Health systems challenges, mitigation strategies and adaptations to maintain essential health services during the COVID-19 pandemic: learnings from the six geopolitical regions in Nigeria.

BACKGROUND: The COVID-19 pandemic control strategies disrupted the smooth delivery of essential health services (EHS) globally. Limited evidence exists on the health systems lens approach to analyzing the challenges encountered in maintaining EHS during the COVID-19 pandemic. This study aimed to identify the health system challenges encountered and document the mitigation strategies and adaptations made across geopolitical zones (GPZs) in Nigeria. METHODS: The national qualitative survey of key actors across the six GPZs in Nigeria involved ten states and the Federal Capital Territory (FCT) which were selected based on resilience, COVID-19 burden and security considerations. A pre-tested key informant guide was used to collect data on service utilization, changes in service utilization, reasons for changes in primary health centres' (PHCs) service volumes, challenges experienced by health facilities in maintaining EHS, mitigation strategies implemented and adaptations to service delivery. Emerging sub-themes were categorized under the appropriate pillars of the health system. RESULTS: A total of 22 respondents were interviewed. The challenges experienced in maintaining EHS cut across the pillars of the health systems including: Human resources shortage, shortages in the supply of personal protective equipments, fear of contracting COVID-19 among health workers misconception, ignorance, socio-cultural issues, lockdown/transportation and lack of equipment/waiting area (. The mitigation strategies included improved political will to fund health service projects, leading to improved accessibility, affordability, and supply of consumables. The health workforce was motivated by employing, redeploying, training, and incentivizing. Service delivery was reorganized by rescheduling appointments and prioritizing some EHS such as maternal and childcare. Sustainable systems adaptations included IPC and telehealth infrastructure, training and capacity building, virtual meetings and community groups set up for sensitization and engagement. CONCLUSION: The mitigation strategies and adaptations implemented were important contributors to EHS recovery especially in the high resilience LGAs and have implications for future epidemic preparedness plans.

United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions.

BACKGROUND: There is no accepted grading system classifying the severity of immediate reactions to drugs. OBJECTIVE: The purpose of this article is to present a proposed grading system developed through the consensus of drug allergy experts from the United States Drug Allergy Registry (USDAR) Consortium. METHODS: The USDAR investigators sought to develop a consensus severity grading system for immediate drug reactions that is applicable to clinical care and research. RESULTS: The USDAR grading scale scores severity levels on a scale of 0 to 4. A grade of no reaction (NR) is used for patients who undergo challenge without any symptoms or signs, and it would confirm a negative challenge result. A grade 0 reaction is indicative of primarily subjective complaints that are commonly seen with both historical drug reactions and during drug challenges, and it would suggest a low likelihood of a true drug allergic reaction. Grades 1 to 4 meet the criteria for a positive challenge result and may be considered indicative of a drug allergy. Grade 1 reactions are suggestive of a potential immediate drug reaction with mild symptoms. Grade 2 reactions are more likely to be immediate drug reactions of moderate severity. Grade 3 reactions have features suggestive of a severe allergic reaction, whereas grade 4 reactions are life-threatening reactions such as anaphylactic shock and fatal anaphylaxis. CONCLUSION: This proposed grading schema for immediate drug reactions improves on prior schemata by being developed specifically for immediate drug reactions and being easy to implement in clinical and research practice.

High-titer post-vaccine COVID-19 convalescent plasma for immunocompromised patients during the first omicron surge.

BACKGROUND: Transplant and hematologic malignancy patients have high Coronavirus disease 2019 (COVID-19) mortality and impaired vaccination responses. Omicron variant evades several monoclonal antibodies previously used in immunocompromised patients. Polyclonal COVID-19 convalescent plasma (CCP) may provide broader neutralizing capacity against new variants at high titers. Vaccination increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer in convalescent donors. METHODS: We conducted a retrospective chart review of hospitalized immunocompromised patients with COVID-19 who received high-titer CCP during the first omicron surge, collected from vaccinated donors within 6 months of pre-omicron COVID-19. Data on safety and outcomes were extracted. RESULTS: A total of 44 immunocompromised patients were included, 59.1% with solid organ transplant, 22.7% with hematopoietic cell transplant, 11.4% with hematologic malignancy, and 6.8% with autoimmune disease. Overall, 95% of CCP units transfused were from recently recovered and vaccinated donors and had SARS-CoV-2 antibody results 8- to 37-fold higher than the Food and Drug Administration's cutoff for high-titer CCP. There were two mild transfusion reactions. A total of 30-day mortality was 4.5%. There were no differences in 100-day mortality by underlying diagnosis, levels of immunosuppression, and timing of CCP administration. Patients with higher immunosuppression had significantly higher mean World Health Organization clinical progression scores at 30-day post-CCP compared to those with lower immunosuppression. CONCLUSIONS: CCP is a safe, globally available treatment for immunocompromised patients with COVID-19. Mortality was lower in our cohort than that of COVID-19 patients with similar immunocompromising conditions. Post-vaccine CCP with very high titers should be prioritized for study in immunocompromised patients. Post-vaccine CCP has the potential to keep pace with new variants by overcoming mutations at sufficiently high titer.

Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression.

The p53 tumor suppressor is a key mediator of cellular responses to various stresses. Here, we show that under conditions of basal physiologic and cell-culture stress, p53 inhibits expression of the CD44 cell-surface molecule via binding to a noncanonical p53-binding sequence in the CD44 promoter. This interaction enables an untransformed cell to respond to stress-induced, p53-dependent cytostatic and apoptotic signals that would otherwise be blocked by the actions of CD44. In the absence of p53 function, the resulting derepressed CD44 expression is essential for the growth and tumor-initiating ability of highly tumorigenic mammary epithelial cells. In both tumorigenic and nontumorigenic cells, CD44's expression is positively regulated by p63, a paralogue of p53. Our data indicate that CD44 is a key tumor-promoting agent in transformed tumor cells lacking p53 function. They also suggest that the derepression of CD44 resulting from inactivation of p53 can potentially aid the survival of immortalized, premalignant cells.

COVID-19 surveillance in Democratic Republic of Congo, Nigeria, Senegal and Uganda: strengths, weaknesses and key Lessons.

INTRODUCTION: As part of efforts to rapidly identify and care for individuals with COVID-19, trace and quarantine contacts, and monitor disease trends over time, most African countries implemented interventions to strengthen their existing disease surveillance systems. This research describes the strengths, weaknesses and lessons learnt from the COVID-19 surveillance strategies implemented in four African countries to inform the enhancement of surveillance systems for future epidemics on the continent. METHODS: The four countries namely the Democratic Republic of Congo (DRC), Nigeria, Senegal, and Uganda, were selected based on their variability in COVID-19 response and representation of Francophone and Anglophone countries. A mixed-methods observational study was conducted including desk review and key informant interviews, to document best practices, gaps, and innovations in surveillance at the national, sub-national, health facilities, and community levels, and these learnings were synthesized across the countries. RESULTS: Surveillance approaches across countries included - case investigation, contact tracing, community-based, laboratory-based sentinel, serological, telephone hotlines, and genomic sequencing surveillance. As the COVID-19 pandemic progressed, the health systems moved from aggressive testing and contact tracing to detect virus and triage individual contacts into quarantine and confirmed cases, isolation and clinical care. Surveillance, including case definitions, changed from contact tracing of all contacts of confirmed cases to only symptomatic contacts and travelers. All countries reported inadequate staffing, staff capacity gaps and lack of full integration of data sources. All four countries under study improved data management and surveillance capacity by training health workers and increasing resources for laboratories, but the disease burden was under-detected. Decentralizing surveillance to enable swifter implementation of targeted public health measures at the subnational level was a challenge. There were also gaps in genomic and postmortem surveillance including community level sero-prevalence studies, as well as digital technologies to provide more timely and accurate surveillance data. CONCLUSION: All the four countries demonstrated a prompt public health surveillance response and adopted similar approaches to surveillance with some adaptations as the pandemic progresses. There is need for investments to enhance surveillance approaches and systems including decentralizing surveillance to the subnational and community levels, strengthening capabilities for genomic surveillance and use of digital technologies, among others. Investing in health worker capacity, ensuring data quality and availability and improving ability to transmit surveillance data between and across multiple levels of the health care system is also critical. Countries need to take immediate action in strengthening their surveillance systems to better prepare for the next major disease outbreak and pandemic.

Clearance of Hepatitis B e Antigen in Untreated Chronic Hepatitis B Virus Infection: A Systematic Review and Meta-analysis.

BACKGROUND: In people with hepatitis B virus (HBV) infection, persistence of hepatitis B e antigen (HBeAg) is associated with clinical progression and need for treatment. HBeAg loss represents partial immune control and is a critical event in the natural history of chronic HBV. METHODS: We conducted a systematic review and meta-analysis of cohort studies that report HBeAg loss among people with untreated chronic HBV. We evaluated HBeAg loss using a random-effects model and conducted subanalysis on region. RESULTS: We screened 10 560 publications, performed 196 full-text analyses, and included 26 studies for meta-analysis. The pooled rate of HBeAg loss was 6.46/100 person-years (PYs) (95% confidence interval, 5.17-8.08). Meta-regression showed that older age of participants and studies in Europe were associated with higher rate of HBeAg loss. Rates per 100 PYs were 7.43 (95% confidence interval, 6.30-8.75; 1 study) in Africa, 3.24 (2.61--4.02; 1 study) in the Eastern Mediterranean, 13.67 (11.21-16.66; 4 studies) in Europe, 7.34 (4.61--11.70; 5 studies) in North America, and 5.53 (4.05--7.55; 15 studies) in the Western Pacific. CONCLUSIONS: Spontaneous HBeAg loss occurs at a rate of 6.46/100 PYs. Variations by region and age group may reflect epidemiological, immunological, or HBV genotype-related differences.

Nutritional Supplementation Would Be Cost-Effective for Reducing Tuberculosis Incidence and Mortality in India: The Ration Optimization to Impede Tuberculosis (ROTI-TB) Model.

BACKGROUND: Undernutrition is the leading cause of tuberculosis (TB) in India and is associated with increased TB mortality. Undernutrition also decreases quality of life and economic productivity. METHODS: We assessed the cost-effectiveness of providing augmented rations to undernourished Indians through the government's Targeted Public Distribution System (TPDS). We used Markov state transition models to simulate disease progression and mortality among undernourished individuals in 3 groups: general population, household contacts (HHCs) of people living with TB, and persons living with human immunodeficiency virus (HIV). The models calculate costs and outcomes (TB cases, TB deaths, and disability-adjusted life years [DALYs]) associated with a 2600 kcal/day diet for adults with body mass index (BMI) of 16-18.4 kg/m2 until they attain a BMI of 20 kg/m2 compared to a status quo scenario wherein TPDS rations are unchanged. We employed deterministic and probabilistic sensitivity analyses to test result robustness. RESULTS: Over 5 years, augmented rations could avert 81% of TB cases and 88% of TB deaths among currently undernourished Indians. Correspondingly, this intervention could forestall 78% and 48% of TB cases and prevent 88% and 70% of deaths among undernourished HHCs and persons with HIV, respectively. Augmented rations resulted in 10-fold higher resolution of undernutrition and were highly cost-effective with (incremental cost-effectiveness ratio [ICER] of $470/DALY averted). ICER was lower for HHCs ($360/DALY averted) and the HIV population ($250/DALY averted). CONCLUSIONS: A robust nutritional intervention would be highly cost-effective in reducing TB incidence and mortality while reducing chronic undernutrition in India.

Development and Validation of a Risk Score for Liver Cirrhosis Prediction in Untreated and Treated Chronic Hepatitis B.

BACKGROUND: Chronic hepatitis B (CHB) can progress to cirrhosis, but there are limited noninvasive tools available to estimate cirrhosis risk, including in patients receiving antiviral therapy. This study developed and validated a simple model to assess risk in CHB patients. METHODS: The derivation cohort included 3000 CHB patients from 6 centers in the United States, with 52.60% receiving antiviral therapy. External validation was performed for 4552 CHB individuals from similar cohorts in Taiwan, with 21.27% receiving therapy. Cox proportional hazards regression analyses were used to screen predictors and develop the risk score for cirrhosis. Areas under receiver operating characteristic curves (AUROCs) were calculated for predictive value. RESULTS: Sex, age, diabetes, antiviral treatment status/duration, hepatitis B e-antigen, and baseline alanine aminotransferase/aspartate aminotransferase levels were significantly associated with increased cirrhosis risk. A 13-point risk score was developed based on these predictors. The AUROCs for predicting cirrhosis risk were 0.82 at 3 years, 0.85 at 5 years, and 0.89 at 10 years in the derivation cohort, and 0.82, 0.79, and 0.77 in the validation cohort, respectively. CONCLUSIONS: We developed and validated a simple cirrhosis prediction model with an independent external cohort that can be applied to both treatment-naive and treatment-experienced CHB patients in diverse settings and locations.

Nocardiosis in Immunocompromised Patients on Alternative Pneumocystis Prophylaxis.

Prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) prevents Pneumocystis jirovecii pneumonia and nocardiosis in immunocompromised patients but sometimes is avoided because of purported allergies or side effects. Of 25 immunocompromised patients receiving alternative prophylaxis in whom nocardiosis developed, 16 subsequently tolerated TMP/SMX treatment. Clinicians should consider TMP/SMX allergy evaluation and rechallenging to assess patient tolerance.

Association of Terry Nails With Liver Cirrhosis.

INTRODUCTION: We looked at the association between Terry nails and liver cirrhosis in an ambulatory population from hepatology and gastroenterology clinics. METHODS: We prospectively investigated the prevalence and determinants of Terry nails in 1,000 consecutive patients from hepatology and gastroenterology clinics at 2 institutions between May 2016 and February 2020. RESULTS: A total of 117 subjects manifested Terry nails, with a 25.6% prevalence in patients with cirrhosis. When adjusted for age, heart failure, diabetes mellitus type 2, and chronic liver disease, cirrhosis was the only significant correlate (odds ratio 5.7 [95% confidence interval 3.3-9.8]), irrespective of liver disease etiology, with a strong association with hepatic fibrosis stage (P < 0.0001). DISCUSSION: Sensitivity and specificity of Terry nails for cirrhosis (25.8%, 92.7%) was similar to palmar erythema but less than spider angioma.

Risk factors for difficult-to-treat hepatitis C virus genotype 4r in Rwanda and implications for elimination in sub-Saharan Africa.

In sub-Saharan Africa, there exist distinct HCV genotype (GT) subtypes harbouring resistance-associated substitutions to commonly used non-structural protein 5A (NS5A) inhibitor-based direct-acting antiviral (DAA) regimens. In particular, GT4r subtype has demonstrated high rates of treatment failure. In the absence of routine viral sequencing in sub-Saharan Africa, it is important to identify sociodemographic, epidemiologic, and clinical characteristics that may be associated with GT4r infection. Methods: A secondary analysis was performed on data from 300 adults with HCV GT4 enrolled in a prospective trial assessing the safety and efficacy of sofosbuvir-ledipasvir in Rwanda in 2017. The association between characteristics at enrolment and GT subtype was assessed by chi-square analysis and logistic regression. In multivariate analysis, there were a higher proportion of participants with GT4r subtype with age <40 years (OR: 3.6, 95% CI: 1.3-10.5, p = 0.02), previous hospitalization (OR: 2.5, 95% CI: 1.3-5.0, p = 0.006), previous surgery (OR: 2.2, 95% CI: 1.1-4.2, p = 0.03), cirrhosis (OR: 3.2, 95% CI: 1.3-7.5, p = 0.008) and baseline HCV RNA >1 million IU/ml (OR: 3.4, 95% CI: 1.6-6.9, p = 0.001). Rwandan adults with GT4r are more likely to be younger, have a history of hospital admissions and surgeries and have more active or advanced liver disease compared to those with other GT4 subtypes. In the absence of advanced diagnostics to assess GT subtype, patients with these characteristics may warrant closer monitoring for treatment failure or alternative DAA regimens. More treatment experience with diverse DAA regimens is urgently needed for GT subtypes particular to this region.

Successful eradication of chronic symptomatic Candida krusei urinary tract infection with increased dose micafungin in a liver and kidney transplant recipient: Case report and review of the literature.

Treatment of symptomatic candiduria is notoriously challenging because of the limited repository of antifungals that achieve adequate urinary concentrations. Fluconazole, amphotericin B-based products, and flucytosine are established treatment options for most Candida species. Candida krusei exhibits intrinsic resistance to fluconazole and decreased susceptibility to amphotericin B and flucytosine. In transplant patients, both amphotericin B-based products and flucytosine are less desirable because of their toxicities. Other triazole antifungals are unappealing because they do not achieve adequate urinary concentrations, have multiple toxicities, and interact with transplant-related immunosuppressive medications. Echinocandins are well-tolerated but have been traditionally deferred in the treatment of symptomatic funguria because of their poor urinary concentrations but there is a small but emerging body of literature supporting their use. Here, we present a case of successful eradication of chronic symptomatic C krusei urinary tract infection with micafungin 150 milligrams daily in a liver and kidney transplant recipient, and we review the literature on treatment of symptomatic candiduria.

Scedosporium apiospermum infection of the urinary system with a review of treatment options and cases in the literature.

Infection with Scedosporium species is associated with a significant morbidity and mortality and is becoming increasingly common, especially in immunocompromised patients. We describe the presentation and successful management of an immunocompromised patient with Scedosporium apiospermum infection of the upper urinary tract system, a rare disease manifestation. The current literature on urinary tract scedosporiosis is further reviewed with emphasis on treatment options and limitations of current antifungal therapy.

Splenic Injury and Hemoperitoneum as a Complication of Colonoscopy: A Case Report and Literature Review.

Colonoscopy rarely results in serious or life-threatening complications. While bleeding, perforation, and cardiorespiratory complications account for a majority of procedural-related complications, splenic injury and resulting hemoperitoneum remain a serious, potentially life-threatening adverse event. Splenic injury is an underreported and underappreciated complication of colonoscopy. In this case, a 71-year-old female presented one day after colonoscopy with splenic injury and hemoperitoneum as a complication of the recent colonoscopy. In addition to reviewing the literature, the case describes systems for grading splenic injury and the use of splenic artery embolization for controlling the bleed. Given the frequent use of colonoscopy as both a screening and therapeutic modality, it is pivotal for the general internist to be familiar with potential complications. Along with this broad sense of potential complications, it is important to use clinical acumen, clinical examination findings, and elicited history to select the imaging modality of choice in a timely manner.

Mast cells recruited to mesenteric lymph nodes during helminth infection remain hypogranular and produce IL-4 and IL-6.

Mast cells (MC) and basophils share expression of the high-affinity receptor for IgE (FcεRI) but can be distinguished by their divergent expression of KIT and CD49b. In BALB/c mice, MC lineage cells expressing high levels of FcεRI by flow cytometry were seen only in bone marrow whereas those expressing intermediate levels of FcεRI were present in bone marrow and spleen of naive mice and in mesenteric lymph nodes (mLN) of Trichinella spiralis-infected mice. These FcεRI(+)KIT(+)CD49b(-) cells had a membrane phenotype similar to i.p. connective tissue-type MC, but were smaller and hypogranular by flow cytometry forward and side scatter profiles, respectively. Consistent with this, they lacked the prominent secretory granules identified by histochemistry and immunodetection for the MC-specific granule proteases that are readily seen in mature jejunal mucosal MC that also are induced by the infection and present at the same time. The concentration of these MC lineage cells in mLN determined by flow cytometry was comparable to that of MC progenitors (MCp) measured by limiting dilution and clonal expansion with maturation. We observed upregulation of IL-4 transcription by MCp in mLN and spleens of helminth-infected 4get mice, and we demonstrated by intracellular cytokine staining production of IL-4 and IL-6 by the mLN MCp in helminth-infected mice. Furthermore, treatment of helminth-infected mice with anti-FcεRI mAb, a protocol known to deplete basophils, also depleted mLN MCp. Thus, this study identifies a hypogranular subset of MCp recruited to mLN by helminth infection that may be an important unrecognized source of cytokines.

Germline findings in cancer predisposing genes from a small cohort of chordoma patients.

INTRODUCTION: Chordoma is a rare slow-growing tumor that occurs along the length of the spinal axis and arises from primitive notochordal remnants (Stepanek et al., Am J Med Genet 75:335-336, 1998). Most chordomas are sporadic, but a small percentage of cases are due to hereditary cancer syndromes (HCS) such as tuberous sclerosis 1 and 2 (TSC1/2), or constitutional variants in the gene encoding brachyury T (TBXT) (Pillay et al., Nat Genet 44:1185-1187, 2012; Yang et al., Nat Genet 41:1176-1178, 2009). PURPOSE: The genetic susceptibility of these tumors is not well understood; there are only a small number of studies that have performed germline genetic testing in this population. METHODS: We performed germline genetic in chordoma patients using genomic DNA extracted by blood or saliva. CONCLUSION: We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors.

Deployment of community health workers across rural sub-Saharan Africa: financial considerations and operational assumptions.

OBJECTIVE: To provide cost guidance for developing a locally adaptable and nationally scalable community health worker (CHW) system within primary-health-care systems in sub-Saharan Africa. METHODS: The yearly costs of training, equipping and deploying CHWs throughout rural sub-Saharan Africa were calculated using data from the literature and from the Millennium Villages Project. Model assumptions were such as to allow national governments to adapt the CHW subsystem to national needs and to deploy an average of 1 CHW per 650 rural inhabitants by 2015. The CHW subsystem described was costed by employing geographic information system (GIS) data on population, urban extents, national and subnational disease prevalence, and unit costs (from the field for wages and commodities). The model is easily replicable and configurable. Countries can adapt it to local prices, wages, population density and disease burdens in different geographic areas. FINDINGS: The average annual cost of deploying CHWs to service the entire sub-Saharan African rural population by 2015 would be approximately 2.6 billion (i.e. 2600 million) United States dollars (US$). This sum, to be covered both by national governments and by donor partners, translates into US$ 6.86 per year per inhabitant covered by the CHW subsystem and into US$ 2.72 per year per inhabitant. Alternatively, it would take an annual average of US$ 3750 to train, equip and support each CHW. CONCLUSION: Comprehensive CHW subsystems can be deployed across sub-Saharan Africa at cost that is modest compared with the projected costs of the primary-health-care system. Given their documented successes, they offer a strong complement to facility-based care in rural African settings.