stakeholders representing various health institutions, such as health ministries and boards, professional bodies, and different types of pharmacies. Participants were identified through purposeful sampling. Content analysis was applied to identify the main themes. RESULTS: A total of 15 Dutch stakeholders were interviewed. It was found that the prevalence of compounding in community pharmacies in the Netherlands has decreased as a result of the practice shifting to specialized compounding pharmacies due to higher costs, lack of space, and the need to fulfill quality requirements. All interviewees considered 3D printing to be a promising compounding technique for community pharmacies, as it offers an automated approach with high digital flexibility and enables adapted formulations, including 'polypills.' Regulatory and quality assurance challenges were considered comparable to those of normal magistral products; however, there remain pending regulatory issues regarding quality control, particularly for Active Pharmaceutical Ingredients containing intermediate feedstock materials (e.g., prefilled cartridges) in 3D printing. 3D printing was believed to become cost effective over time. CONCLUSION: In the Netherlands, specialized compounding pharmacies have largely taken over compounding activities. 3D printing could be introduced within this system; however, challenges regarding how to regulate prefilled cartridges have yet to be addressed. Compounding using 3D printing in regular community pharmacies could enhance patients' individualized treatment; however, this activity would require incentives to stimulate the return of compounding to normal pharmacy practice.

Data-enriched edible pharmaceuticals (DEEPs): Patients' preferences, perceptions, and acceptability of new dosage forms and their digital aspects - An interview study.

Background: In the field of pharmaceuticals, there is a shift away from the traditional "one-size-fits-all" concept to a more patient-centered one. A potential approach to obtain personalized medicine is with printed Data-Enriched Edible Pharmaceuticals (DEEPs). DEEPs that are printed in the pattern of QR codes contain both the patient-tailored dose and data that can be used to give patients personalized drug information and combat counterfeit medicines. Objectives: The study aims to explore patients' preferences, perceptions, and acceptability of DEEPs, and the digital aspects of them. Methods: Thirteen participants, living in Denmark, were interviewed twice using a semi-structured approach. Interviews were conducted face-to-face or via video calls. The interviews were transcribed, translated, and analyzed using thematic coding analysis. Results: The participants found it useful to participate in the design of their own medicine. The orodispersible nature of DEEPs and the possibility to select color, embedded images, flavors, and physical dimensions of DEEPs were considered beneficial for patients' adherence. Patients' personal preferences, convenience, and aesthetics were the main drivers for their favored design of DEEPs. The acceptability of digital healthcare in connection to DEEPs was found to be related to the participants' level of digital literacy. Conclusions: The participants generally had a positive attitude towards DEEPs and the digital aspects of them. However, to accept digital healthcare in connection to DEEPs, it should be adaptable and easy to use for everyone. The combination of digital healthcare and on-demand fabricated DEEPs could potentially contribute to higher patient adherence and safety in the future.

Scenarios for 3D printing of personalized medicines - A case study.

Background: 3D printing is a promising new technology for medicines' production. It employs additive manufacturing techniques, and is ideal for producing personalized medicines (e.g., patient-tailored dose, dosage form, drug release kinetics). Objective: To investigate how 3D printing technologies can be implemented in a European pharmaceutical system, by suggesting different scenarios and assessing aspects that could affect its implementation. Method: Qualitative, semi-structured interviews were conducted with key stakeholders (e.g., from ministry, authorities, research organizations, pharmacies) in the Netherlands to elicit perspectives on 3D printing of personalized medicines. The Netherlands were chosen since it has a strong tradition in compounding. Five general scenarios were investigated: placing the 3D printers in industry, community pharmacies, hospital pharmacies, compounding facilities, and in patients' homes. Content analysis was used, building on verbatim transcripts. Results: Fifteen stakeholders were interviewed. Regulatory, economic, ethical and organizational challenges were identified to varying degrees in the different scenarios. The industry and home scenarios were associated with the most challenges, hospital pharmacies and compounding facilities with the least. Other important aspects identified were the role of community pharmacies, and who should design the tablets to be printed. Conclusion: All potential scenarios for 3D printing of personalized medicines include challenges. These should be taken into account when pursuing the use of 3D printing of medicine.

Active Case Finding for Communicable Diseases in Prison Settings: Increasing Testing Coverage and Uptake Among the Prison Population in the European Union/European Economic Area.

Prison populations are disproportionally affected by communicable diseases when compared with the general community because of a complex mix of socioeconomic determinants and environmental factors. Tailored and adequate health care provision in prisons has the potential to reach vulnerable and underserved groups and address their complex needs. We investigated the available evidence on modalities and effectiveness of active case-finding interventions in prisons by searching PubMed, Embase, and the Cochrane Library for records on prison and active case finding with no language limit. Conference abstracts and unpublished research reports also were retrieved. We analyzed the findings by testing modality, outcomes, and study quality. The included 90 records-63 peer-reviewed, 26 from gray literature, and 1 systematic review-reported variously on viral hepatitis, human immunodeficiency virus, sexually transmitted infections, and tuberculosis. No records were retrieved for other communicable diseases. Provider-initiated opt-in testing was the most frequently investigated modality. Testing at entry and provider-initiated testing were reported to result in comparatively higher uptake ranges. However, no comparative studies were identified that reported statistically significant differences between testing modalities. Positivity rates among tested inmates ranged broadly but were generally high for all diseases. The evidence on active case finding in correctional facilities is limited, heterogeneous, and of low quality, making it challenging to draw conclusions on the effect of different testing modalities. Scale-up of provider-initiated testing in European correctional facilities could substantially reduce the undiagnosed fraction and, hence, prevent additional disease transmission in both prison settings and the community at large.

Treatment of Latent Tuberculosis Infection: An Updated Network Meta-analysis.

BACKGROUND: Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI. PURPOSE: To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children. DATA SOURCES: PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied. STUDY SELECTION: Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB). DATA EXTRACTION: 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol. DATA SYNTHESIS: The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy. LIMITATION: Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies. CONCLUSION: Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin. PRIMARY FUNDING SOURCE: U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).

The epidemiology of invasive meningococcal disease in EU/EEA countries, 2004-2014.

BACKGROUND: Invasive meningococcal disease (IMD) is a major cause of bacterial meningitis and septicaemia although infection by some serogroups may be prevented through vaccination. We aimed to describe the epidemiology of IMD in EU/EEA countries during 2004-2014 to monitor serogroup- and age-specific trends, and compare country trends by the period of meningococcal C conjugate (MCC) vaccine introduction. METHODS: We analysed IMD surveillance data by age, gender, serogroup, country and outcome. We estimated the percentage change in annual notification rate (NR), using linear regression analysis of the log of the annual NR. We grouped countries by the year they introduced MCC vaccination into their routine immunisation programmes. RESULTS: The overall NR was 0.9/100 000 population, and decreased 6.6% (95%CI: -8.0%;-5.1%) annually. Infants had the highest NR (16.0/100 000), and there were decreasing trends in all age groups <50years. Serogroup B (SgB) caused 74% of all cases, and the majority of cases in all age groups. There were decreasing trends in SgB and serogroup C (SgC) and an increasing trend in serogroup Y. Countries that introduced MCC vaccination before, and between 2004 and 2014, had decreasing trends in NR of SgC, but not countries without routine MCC vaccination. CONCLUSIONS: Our findings support evidence that routine MCC vaccination was the driving force behind the decreasing SgC trend. Vaccinating against SgB in the first year of life could help reduce the burden of IMD due to this serogroup. Changing serogroup-specific NR trends highlight the need for high-quality surveillance data to accurately assess the changing epidemiology of IMD, the effectiveness and impact of implemented vaccines, and the need for future vaccines.

Image-based medical expert teleconsultation in acute care of injuries. A systematic review of effects on information accuracy, diagnostic validity, clinical outcome, and user satisfaction.

OBJECTIVE: To systematically review the literature on image-based telemedicine for medical expert consultation in acute care of injuries, considering system, user, and clinical aspects. DESIGN: Systematic review of peer-reviewed journal articles. DATA SOURCES: Searches of five databases and in eligible articles, relevant reviews, and specialized peer-reviewed journals. ELIGIBILITY CRITERIA: Studies were included that covered teleconsultation systems based on image capture and transfer with the objective of seeking medical expertise for the diagnostic and treatment of acute injury care and that presented the evaluation of one or several aspects of the system based on empirical data. Studies of systems not under routine practice or including real-time interactive video conferencing were excluded. METHOD: The procedures used in this review followed the PRISMA Statement. Predefined criteria were used for the assessment of the risk of bias. The DeLone and McLean Information System Success Model was used as a framework to synthesise the results according to system quality, user satisfaction, information quality and net benefits. All data extractions were done by at least two reviewers independently. RESULTS: Out of 331 articles, 24 were found eligible. Diagnostic validity and management outcomes were often studied; fewer studies focused on system quality and user satisfaction. Most systems were evaluated at a feasibility stage or during small-scale pilot testing. Although the results of the evaluations were generally positive, biases in the methodology of evaluation were concerning selection, performance and exclusion. Gold standards and statistical tests were not always used when assessing diagnostic validity and patient management. CONCLUSIONS: Image-based telemedicine systems for injury emergency care tend to support valid diagnosis and influence patient management. The evidence relates to a few clinical fields, and has substantial methodological shortcomings. As in the case of telemedicine in general, user and system quality aspects are poorly documented, both of which affect scale up of such programs.

High effective coverage of vector control interventions in children after achieving low malaria transmission in Zanzibar, Tanzania.

BACKGROUND: Formerly a high malaria transmission area, Zanzibar is now targeting malaria elimination. A major challenge is to avoid resurgence of malaria, the success of which includes maintaining high effective coverage of vector control interventions such as bed nets and indoor residual spraying (IRS). In this study, caretakers' continued use of preventive measures for their children is evaluated, following a sharp reduction in malaria transmission. METHODS: A cross-sectional community-based survey was conducted in June 2009 in North A and Micheweni districts in Zanzibar. Households were randomly selected using two-stage cluster sampling. Interviews were conducted with 560 caretakers of under-five-year old children, who were asked about perceptions on the malaria situation, vector control, household assets, and intention for continued use of vector control as malaria burden further decreases. RESULTS: Effective coverage of vector control interventions for under-five children remains high, although most caretakers (65%; 363/560) did not perceive malaria as presently being a major health issue. Seventy percent (447/643) of the under-five children slept under a long-lasting insecticidal net (LLIN) and 94% (607/643) were living in houses targeted with IRS. In total, 98% (628/643) of the children were covered by at least one of the vector control interventions. Seasonal bed-net use for children was reported by 25% (125/508) of caretakers of children who used bed nets. A high proportion of caretakers (95%; 500/524) stated that they intended to continue using preventive measures for their under-five children as malaria burden further reduces. Malaria risk perceptions and different perceptions of vector control were not found to be significantly associated with LLIN effective coverage. CONCLUSIONS: While the majority of caretakers felt that malaria had been reduced in Zanzibar, effective coverage of vector control interventions remained high. Caretakers appreciated the interventions and recognized the value of sustaining their use. Thus, sustaining high effective coverage of vector control interventions, which is crucial for reaching malaria elimination in Zanzibar, can be achieved by maintaining effective delivery of these interventions.

A qualitative study on caretakers' perceived need of bed-nets after reduced malaria transmission in Zanzibar, Tanzania.

BACKGROUND: The elimination of malaria in Zanzibar is highly dependent on sustained effective coverage of bed-nets to avoid malaria resurgence. The Health Belief Model (HBM) framework was used to explore the perceptions of malaria and bed-net use after a noticeable reduction in malaria incidence. METHODS: Nineteen in-depth interviews were conducted with female and male caretakers of children under five in North A district, Zanzibar. Deductive content analysis was used to identify meaning units that were condensed, coded and assigned to pre-determined elements of the HBM. RESULTS: Awareness of malaria among caretakers was high but the illness was now seen as easily curable and uncommon. In addition to the perceived advantage of providing protection against malaria, bed-nets were also thought to be useful for avoiding mosquito nuisance, especially during the rainy season when the malaria and mosquito burden is high. The discomfort of sleeping under a net during the hot season was the main barrier that interrupted consistent bed-net usage. The main cue to using a bed-net was high mosquito density, and children were prioritized when it came to bed-net usage. Caretakers had high perceived self-efficacy and did not find it difficult to use bed-nets. Indoor Residual Spraying (IRS), which was recognized as an additional means of mosquito prevention, was not identified as an alternative for bed-nets. A barrier to net ownership was the increasingly high cost of bed-nets. CONCLUSIONS: Despite the reduction in malaria incidence and the resulting low malaria risk perceptions among caretakers, the benefit of bed-nets as the most proficient protection against mosquito bites upholds their use. This, in combination with the perceived high self-efficacy of caretakers, supports bed-net usage, while seasonality interrupts consistent use. High effective coverage of bed-nets could be further improved by reinforcing the benefits of bed-nets, addressing the seasonal heat barrier by using nets with larger mesh sizes and ensuring high bed-net ownership rates through sustainable and affordable delivery mechanisms.

System effectiveness of a targeted free mass distribution of long lasting insecticidal nets in Zanzibar, Tanzania.

BACKGROUND: Insecticide-treated nets (ITN) and long-lasting insecticidal treated nets (LLIN) are important means of malaria prevention. Although there is consensus regarding their importance, there is uncertainty as to which delivery strategies are optimal for dispensing these life saving interventions. A targeted mass distribution of free LLINs to children under five and pregnant women was implemented in Zanzibar between August 2005 and January 2006. The outcomes of this distribution among children under five were evaluated, four to nine months after implementation. METHODS: Two cross-sectional surveys were conducted in May 2006 in two districts of Zanzibar: Micheweni (MI) on Pemba Island and North A (NA) on Unguja Island. Household interviews were conducted with 509 caretakers of under-five children, who were surveyed for socio-economic status, the net distribution process, perceptions and use of bed nets. Each step in the distribution process was assessed in all children one to five years of age for unconditional and conditional proportion of success. System effectiveness (the accumulated proportion of success) and equity effectiveness were calculated, and predictors for LLIN use were identified. RESULTS: The overall proportion of children under five sleeping under any type of treated net was 83.7% (318/380) in MI and 91.8% (357/389) in NA. The LLIN usage was 56.8% (216/380) in MI and 86.9% (338/389) in NA. Overall system effectiveness was 49% in MI and 87% in NA, and equity was found in the distribution scale-up in NA. In both districts, the predicting factor of a child sleeping under an LLIN was caretakers thinking that LLINs are better than conventional nets (OR = 2.8, p = 0.005 in MI and 2.5, p = 0.041 in NA), in addition to receiving an LLIN (OR = 4.9, p < 0.001 in MI and in OR = 30.1, p = 0.001 in NA). CONCLUSIONS: Targeted free mass distribution of LLINs can result in high and equitable bed net coverage among children under five. However, in order to sustain high effective coverage, there is need for complimentary distribution strategies between mass distribution campaigns. Considering the community's preferences prior to a mass distribution and addressing the communities concerns through information, education and communication, may improve the LLIN usage.

Adherence to artesunate-amodiaquine combination therapy for uncomplicated malaria in children in Zanzibar, Tanzania.

OBJECTIVES: To estimate caretaker adherence to co-blistered, but not co-formulated, artesunate-amodiaquine (AsAq) for uncomplicated malaria and identify factors associated with caretaker adherence. METHODS: Cross sectional household survey of caretakers of 210 children under 5 years of age who had been prescribed and dispensed AsAq at 21 public health facilities (HFs). The caretakers were interviewed in their homes on the 4th day of receiving the 3 day treatment. Adherence of caretakers was assessed by self report and pill count. RESULTS: Caretaker adherence to AsAq was 77% (95% CI: 67%-87%). Non-adherence resulted in under-dosing (3/4) of the time and was most often in the form of wrong daily doses due to misunderstanding or forgetting the correct dose regimens. Predictors of adherence were education exceeding 7 years (OR = 5.08, P = 0.008) and receiving the exact number of pills to complete the treatment regimen (OR = 4.09, P = 0.006). All caretakers of children who were administered the first dose at the HF had adhered to the treatment. CONCLUSION: We found moderate levels of caretaker adherence to AsAq. Further improvement could be achieved by producing dose-specific packaging for infants, providing clear instructions and giving the first dose under observation at the HF.

Accuracy of hepatitis C virus core antigen testing in pools among seroconverters.

BACKGROUND: Screening blood units for hepatitis C virus (HCV) with nucleic acid testing (NAT) reduces the risk associated with the long "window period" (8-9 weeks) after HCV infection. The feasibility of adding the HCV core antigen assay in pools to the existing anti-HCV individual screening was examined as an alternative of NAT, for early detection of HCV. STUDY DESIGN AND METHODS: Eighteen HCV seroconversion panels were tested for HCV antibodies, HCV antigen, and HCV RNA. Each sample was tested for HCV antigen individually and in pools of 3, 6, and 12. Statistical analyses included estimation of time until detection of the first positive HCV antigen bleed in each pool size, with a locally weighted regression (LOWESS) model. Sensitivity was calculated compared to NAT. RESULTS: Detection of HCV antigen in individual samples and in pools of 3 and 6 significantly preceded the detection of antibodies by 63, 53, and 46 days, respectively. Although the sensitivity of the HCV antigen test decreased with the increase in pool size, the estimated overall sensitivity of the "two-stage" antigen and antibody screening (where NAT of individual samples was the gold standard) was not significantly different between individual and the different pool sizes. CONCLUSION: Screening for HCV antigen in pools of 6 can be considered an efficient and easier-to-implement alternative to the costly NAT for identifying blood donors in the seroconversion period. It may offer a cost-effective approach in resource utilization in poor countries, that, after the implementation of HCV antibody testing, want to further improve blood safety.