Pneumococcal carriage and transmission in Karonga district, Malawi, before and after introduction of 13-valent pneumococcal conjugate vaccination

Streptococcus pneumoniae (pneumococcus) is a leading cause of childhood morbidity and mortality worldwide. Thirteen-valent pneumococcal conjugate vaccine (PCV-13) was introduced in the Malawian infant immunisation programme in November 2011. PCV-13 is currently given at a “3+0” schedule: doses are given at 6, 10 and 14 weeks and no booster dose is currently implemented. The aim of this thesis was to study pneumococcal carriage and transmission in Karonga District, Malawi, before and after introduction of PCV-13, in order to review the effect of the current pneumococcal vaccination programme on carriage, and to give recommendations on the implementation of different vaccination strategies in Malawi. Pneumococcal carriage studies were conducted in Karonga between 2008 and 2014, with a focus on infants born to an HIV-positive mother, and HIV-positive adults, both of whom are at high risk of invasive pneumococcal disease. We found no difference in pneumococcal acquisition in infants by maternal HIV-status. A greater proportion of infant pneumococcal acquisition was attributable to carriage in other children <5 years in the household than to maternal carriage. Pneumococcal carriage in HIV-positive adults in Malawi remained high despite up to two years of antiretroviral treatment, indicating a failure of reconstitution of respiratory mucosal immune response. An analysis on the uptake and timeliness of PCV-13 vaccination showed that despite high vaccination coverage in this setting, delays in vaccination were common. Infants born to lower educated or farming mothers and those living more remotely were at greater risk of being not fully vaccinated and being vaccinated late. Carriage studies conducted in 2014, two years post PCV-13 introduction, showed that carriage of vaccine type (VT) pneumococci had decreased in vaccinated children and unvaccinated older age groups, but that a reservoir of VT carriage was still present. VT carriage had not decreased in unvaccinated children <5 years. Carriage of non-vaccine type pneumococci (NVT) had increased in vaccinated children. Our results suggest that a herd immunity effect is taking place albeit slowly in comparison to other countries. Waning immunity seemed to occur in vaccinated children 1-4 years. Our mathematical modelling studies provided further evidence for waning immunity. An immunity half-life between 6 months and 1 year was found to fit best with the observed post-vaccination carriage prevalence. If the immunity half-life were to be increased to 2 years, this would have a large impact on VT carriage decline in vaccinated and unvaccinated age groups. In the stochastic individual-based transmission models, which included explicit household transmission, an indirect vaccine effect was observed immediately after introduction of PCV-13. Adding a booster dose to the current three-dose schedule (3+1 schedule) would be beneficial for vaccinated and unvaccinated groups. Replacing the current 3+0 schedule with a 2+1 schedule (booster dose at 9 months) initially resulted in slower VT decline, but seemed to be associated with a longer-term gain in lower VT carriage in 1-4 year olds. Maternal vaccination did not result in additional VT carriage reduction in the infant. Ongoing surveillance is required to assess VT carriage in this population and monitor waning immunity and serotype replacement in vaccination individuals. A review of the vaccination schedule may be required to optimise total population impact in this high carriage setting. There is need for cheaper, more effective, serotype-independent pneumococcal vaccines. Potentially cheaper PCVs produced in India are in the pipeline, as well as a couple of new generation vaccines that are currently in phase 2 clinical trials. The next decade is promising to be an exciting time for pneumococcal researchers and policy makers worldwide, as new vaccines will pose interesting possibilities to further decrease pneumococcal carriage and disease worldwide

Stage-Specific Sampling by Pattern Recognition Receptors during Candida albicans Phagocytosis

Candida albicans is a medically important pathogen, and recognition by innate immune cells is critical for its clearance. Although a number of pattern recognition receptors have been shown to be involved in recognition and phagocytosis of this fungus, the relative role of these receptors has not been formally examined. In this paper, we have investigated the contribution of the mannose receptor, Dectin-1, and complement receptor 3; and we have demonstrated that Dectin-1 is the main non-opsonic receptor involved in fungal uptake. However, both Dectin-1 and complement receptor 3 were found to accumulate at the site of uptake, while mannose receptor accumulated on C. albicans phagosomes at later stages. These results suggest a potential role for MR in phagosome sampling; and, accordingly, MR deficiency led to a reduction in TNF-α and MCP-1 production in response to C. albicans uptake. Our data suggest that pattern recognition receptors sample the fungal phagosome in a sequential fashion

Factors associated with skin and soft tissue infections among people who inject drugs in the United Kingdom: A comparative examination of data from two surveys

Background People who inject drugs (PWID) are at high risk of injection-related skin and soft tissue infections (SSTI). If not treated promptly, these can lead to serious health complications, which are a considerable healthcare burden. Data from two community surveys, with different approaches, were used to assess SSTI prevalence and associated factors among PWID to inform intervention implementation. Methods Data were analysed from two surveys, a national surveillance survey (n=2,874; 2017–18) of infections among PWID in the United Kingdom (UK) and an in-depth survey (n=455; 2018–19) of SSTI among PWID based in London, UK. Multivariable logistic regression models were constructed to ascertain the factors associated with self-reported SSTI. Results High prevalence of SSTI were reported in both samples: 52 % of participants from the national surveillance survey reported having SSTI within the preceding 12 months and 65 % of the London sample reported a lifetime history of SSTI. The factors associated with SSTI in both surveys were similar, including older age; number of years injecting; number of attempts required to inject into the vein; injecting into the hands, feet, groin or neck and re-using or sharing needles/syringes. Conclusions The number of PWID reporting SSTI in the UK is concerningly high. The two surveys used different recruitment approaches but found similar associations. We provide strong evidence of a relationship between venous access difficulty and SSTI. To stem the increase of SSTI and related complications in the UK, it is crucial that interventions attend to the underlying causes of venous damage among PWID

Sexualised drug use in the United Kingdom (UK): A review of the literature

Background: Sexualised drug use (SDU) refers to the use of drugs in a sexual context. This includes ‘Chemsex’- the use of drugs (specifically crystal methamphetamine, GHB/GBL and mephedrone) before or during planned sexual activity to sustain, enhance, disinhibit or facilitate the experience. Here we aimed to synthesise available UK prevalence data for Chemsex, SDU and the use of Chemsex drugs in an undefined context (CDU) in men who have sex with men (MSM). Methods: Papers published between January 2007 and August 2017 reporting Chemsex, SDU and/or Chemsex drug use (CDU) prevalence in MSM were identified through PubMed. Citations were searched for further eligible publications. We also conducted a review of national surveillance data, extracting prevalence data for Chemsex, SDU or CDU. Synthesized data were then assessed to determine the time at which these drugs were taken, in this case just prior to or during sexual activity (event-level). Results: Our search identified 136 publications, of which 28 were included in the final data synthesis. Three of the four surveillance systems assessed provided SDU or CDU data in MSM. Few publications included event-level data for Chemsex (n = 4), with prevalence estimates ranging from 17% among MSM attending sexual health clinics (SHC) to 31% in HIV-positive MSM inpatients. Prevalence estimates for SDU (n = 7 publications) also varied considerably between 4% in MSM receiving HIV care to 41% among MSM attending SHC for HIV post-exposure prophylaxis (PEP). Eighteen publications provided data for CDU. Conclusion: Prevalence estimates varied considerably due to differences in the definition used and population assessed. Standardised definitions and studies with representative national samples of MSM are required to improve our understanding of the extent of Chemsex and its associated risks. Longitudinal event-level data for SDU and Chemsex are needed to monitor impact of interventions. © 201

Epidemiology of Confirmed COVID-19 Deaths in Adults, England, March-December 2020

Of the 58,186 coronavirus deaths among adults in England during March-December 2020, 77% occurred in hospitals, 93% were in patients >60 years, and 91% occurred within 28 days of positive specimen. Cumulative mortality rates were highest among persons of Black, Asian, other, or mixed ethnicities and in socioeconomically deprived areas

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

Optical to near-infrared transit observations of super-Earth GJ1214b: water-world or mini-Neptune?

GJ1214b is thought to be either a mini-Neptune with a thick, hydrogen-rich atmosphere, or a planet with a composition dominated by water. In the case of a hydrogen-rich atmosphere, molecular absorption and scattering processes may result in detectable radius variations as a function of wavelength. The aim of this paper is to measure these variations. We have obtained observations of the transit of GJ1214b in the r- and I-band with the INT, in the g, r, i and z bands with the 2.2 meter MPI/ESO telescope, in the Ks-band with the NOT, and in the Kc-band with the WHT. By comparing the transit depth between the the different bands, which is a measure for the planet-to-star size ratio, the atmosphere is investigated. We do not detect clearly significant variations in the planet-to-star size ratio as function of wavelength. Although the ratio at the shortest measured wavelength, in g-band, is 2sigma larger than in the other bands. The uncertainties in the Ks and Kc bands are large, due to systematic features in the light curves. The tentative increase in the planet-to-star size ratio at the shortest wavelength could be a sign of an increase in the effective planet-size due to Rayleigh scattering, which would require GJ1214b to have a hydrogen-rich atmosphere. If true, then the atmosphere has to have both clouds, to suppress planet-size variations at red optical wavelengths, as well as a sub-solar metallicity, to suppress strong molecular features in the near- and mid-infrared. However, star spots, which are known to be present on the hoststar's surface, can (partly) cancel out the expected variations in planet-to-star size ratio, due to the lower surface temperature of the spots . A hypothetical spot-fraction of 10% would be able to raise the infrared points sufficiently with respect to the optical measurements to be inconsistent with a water-dominated atmosphere. [abridged]Comment: 13 pages, 8 figures. Accepted for publication in A&

Usage of low dead space syringes and association with hepatitis C prevalence amongst people who inject drugs in the UK

IntroductionSyringes with attached needles (low dead space syringes [LDSS]) retain far less blood following injection than syringes with detachable needles (high dead space syringes [HDSS]). People who inject drugs (PWID) who share needles/syringes may be less likely to acquire Hepatitis C virus (HCV) infection using LDSS, compared with HDSS, but data are limited.MethodsUtilising drug behaviour and HCV antibody testing data from the UK 2014/2015 Unlinked Anonymous Monitoring Survey of PWID, we calculated the percentage of syringes used in the past month that were LDSS. We investigated which injecting characteristics and demographic factors were associated with 100% LDSS (against 0-99%) usage, and whether 100% LDSS use was associated with antibody HCV-status, after adjusting for confounders.ResultOf 2,174 participants, 55% always used LDSS, 27% always used HDSS, and 17% used both LDSS and HDSS. PWID that had injected into their groin during the past month were unlikely to use LDSS, adjusted odds ratio (aOR) 0.14 (95% confidence interval 0.11-0.17), compared to those not using the groin. Those injecting crack were less likely to use LDSS than those not, aOR 0.79 (0.63-0.98). Polydrug use was negatively associated with LDSS use, aOR 0.88 (0.79-0.98) per additional drug. LDSS use was associated with lower prevalent HCV among all PWID (aOR 0.77, [0.64-0.93]), which was stronger among recent initiates (aOR 0.53 [0.30-0.94]) than among experienced PWID (aOR 0.81 [0.66-0.99]).DiscussionPeople who inject into their groin were less likely to use LDSS. Exclusive LDSS use was associated with lower prevalence of HCV amongst PWID that started injecting recently, suggesting LDSS use is protective against HCV

Exclusive enteral nutrition mediates gut microbial and metabolic changes that are associated with remission in children with Crohn’s disease

GD and AWW receive core funding support from the Scottish Government’s Rural and Environmental Science and Analytical Services (RESAS) Division. JW was funded by the Wellcome Trust [Grant No. 098051]. JVL is funded by MRC New Investigator Grant (MR/P002536/1) and ERC Starting Grant (715662). JK is funded by NIHR: II-OL-1116-10027, NIH: R01-CA204403-01A1, Horizon H2020: ITN GROWTH. Imperial Biomedical Research Centre, SAGES research grant. Infrastructure support for this research was provided by the NIHR Imperial biomedical Research Centre (BRC). Microbiota analyses were carried out using the Maxwell computer cluster at the University of Aberdeen. We thank the Illumina MiSeq team at the Wellcome Sanger Institute for their assistance. This work was partially described in the Ph.D. thesis of KD (Retrieved 2020, Pediatric inflammatory bowel disease Monitoring, nutrition and surgery, https://pure.uva.nl/ws/files/23176012/Thesis_complete_.pdf).Peer reviewedPublisher PD

Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort study

Background: Rotavirus is a major contributor to child mortality. The effect of rotavirus vaccine on diarrhoea mortality has been estimated in middle-income but not low-income settings, where mortality is high and vaccine effectiveness in reducing admissions to hospital is lower. Empirical population-based mortality studies have not been done in any setting. Malawi introduced monovalent rotavirus vaccine (RV1) in October, 2012. We aimed to investigate the impact and effectiveness of the RV1 vaccine in reducing diarrhoea-associated mortality in infants aged 10–51 weeks. Methods: In this population-based cohort study, we included infants born between Jan 1, 2012, and June 1, 2015, in Mchinji, Central Malawi and analysed data on those surviving 10 weeks. Individual vaccination status was extracted from caregiver-held records or report at home visits at 4 months and 1 year of age. Survival to 1 year was confirmed at home visit, or cause of death ascertained by verbal autopsy. We assessed impact (1 minus mortality rate ratio following vs before vaccine introduction) using Poisson regression. Among vaccine-eligible infants (born from Sept 17, 2012), we assessed effectiveness (1 minus hazard ratio) using Cox regression. Findings: Between Jan 1, 2012, and June 1, 2015, we recruited 48 672 livebirths in Mchinji, among whom 38 518 were vaccine-eligible and 37 570 survived to age 10 weeks. Two-dose versus zero-dose effectiveness analysis included 28 141 infants, of whom 101 had diarrhoea-associated death before 1 year of age. Diarrhoea-associated mortality declined by 31% (95% CI 1–52; p=0·04) after RV1 introduction. Effectiveness against diarrhoea-mortality was 34% (95% CI –28 to 66; p=0·22). Interpretation: RV1 was associated with substantial reduction in diarrhoea-associated deaths among infants in this rural sub-Saharan African setting. These data add considerable weight to evidence showing the impact of rotavirus vaccine programmes. Funding: Wellcome Trust and GlaxoSmithKline Biologicals