Early iron supplementation in exclusively breastfed Gambian infants: a randomized controlled trial.

Objective: To investigate the effect of daily iron supplementation for 14 weeks on the serum iron concentration and other markers of iron status in exclusively breastfed infants in Gambia. Methods: A placebo-controlled, randomized, double-blind trial was performed in rural Gambia between 3 August 2021 and 9 March 2022. Overall, 101 healthy, exclusively breastfed infants aged 6 to 10 weeks were recruited at vaccination clinics and through community health workers. Infants were randomized to receive iron supplementation (7.5 mg/day as ferrous sulfate in sorbitol solution) or placebo for 98 days. Venous blood samples were collected at baseline and on day 99 to assess the serum iron concentration and other markers of iron and haematological status. Findings: At day 99, the serum iron concentration was significantly higher in the iron supplementation group than the placebo group (crude difference in means: 2.5 µmol/L; 95% confidence interval: 0.6 to 4.3) and there were significant improvements in other iron and haematological markers. There were 10 serious adverse events (five in each group), 106 non-serious adverse events (54 with iron supplementation; 52 with placebo) and no deaths. There was no marked difference between the groups in maternally reported episodes of diarrhoea, fever, cough, skin infection, eye infection or nasal discharge. Conclusion: In exclusively breastfed Gambian infants, iron supplementation from 6 weeks of age was associated with a significant improvement in markers of iron status at around 6 months of age. There was no indication of adverse effects on growth or infections.

Prevalence and mortality rate of abdominal surgical emergencies in Sub-Saharan Africa: a systematic review and meta-analysis.

INTRODUCTION: Abdominal surgical emergencies remain prevalent in various healthcare settings, particularly in regions with limited access to basic surgical care, such as Africa. The aim of this literature review is to systematically assess publications on abdominal surgical emergencies in adults in sub-Saharan Africa to estimate their prevalence and mortality rate. METHODOLOGY: A systematic review was conducted. The latest search was performed on October 31, 2022. We estimated the pooled prevalence with a 95% confidence interval (CI) for each abdominal surgical emergency, as well as overall postoperative mortality and morbidity rates. RESULTS: A total of 78 studies were included, and 55.1% were single-center retrospective and monocentric studies. The mean age of the patients was 32.5 years, with a sex ratio of 1.94. The prevalence of each abdominal surgical emergency among all of them was as follows: appendicitis: 30.0% (95% CI: 26.1-33.9); bowel obstruction: 28.6% (95% CI: 25.3-31.8); peritonitis: 26.6% (95% CI: 22.2-30.9); strangulated hernias: 13,4% (95% CI: 10,3-16,5) and abdominal trauma: 9.4% (95% CI: 7.5-11.3). The prevalence of complications was as follows: mortality rate: 7.4% (95% CI: 6.0-8.8); overall postoperative morbidity: 24.2% (95% CI: 19.4-29.0); and surgical site infection 14.4% (95% CI: 10.86-18.06). CONCLUSION: Our study revealed a high prevalence of postoperative complications associated with abdominal surgical emergencies in sub-Saharan Africa. More research and efforts should be made to improve access and quality of patient care.

Institutional determinants of insurance penetration in Africa.

This paper investigates the institutional determinants of insurance demand in Africa. We used a panel of 42 countries over the period 1996-2017. A system GMM approach was used for the estimations. Consistent with previous results, we find that institutional quality has positive and significant effects on insurance penetration in Africa. Specifically, regulatory quality, rule of law, control of corruption, political stability and absence of violence, and government effectiveness are the five institutional quality indicators that have positive and significant effects on the demand for total insurance and life insurance. However, only regulatory quality, control of corruption and government effectiveness are positively associated with non-life insurance demand. This indicates that governments should improve the business environment and strengthen the political environment to boost insurance development in Africa. Supplementary Information: The online version contains supplementary material available at 10.1057/s41288-022-00278-2.

Strategic Variants of CSP Delivered as SynDNA Vaccines Demonstrate Heterogeneity of Immunogenicity and Protection from Plasmodium Infection in a Murine Model.

Malaria infects millions of people every year, and despite recent advances in controlling disease spread, such as vaccination, it remains a global health concern. The circumsporozoite protein (CSP) has long been acknowledged as a key target in antimalarial immunity. Leveraging the DNA vaccine platform against this formidable pathogen, the following five synthetic DNA vaccines encoding variations of CSP were designed and studied: 3D7, GPI1, ΔGPI, TM, and DD2. Among the single CSP antigen constructs, a range of immunogenicity was observed with ΔGPI generating the most robust immunity. In an intravenous (i.v.) sporozoite challenge, the best protection among vaccinated mice was achieved by ΔGPI, which performed almost as well as the monoclonal antibody 311 (MAb 311) antibody control. Further analyses revealed that ΔGPI develops high-molecular-weight multimers in addition to monomeric CSP. We then compared the immunity generated by ΔGPI versus synDNA mimics for the antimalaria vaccines RTS,S and R21. The anti-CSP antibody responses induced were similar among these three immunogens. T cell responses demonstrated that ΔGPI induced a more focused anti-CSP response. In an infectious mosquito challenge, all three of these constructs generated inhibition of liver-stage infection as well as immunity from blood-stage parasitemia. This study demonstrates that synDNA mimics of complex malaria immunogens can provide substantial protection as can a novel synDNA vaccine ΔGPI.

Gametocyte carriage after seasonal malaria chemoprevention in Plasmodium falciparum infected asymptomatic children.

BACKGROUND: Treatment of clinical Plasmodium falciparum malaria with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) is associated with increased post-treatment gametocyte carriage. The effect of seasonal malaria chemoprevention (SMC) with SP and AQ on gametocyte carriage was assessed in asymptomatic P. falciparum infected children. METHODS: The study was carried out in eastern Gambia. Asymptomatic P. falciparum malaria infected children aged 24-59 months old who were eligible to receive SMC (SMC group) and children 5-8 years that were not eligible to receive SMC (comparison group) were recruited. Gametocytaemia was determined by molecular methods before and after SMC administration. Gametocyte carriage between the groups was compared using the chi-squared test and within-person using conditional logistic regression. RESULTS: During the 2017 and 2018 malaria transmission seasons, 65 and 75 children were recruited in the SMC and comparison groups, respectively. Before SMC administration, gametocyte prevalence was 10.7% (7/65) in the SMC group and 13.3% (10/75) in the comparison group (p = 0.64). At day 13 (IQR 12, 13) after SMC administration, this was 9.4% (5/53) in children who received at least the first dose of SMC treatment and 12.7% (9/71) for those in the comparison group (p = 0.57). Similarly, there was no difference in prevalence of gametocytes between children that adhered to all 3-day doses of SMC treatment 15.6% (5/32) and those in the comparison group (p = 0.68). In the SMC group, within-group gametocyte carriage was similar before and after SMC administration in children that received at least the first dose of SMC treatment (OR 0.6, 95% CI 0.14-2.51; p = 0.48) and in those that adhered to all 3-day doses of SMC treatment (OR 1.0, 95% CI 0.20-4.95; p = 1.0). CONCLUSION: In this study with relative low gametocyte prevalence prior to SMC treatment, no evidence was observed that SMC treatment increased gametocyte carriage in asymptomatic P. falciparum malaria infected children.

Antibody responses to a suite of novel serological markers for malaria surveillance demonstrate strong correlation with clinical and parasitological infection across seasons and transmission settings in The Gambia.

BACKGROUND: As malaria transmission declines, sensitive diagnostics are needed to evaluate interventions and monitor transmission. Serological assays measuring malaria antibody responses offer a cost-effective detection method to supplement existing surveillance tools. METHODS: A prospective cohort study was conducted from 2013 to 2015 in 12 villages across five administrative regions in The Gambia. Serological analysis included samples from the West Coast Region at the start and end of the season (July and December 2013) and from the Upper River Region in July and December 2013 and April and December 2014. Antigen-specific antibody responses to eight Plasmodium falciparum (P. falciparum) antigens-Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175 RIII-V, PfMSP119, PfAMA1, and PfGLURP.R2-were quantified using a multiplexed bead-based assay. The association between antibody responses and clinical and parasitological endpoints was estimated at the individual, household, and population level. RESULTS: Strong associations were observed between clinical malaria and concurrent sero-positivity to Etramp5.Ag1 (aOR 4.60 95% CI 2.98-7.12), PfMSP119 (aOR 4.09 95% CI 2.60-6.44), PfAMA1 (aOR 2.32 95% CI 1.40-3.85), and PfGLURP.R2 (aOR 3.12, 95% CI 2.92-4.95), while asymptomatic infection was associated with sero-positivity to all antigens. Village-level sero-prevalence amongst children 2-10 years against Etramp5.Ag1, HSP40.Ag1, and PfMSP119 showed the highest correlations with clinical and P. falciparum infection incidence rates. For all antigens, there were increased odds of asymptomatic P. falciparum infection in subjects residing in a compound with greater than 50% sero-prevalence, with a 2- to 3-fold increase in odds of infection associated with Etramp5.Ag1, GEXP18, Rh2.2030, PfMSP119, and PfAMA1. For individuals residing in sero-positive compounds, the odds of clinical malaria were reduced, suggesting a protective effect. CONCLUSIONS: At low transmission, long-lived antibody responses could indicate foci of malaria transmission that have been ongoing for several seasons or years. In settings where sub-patent infections are prevalent and fluctuate below the detection limit of polymerase chain reaction (PCR), the presence of short-lived antibodies may indicate recent infectivity, particularly in the dry season when clinical cases are rare. Serological responses may reflect a persistent reservoir of infection, warranting community-targeted interventions if individuals are not clinically apparent but have the potential to transmit. Therefore, serological surveillance at the individual and household level may be used to target interventions where there are foci of asymptomatically infected individuals, such as by measuring the magnitude of age-stratified antibody levels or identifying areas with clustering of above-average antibody responses across a diverse range of serological markers.

Sero-epidemiological evaluation of malaria transmission in The Gambia before and after mass drug administration.

BACKGROUND: As The Gambia aims to achieve malaria elimination by 2030, serological assays are a useful surveillance tool to monitor trends in malaria incidence and evaluate community-based interventions. METHODS: Within a mass drug administration (MDA) study in The Gambia, where reduced malaria infection and clinical disease were observed after the intervention, a serological sub-study was conducted in four study villages. Spatio-temporal variation in transmission was measured with a panel of recombinant Pf antigens on a multiplexed bead-based assay. Village-level antibody levels were quantified as under-15 sero-prevalence, sero-conversion rates, and age-adjusted antibody acquisition rates. Antibody levels prior to MDA were assessed for association with persistent malaria infection after community chemoprophylaxis. RESULTS: Seasonal changes in antibodies to Etramp5.Ag1 were observed in children under 15 years in two transmission settings-the West Coast and Upper River Regions (4.32% and 31.30% Pf prevalence, respectively). At the end of the malaria season, short-lived antibody responses to Etramp5.Ag1, GEXP18, HSP40.Ag1, EBA175 RIII-V, and Rh2.2030 were lower amongst 1-15 year olds in the West Coast compared to the Upper River, reflecting known differences in transmission. Prior to MDA, individuals in the top 50th percentile of antibody levels had two-fold higher odds of clinical malaria during the transmission season, consistent with previous findings from the Malaria Transmission Dynamics Study, where individuals infected before the implementation of MDA had two-fold higher odds of re-infection post-MDA. CONCLUSIONS: Serological markers can serve dual functions as indicators of malaria exposure and incidence. By monitoring age-specific sero-prevalence, the magnitude of age-stratified antibody levels, or identifying groups of individuals with above-average antibody responses, these antigens have the potential to complement conventional malaria surveillance tools. Further studies, particularly cluster randomised trials, can help establish standardised serological protocols to reliably measure transmission across endemic settings.

Rapid reduction of malaria transmission following the introduction of indoor residual spraying in previously unsprayed districts: an observational analysis of Mopti Region, Mali, in 2017.

BACKGROUND: The National Malaria Control Programme (NMCP) of Mali has had recent success decreasing malaria transmission using 3rd generation indoor residual spraying (IRS) products in areas with pyrethroid resistance, primarily in Ségou and Koulikoro Regions. In 2015, national survey data showed that Mopti Region had the highest under 5-year-old (u5) malaria prevalence at 54%-nearly twice the national average-despite having high access to long-lasting insecticidal nets (LLINs) and seasonal malaria chemoprevention (SMC). Accordingly, in 2016 the NMCP and other stakeholders shifted IRS activities from Ségou to Mopti. Here, the results of a series of observational analyses utilizing routine malaria indicators to evaluate the impact of this switch are presented. METHODS: A set of retrospective, eco-observational time-series analyses were performed using monthly incidence rates of rapid diagnostic test (RDT)-confirmed malaria cases reported in the District Health Information System 2 (DHIS2) from January 2016 until February 2018. Comparisons of case incidence rates were made between health facility catchments from the same region that differed in IRS status (IRS vs. no-IRS) to describe the general impact of the 2016 and 2017 IRS campaigns, and a difference-in-differences approach comparing changes in incidence from year-to-year was used to describe the effect of suspending IRS operations in Ségou and introducing IRS operations in Mopti in 2017. RESULTS: Compared to communities with no IRS, cumulative case incidence rates in IRS communities were reduced 16% in Ségou Region during the 6 months following the 2016 campaign and 31% in Mopti Region during the 6 months following the 2017 campaign, likely averting a total of more than 22,000 cases of malaria that otherwise would have been expected during peak transmission months. Across all comparator health facilities (HFs) where there was no IRS in either year, peak malaria case incidence rates fell by an average of 22% (CI95 18-30%) from 2016 to 2017. At HFs in communities of Mopti where IRS was introduced in 2017, peak incidence fell by an average of 42% (CI95 31-63%) between these years, a significantly greater decrease (p = 0.040) almost double what was seen in the comparator HFCAs. The opposite effect was observed in Ségou Region, where peak incidence at those HFs where IRS was withdrawn after the 2016 campaign increased by an average of 106% (CI95 63-150%) from year to year, also a significant difference-in-differences compared to the comparator no-IRS HFs (p < 0.0001). CONCLUSION: Annual IRS campaigns continue to make dramatic contributions to the seasonal reduction of malaria transmission in communities across central Mali, where IRS campaigns were timed in advance of peak seasonal transmission and utilized a micro-encapsulated product with an active ingredient that was of a different class than the one found on the LLINs used throughout the region and to which local malaria vectors were shown to be susceptible. Strategies to help mitigate the resurgence of malaria cases that can be expected should be prioritized whenever the suspension of IRS activities in a particular region is considered.

Combining next-generation indoor residual spraying and drug-based malaria control strategies: observational evidence of a combined effect in Mali.

BACKGROUND: Ségou Region in central Mali is an area of high malaria burden with seasonal transmission. The region reports high access to and use of long-lasting insecticidal nets (LLINs), though the principal vector, Anopheles gambiae, is resistant to pyrethroids. From 2011 until 2016, several high-burden districts of Ségou also received indoor residual spraying (IRS), though in 2014 concerns about pyrethroid resistance prompted a shift in IRS products to a micro-encapsulated formulation of the organophosphate insecticide pirimiphos-methyl. Also in 2014, the region expanded a pilot programme to provide seasonal malaria chemoprevention (SMC) to children aged 3-59 months in two districts. The timing of these decisions presented an opportunity to estimate the impact of both interventions, deployed individually and in combination, using quality-assured passive surveillance data. METHODS: A non-randomized, quasi-experimental time series approach was used to analyse monthly trends in malaria case incidence at the district level. Districts were stratified by intervention status: an SMC district, an IRS district, an IRS + SMC district, and control districts that received neither IRS nor SMC in 2014. The numbers of positive rapid diagnostic test (RDT +) results reported at community health facilities were aggregated and epidemiological curves showing the incidence of RDT-confirmed malaria cases per 10,000 person-months were plotted for the total all-ages and for the under 5 year old (u5) population. The cumulative incidence of RDT + malaria cases observed from September 2014 to February 2015 was calculated in each intervention district and compared to the cumulative incidence reported from the same period in the control districts. RESULTS: Cumulative peak-transmission all-ages incidence was lower in each of the intervention districts compared to the control districts: 16% lower in the SMC district; 28% lower in the IRS district; and 39% lower in the IRS + SMC district. The same trends were observed in the u5 population: incidence was 15% lower with SMC, 48% lower with IRS, and 53% lower with IRS + SMC. The SMC-only intervention had a more moderate effect on incidence reduction initially, which increased over time. The IRS-only intervention had a rapid, comparatively large impact initially that waned over time. The impact of the combined interventions was both rapid and longer lasting. CONCLUSION: Evaluating the impact of IRS with an organophosphate and SMC on reducing incidence rates of passive RDT-confirmed malaria cases in Ségou Region in 2014 suggests that combining the interventions had a greater effect than either intervention used individually in this high-burden region of central Mali with pyrethroid-resistant vectors and high rates of household access to LLINs.

In Vivo Delivery of a DNA-Encoded Monoclonal Antibody Protects Non-human Primates against Zika Virus.

Zika virus (ZIKV) infection is endemic to several world regions, and many others are at high risk for seasonal outbreaks. Synthetic DNA-encoded monoclonal antibody (DMAb) is an approach that enables in vivo delivery of highly potent mAbs to control infections. We engineered DMAb-ZK190, encoding the mAb ZK190 neutralizing antibody, which targets the ZIKV E protein DIII domain. In vivo-delivered DMAb-ZK190 achieved expression levels persisting >10 weeks in mice and >3 weeks in non-human primate (NHPs), which is protective against ZIKV infectious challenge. This study is the first demonstration of infectious disease control in NHPs following in vivo delivery of a nucleic acid-encoded antibody, supporting the importance of this new platform.

An observational analysis of the impact of indoor residual spraying with non-pyrethroid insecticides on the incidence of malaria in Ségou Region, Mali: 2012-2015.

BACKGROUND: Ségou Region in Central Mali is an area of high malaria burden with seasonal transmission, high access to and use of long-lasting insecticidal nets (LLINs), and resistance to pyrethroids and DDT well documented in Anopheles gambiae s.l. (the principal vector of malaria in Mali). Ségou has recently received indoor residual spraying (IRS) supported by Mali's collaboration with the US President's Malaria Initiative/Africa Indoor Residual Spraying programme. From 2012 to 2015, two different non-pyrethroid insecticides: bendiocarb in 2012 and 2013 and pirimiphos-methyl in 2014 and 2015, were used for IRS in two districts. This report summarizes the results of observational analyses carried out to assess the impact of these IRS campaigns on malaria incidence rates reported through local and district health systems before and after spraying. METHODS: A series of retrospective time series analyses were performed on 1,382,202 rapid diagnostic test-confirmed cases of malaria reported by district routine health systems in Ségou Region from January 2012 to January 2016. Malaria testing, treatment, surveillance and reporting activities remained consistent across districts and years during the study period, as did LLIN access and use estimates as well as An. gambiae s.l. insecticide resistance patterns. Districts were stratified by IRS implementation status and all-age monthly incidence rates were calculated and compared across strata from 2012 to 2014. In 2015 a regional but variable scale-up of seasonal malaria chemoprevention complicated the region-wide analysis; however IRS operations were suspended in Bla District that year so a difference in differences approach was used to compare 2014 to 2015 changes in malaria incidence at the health facility level in children under 5-years-old from Bla relative to changes observed in Barouéli, where IRS operations were consistent. RESULTS: During 2012-2014, rapid reductions in malaria incidence were observed during the 6 months following each IRS campaign, though most of the reduction in cases (70% of the total) was concentrated in the first 2 months after each campaign was completed. Compared to non-IRS districts, in which normal seasonal patterns of malaria incidence were observed, an estimated 286,745 total fewer cases of all-age malaria were observed in IRS districts. The total cost of IRS in Ségou was around 9.68 million USD, or roughly 33.75 USD per case averted. Further analysis suggests that the timing of the 2012-2014 IRS campaigns (spraying in July and August) was well positioned to maximize public health impact. Suspension of IRS in Bla District after the 2014 campaign resulted in a 70% increase in under-5-years-old malaria incidence rates from 2014 to 2015, significantly greater (p = 0.0003) than the change reported from Barouéli District, where incidence rates remained the same. CONCLUSIONS: From 2012 to 2015, the annual IRS campaigns in Ségou are associated with several hundred thousand fewer cases of malaria. This work supports the growing evidence that shows that IRS with non-pyrethroid insecticides is a wise public health investment in areas with documented pyrethroid resistance, high rates of LLIN coverage, and where house structures and population densities are appropriate. Additionally, this work highlights the utility of quality-assured and validated routine surveillance and well defined observational analyses to rapidly assess the impact of malaria control interventions in operational settings, helping to empower evidence-based decision making and to further grow the evidence base needed to better understand when and where to utilize new vector control tools as they become available.

Haem iron versus ferrous iron salts to treat iron deficiency anaemia in Gambian children: protocol for randomised controlled trial {1}.

BACKGROUND: The World Health Organization recommends universal iron supplementation for children aged 6-23 months in countries where anaemia is seen in over 40% of the population. Conventional ferrous salts have low efficacy due to low oral absorption in children with inflammation. Haem iron is more bioavailable, and its absorption may not be decreased by inflammation. This study aims to compare daily supplementation with haem iron versus ferrous sulphate on haemoglobin concentration and serum ferritin concentration after 12 weeks of supplementation. METHODS: This will be a two-arm, randomised controlled trial. Gambian children aged 6-12 months with anaemia will be recruited within a predefined geographical area and recruited by trained field workers. Eligible participants will be individually randomised using a 1:1 ratio within permuted blocks to daily supplementation for 12 weeks with either 10.0 mg of elemental iron as haem or ferrous sulphate. Safety outcomes such as diarrhoea and infection-related adverse events will be assessed daily by the clinical team (see Bah et al. Additional file 4_Adverse event eCRF). Linear regression will be used to analyse continuous outcomes, with log transformation to normalise residuals as needed. Binary outcomes will be analysed by binomial regression or logistic regression, Primary analysis will be by modified intention-to-treat (i.e., those randomised and who ingested at least one supplement dose of iron), with multiple imputations to replace missing data. Effect estimates will be adjusted for baseline covariates (C-reactive protein, alpha-1-acid glycoprotein, haemoglobin, ferritin, soluble transferrin receptor). DISCUSSION: This study will determine if therapeutic supplementation with haem iron is more efficacious than with conventional ferrous sulphate in enhancing haemoglobin and ferritin concentrations in anaemic children aged 6-12 months. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR202210523178727.

Solid pseudopapillary tumor of the pancreas mistaken for gastrointestinal stromal tumor: A case report.

Solid pseudopapillary epithelial neoplasms of the pancreas are rare entities, first described in 1959 by Frantz. These tumors represent less than 2% of pancreatic cancers and mainly affect young women. They can reach a significant size and its radiological features can lead to diagnostic pitfalls, such as gastrointestinal stromal tumors, which are rare soft-tissue sarcomas that can appear anywhere along the gastrointestinal tract. Clinicians and radiologists need to be aware of the existing diagnostic pitfalls between these two entities, because of their possible similarities. We report here the case of a 33-year-old woman with a solid pseudopapillary epithelial neoplasms of the pancreas initially misdiagnosed as an exophytic gastric stromal tumor.

Water vapor thermal therapy for indwelling urinary catheter removal in frail patients.

PURPOSE: To report the efficacy and safety of water vapor thermal therapy to achieve catheter removal in frail patients with refractory acute urinary retention. METHODS: Data from consecutive frail patients with indwelling urinary catheter undergoing the Rezum™ therapy (Boston Scientific Corporation, Marlborough, MA) at a single center between October 2017 and June 2021 were prospectively collected. The included patients were deemed unfit or at high risk of complications for conventional benign prostatic hyperplasia (BPH) surgery. Prostate volumes up to 120 mL were considered eligible. The primary endpoint was successful cessation of catheter dependency, assessed postoperatively and up to 1 year of follow-up. RESULTS: A total of 24 men met our inclusion criteria. The median age, Charlson comorbidity index, and duration of preoperative catheterization were 77 years (IQR 67-86), 6 (IQR 3-7), and 113 days (IQR 87-159), respectively. Two cases (8.3%) of postoperative complications were recorded (Clavien II and Clavien IIIa). After a median postoperative catheterization time of 21 days (IQR 11-32), all patients regained spontaneous voiding. During follow-up, two patients died and a total of 22 patients completed the 1 year follow-up. All patients maintained spontaneous voiding without recurrence of urinary retention. No surgical retreatment was performed. In terms of pharmacological management, 22/24 patients (91.7%) had a BPH medication pre-Rezum™; this decreased to 8/22 patients (36.3%) post-Rezum™ (p < 0.001). CONCLUSIONS: In this single-institution, prospective, and observational study, water vapor thermal therapy was found to be effective and safe in restoring successful spontaneous voiding in a cohort of elderly and frail patients.

Black in Cancer: Two Years of Empowering the Next Generation.

In the 2 years since the inception of Black in Cancer, we have modeled an action-oriented commitment to improving Black representation across all levels of the cancer spectrum. We reflect on our successes and consider new ways to innovate and inspire the cancer community.

Host-cell Interactions of Engineered T cell Micropharmacies.

Genetically engineered, cytotoxic, adoptive T cells localize to antigen positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with an orthogonal killing mechanism to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Here, we also expand the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with TCR-engineered T cells. We demonstrate that SEAKER cells localize specifically to tumors, and activate bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells are efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.

Host Interactions with Engineered T-cell Micropharmacies.

Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)-engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.

Effects of cortisol on pregnancy rate and corpus luteum function in heifers: an in vivo study.

To determine whether glucocorticoids affect the function of the bovine corpus luteum (CL) during the estrous cycle and early pregnancy, we examined the effects of exogenous cortisol or reduced endogenous cortisol on the secretion of progesterone (P4) and on pregnancy rate. In preliminary experiments, doses of cortisol and metyrapone (an inhibitor of cortisol synthesis) were established (n=33). Cortisol in effective doses of 10 mg blocked tumor necrosis factor-induced prostaglandin F(2α) secretion as measured by its metabolite (PGFM) concentrations in the blood. Metyrapone in effective doses of 500 mg increased the P4 concentration. Thus, both reagents were then intravaginally applied in the chosen doses daily from Day 15 to 18 after estrus (Day 0) in noninseminated heifers (n=18) or after artificial insemination (n=36). Pregnancy was confirmed by transrectal ultrasonography between Days 28-30 after insemination. Plasma concentrations of P4 were lower in cortisol-treated heifers than in control heifers on Days 17 and 18 of the estrous cycle (P<0.05). However, the interestrus intervals were not different between control and cortisol-treated animals (P>0.05). Moreover, metyrapone increased P4 and prolonged the CL lifespan in comparison to control animals (P<0.05). Interestingly, in inseminated heifers, cortisol increased the pregnancy rate (75%) compared with control animals (58%), whereas metyrapone reduced the pregnancy rate to 16.7% (P<0.05). The overall results suggest that cortisol, depending on the physiological status of heifers (pregnant vs. nonpregnant), modulates CL function by influencing P4 secretion. Cortisol may have a positive influence on CL function during early pregnancy, leading to support of embryo implantation and resulting in higher rates of pregnancy in heifers.

Iron supplementation of breastfed Gambian infants from 6 weeks to 6 months of age: protocol for a randomised controlled trial.

Background: A recent analysis showed that plasma iron concentrations decline rapidly from birth in Gambian infants, irrespective of sex or birthweight, to concentrations well below normal expected values for iron-replete children older than two months of age (typically >10 µmol/L). The development and function of neural and immune cells may thus be compromised before the minimum age at which children should receive iron supplementation as per World Health Organisation recommendations. Methods: This study is a two-arm, double-blind, placebo-controlled, randomised superiority trial. Infants will be randomised to receive iron drops (7.5mg/day of iron as ferrous sulphate) or placebo daily for 98 days, to test the impact on serum iron concentrations in healthy, breastfed infants (n = 100) aged 6-10 weeks at enrolment. Participants will be visited daily and supplemented by the field team. Daily health and weekly breastfeeding questionnaires will be administered. Anthropometry, and venous blood and faecal samples will be collected at enrolment and after 98 days of supplementation with serum iron as the primary endpoint. Low birthweight (less than 2.5kg at birth) and infants born prematurely (< 37 weeks) will not be excluded. Formula-fed and infants with any illness will be excluded. An additional study exploring maternal stakeholder perspectives of the intervention will be conducted by means of maternal interviews and four focus group discussions with local stakeholders. Discussion: Most breast-fed Gambian infants have very low circulating iron levels by five months of age. This study will introduce iron supplements much earlier in infancy than has previously been attempted in a low-income setting with the primary aim of increasing serum iron concentration. Trial registration: Clincaltrials.gov ( NCT04751994); 12 th February 2021.

DNA immunotherapy targeting BARF1 induces potent anti-tumor responses against Epstein-Barr-virus-associated carcinomas.

Latent Epstein-Barr virus (EBV) infection is associated with several types of cancer. Several clinical studies have targeted EBV antigens as immune therapeutic targets with limited efficacy of EBV malignancies, suggesting that additional targets might be important. BamHI-A rightward frame 1 (BARF1) is an EBV antigen that is highly expressed in EBV+ nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC). BARF1 antigen can transform human epithelial cells in vivo. BARF1-specific antibodies and cytotoxic T cells were detected in some EBV+ NPC patients. However, BARF1 has not been evaluated as an antigen in the context of therapeutic immunization. Its possible importance in this context is unclear. Here, we developed a synthetic-DNA-based expression cassette as immunotherapy targeting BARF1 (pBARF1). Immunization with pBARF1 induced potent antigen-specific humoral and T cell responses in vivo. Immunization with pBARF1 plasmid impacted tumor progression through the induction of CD8+ T cells in novel BARF1+ carcinoma models. Using an in vivo imaging system, we observed that pBARF1-immunized animals rapidly cleared cancer cells. We demonstrated that pBARF1 can induce antigen-specific immune responses that can impact cancer progression. Further study of this immune target is likely important as part of therapeutic approaches for EBV+ malignancies.