The effectiveness of revaccination with pneumococcal polysaccharide vaccine for preventing pneumococcal disease in older adults in England: A population-based cohort study.

BACKGROUND: Pneumococcal disease in older adults in the United Kingdom is rising despite immunisation. A key gap in the literature is the clinical effectiveness of revaccination with the pneumococcal polysaccharide vaccine (PPV23). METHODS: A cohort study was performed in England, using electronic medical records in the Clinical Practice Research Datalink. Individuals aged ≥64 years and vaccinated with PPV23 were included. Rates of hospitalised pneumonia (HP) and invasive pneumococcal disease (IPD) were compared between individuals receiving a single PPV23 dose versus those receiving two doses using multi-level Cox proportional hazards models. Propensity score weighting was performed to minimise the effect of confounding covariates across the comparison groups. RESULTS: Between 2006 and 2019, there were 462 505 eligible participants. Of those, 6747 (1·5 %) received revaccination. Two doses compared to one dose was associated with an increased risk of HP (adjusted Hazard Ratio [aHR] 1·95; 95 %CI 1·74-2·20) and IPD (aHR 1·44; 95 %CI 1·41-1·46). In participants aged 64-74 years PPV23 revaccination was associated with more IPD (aHR 2·02; 95 %CI 1·75-2·33) and HP (aHR 1·46; 95 %CI 1·42-1.49). In those aged ≥75 years PPV23 revaccination was associated with more HP (aHR 1·12; 95 %CI 1·08-1·16) with no statistically significant difference detected in risk of IPD (aHR 1·20; 95 %CI 0·94-1·52). CONCLUSIONS: No clear benefit of PPV23 revaccination was measured in older adults in this observational study. The small proportion of revaccinated subjects limits the strength of the conclusions. Further research evaluating the clinical effectiveness of PPV23 revaccination is required.

Experimental pneumococcal carriage in people living with HIV in Malawi: the first controlled human infection model in a key at-risk population.

Background: As well as suffering a high burden of pneumococcal disease people living with HIV (PLHIV) may contribute to community transmission in sub-Saharan African (sSA) settings. Pneumococcal vaccination is not currently offered to PLHIV in sSA but may prevent disease and reduce transmission. More evidence of vaccine effectiveness against carriage in PLHIV is needed. An Experimental Human Pneumococcal Carriage model (EHPC) has been safely and acceptably used in healthy adults in Malawi to evaluate pneumococcal vaccines against carriage and to identify immune correlates of protection from carriage. This study will establish the same model in PLHIV and will be the first controlled human infection model (CHIM) in this key population. Methods: Healthy participants with and without HIV will be inoculated intranasally with Streptococcus pneumoniae serotype 6B. Sequential cohorts will be challenged with increasing doses to determine the optimal safe challenge dose to establish experimental carriage. Nasal fluid, nasal mucosal, and blood samples will be taken before inoculation and on days 2, 7, 14, and 21 following inoculation to measure pneumococcal carriage density and identify immune correlates of protection from carriage. The vast majority of natural pneumococcal carriage events in PLHIV do not result in invasive disease and no invasive disease is expected in this study. However, robust participant safety monitoring is designed to identify signs of invasive disease early should they develop, and to implement treatment immediately. Participants will complete a Likert-style questionnaire at study-end to establish acceptability. Interpretations: We expect the EHPC model to be safely and acceptably implemented in PLHIV. The CHIM can then be used to accelerate pneumococcal vaccine evaluations in this population, and an evidence-based pneumococcal vaccination policy for PLHIV in sSA.

Comprehensive review of safety in Experimental Human Pneumococcal Challenge.

INTRODUCTION: Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies. METHODS: A single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation. RESULTS: In 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = <0.001). The majority were mild (pneumococcal group = 72.7% [120/165 reported symptoms], non-pneumococcal = 86.7% [124/143 reported symptoms]). 1.6% (23/1416) required antibiotics for safety. DISCUSSION: No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated. CONCLUSION: Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place.

Survival and Long-term Effects of Kidney-sparing Surgery Versus Radical Nephroureterectomy on Kidney Function in Patients with Upper Urinary Tract Urothelial Carcinoma.

Background: Current European Association of Urology (EAU) guidelines discriminate between high- and low-risk upper urinary tract urothelial carcinoma (UTUC) to determine treatment by means of radical nephroureterectomy (RNU) or kidney-sparing surgery (KSS). Objective: To compare long-term oncological outcomes and renal function for patients with UTUC treated by RNU versus KSS. Design setting and participants: A retrospective cohort study, including 186 renal units with nonmetastatic UTUC treated in a tertiary referral centre between 2010 and 2021, was conducted. Intervention: RNU, ureterorenoscopy, percutaneous tumour resection, and segmental ureteral resection. Outcome measurements and statistical analysis: Recurrence-free survival, metastasis-free survival (MFS), overall survival (OS), cancer-specific survival (CSS), and renal function were analysed by means of the log-rank test and the independent-sample t test. Results and limitations: OS was 71.1% for the RNU group and 81.9% for the KSS group. In a cohort matched for propensity weight based on EAU risk stratification progression-free survival (PFS; RNU 96.0%; KSS 86.0%), MFS (RNU 72.0%; KSS 84.0%), CSS (RNU 84.0%; KSS 86.0%), and OS (RNU 76.0%; KSS 76.0%) were all similar between both groups. No significant differences in renal function were seen at 2 and 5 yr after the intervention. Although this series represents the largest cohort of (high-risk) UTUC patients treated by means of KSS to date, it is not suitable for performing a multivariate analysis. Conclusions: PFS, MFS, CSS, and OS were all comparable when analysing the RNU and KSS groups. Similar results for groups with evenly distributed risk factors and a large percentage of high-risk disease suggest that current risk stratification might not be accurate in discriminating low-risk from high-risk disease. Patient summary: In this report, we looked at outcomes for upper urinary tract urothelial carcinoma in a specialised hospital. We conclude that kidney-sparing surgery and radical nephroureterectomy have comparable outcomes and that risk factors for worse outcome might not be identified correctly.

Unintended Pregnancy in Gaborone, Botswana: A Cross-Sectional Study.

Rates of unintended pregnancy in sub-Saharan Africa range from 20-40%. Unintended pregnancy leads to increased maternal and infant mortality, and higher rates of abortions. Potentially high levels of unintended pregnancy in Botswana, against the backdrop of the popularity of short-acting, less-effective contraception, could suggest that the methods available to women are not meeting their contraceptive needs. Little data exists on unintended pregnancy in Botswana. We assessed levels of unintended pregnancy and contraceptive use among 231 pregnant women presenting to the antenatal clinic at the largest hospital in Botswana. Forty-three percent of pregnancies were reported as unintended. Of women with an unintended pregnancy, 72% reported using a contraceptive method to prevent pregnancy at the time of conception. Of the women with unintended pregnancy despite contraceptive use, 88% were using male condoms as their only method of contraception. Women reporting unintended pregnancy were more likely to have had more previous births (p=0.05). While barrier protection with condoms is essential for the prevention of HIV and other STIs, condom use alone may not be meeting the contraceptive needs of women in Botswana. Increased promotion of dual-method contraceptive use with condoms is needed.

Prevalence and treatment outcomes of routine Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis testing during antenatal care, Gaborone, Botswana.

OBJECTIVES: Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) are curable, mostly asymptomatic, STIs that cause adverse maternal and perinatal outcomes. Most countries do not test for those infections during antenatal care. We implemented a CT, NG and TV testing and treatment programme in an antenatal clinic in Gaborone, Botswana. METHODS: We conducted a prospective study in the antenatal clinic at Princess Marina Hospital in Gaborone, Botswana. We offered pregnant women who were 18 years or older and less than 35 weeks of gestation, CT, NG and TV testing using self-collected vaginal swabs. Testing was conducted using a GeneXpert® CT/NG and TV system. Those who tested positive were given directly observed antibiotic therapy and asked to return for a test of cure. We determined the prevalence of infections, uptake of treatment and proportion cured. The relationships between positive STI test and participant characteristics were assessed. RESULTS: We enrolled 400 pregnant women. Fifty-four (13.5%) tested positive for CT, NG and/or TV: 31 (8%) for CT, 5 (1.3%) for NG and 21 (5%) for TV. Among those who tested positive, 74% (40) received same-day, in person results and treatment. Among those who received delayed results (6), 67% (4) were treated. Statistical comparisons showed that being unmarried and HIV infected were positively association CT, NG and/or TV infection. Self-reported STI symptoms were not associated with CT, NG and/or TV infection. CONCLUSION: The prevalence of CT, NG and/or TV was high, particularly among women with HIV infection. Among women with CT, NG and/or TV infection, those who received same-day results were more likely to be treated than those who received delayed results. More research is needed on the costs and benefits of integrating highly sensitive and specific STI testing into antenatal care in Southern Africa.

Histone deacetylases (HDACs) in frontotemporal lobar degeneration.

AIMS: Frontotemporal lobar degeneration (FTLD) is clinically and pathologically heterogeneous. Although associated with variations in MAPT, GRN and C9ORF72, the pathogenesis of these, and of other nongenetic, forms of FTLD, remains unknown. Epigenetic factors such as histone regulation by histone deacetylases (HDAC) may play a role in the dysregulation of transcriptional activity, thought to underpin the neurodegenerative process. METHODS: The distribution and intensity of HDACs 4, 5 and 6 was assessed semi-quantitatively in immunostained sections of temporal cortex with hippocampus, and cerebellum, from 33 pathologically confirmed cases of FTLD and 27 controls. RESULTS: We found a significantly greater intensity of cytoplasmic immunostaining for HDAC4 and HDAC6 in granule cells of the dentate gyrus in cases of FTLD overall compared with controls, and specifically in cases of FTLD tau-Picks compared with FTLD tau-MAPT and controls. No differences were noted between FTLD-TDP subtypes, or between the different genetic and nongenetic forms of FTLD. No changes were seen in HDAC5 in any FTLD or control cases. CONCLUSIONS: Dysregulation of HDAC4 and/or HDAC6 could play a role in the pathogenesis of FTLD-tau associated with Pick bodies, although their lack of immunostaining implies that such changes do not contribute directly to the formation of Pick bodies.