Classification of income, profit and loss, and general balance sheet accounts for steam roads

This Classification of Income, Profit and Loss, and General Balance Sheet Accounts supersedes the Form of Income and Profit and Loss Statement for Steam Roads, First Issue, effective July 1, 1912, and the Form of General Balance Sheet Statement, First Revised Issue, effective June 15, 1910. It also supersedes conflicting instructions in Accounting Bulletin No. 8. The general and special instructions contain a comprehensive statement of the principles underlying the classification, indicating generally the application of the accounting rules. The attention of accounting officers is called to the importance of requiring all employees who are assigned to accounting work in connection with income, profit and loss, and general balance-sheet accounts to familiarize themselves thoroughly with these instructions

Pneumococcal pneumonia and carriage in Africa before and after introduction of pneumococcal conjugate vaccines, 2000-2019:protocol for systematic review

INTRODUCTION:Africa harbours a high burden of pneumococcal disease, with associated high mortality rates. Despite 34 countries introducing the pneumococcal conjugate vaccine, which reduces the risk of pneumococcal carriage (a prerequisite for disease) of some of the most pathogenic pneumococcal serotypes, it remains uncertain whether they will achieve the sustained direct or indirect protection necessary to reduce pneumococcal carriage to levels sufficient to interrupt transmission and disease. We will therefore summarise the available data on the impact of the pneumococcal conjugate vaccine in reducing vaccine serotype carriage and pneumococcal pneumonia in Africa between 2000 and 2019. METHODS AND ANALYSIS:Using a predetermined search strategy, we will conduct a comprehensive search of PubMed, MEDLINE database, the Excerpta Medica Database, the ISI Web of Science (Science Citation Index), Scopus and the African Index Medicus to identify published studies reporting the prevalence of Streptococcus pneumoniae carriage (vaccine type and non-vaccine type), incidence rates of pneumococcal pneumonia and mortality among children, adults and HIV-infected (all-ages) pre-pneumococcal conjugate vaccine (PCV) and post-PCV introduction (published between 1st January 2000 and 31st December 2019) in African countries that have introduced PCVs (PCV7/PCV10/PCV13) in their routine national immunisation programme. The studies retained and data extracted will be assessed for bias using prevalidated tools and checklists. Heterogeneity across studies will be assessed using the χ2 test on Cochrane Q statistic. A random effect meta-analysis will be used to estimate the overall prevalence of pneumococcal carriage and incidence of pneumococcal pneumonia across studies with similar characteristics. Results will be reported in compliance with the Meta-Analysis Of Observational Studies in Epidemiology guidelines. The protocol has been prepared in accordance to the 2015 guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses. ETHICS AND DISSEMINATION:This systematic review will not require ethical approval as we will be using already published data. The final manuscript will be submitted for publication in a peer-reviewed journal and presented at conferences. PROSPERO REGISTRATION NUMBER:CRD42019130976

Varying efficacy of artesunate+amodiaquine and artesunate+sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in the Democratic Republic of Congo: a report of two in-vivo studies

BACKGROUND: Very few data on anti-malarial efficacy are available from the Democratic Republic of Congo (DRC). DRC changed its anti-malarial treatment policy to amodiaquine (AQ) and artesunate (AS) in 2005. METHODS: The results of two in vivo efficacy studies, which tested AQ and sulphadoxine-pyrimethamine (SP) monotherapies and AS+SP and AS+AQ combinations in Boende (Equatorial province), and AS+SP, AS+AQ and SP in Kabalo (Katanga province), between 2003 and 2004 are presented. The methodology followed the WHO 2003 protocol for assessing the efficacy of anti-malarials in areas of high transmission. RESULTS: Out of 394 included patients in Boende, the failure rates on day 28 after PCR-genotyping adjustment of AS+SP and AS+AQ were estimated as 24.6% [95% CI: 16.6-35.5] and 15.1% [95% CI: 8.6-25.7], respectively. For the monotherapies, failure rates were 35.9% [95% CI: 27.0-46.7] for SP and 18.3% [95% CI: 11.6-28.1] for AQ. Out of 207 patients enrolled in Kabalo, the failure rate on day 28 after PCR-genotyping adjustment was 0 [1-sided 95% CI: 5.8] for AS+SP and AS+AQ [1-sided 95% CI: 6.2]. It was 19.6% [95% CI: 11.4-32.7] for SP monotherapy. CONCLUSION: The finding of varying efficacy of the same combinations at two sites in one country highlights one difficulty of implementing a uniform national treatment policy in a large country. The poor efficacy of AS+AQ in Boende should alert the national programme to foci of resistance and emphasizes the need for systems for the prospective monitoring of treatment efficacy at sentinel sites in the country

Hepatitis B vaccination impact and the unmet need for antiviral treatment in Blantyre, Malawi

BACKGROUND: Hepatitis B is the leading cause of cirrhosis and liver cancer in sub-Saharan Africa. To reduce hepatitis-associated mortality, antiviral treatment programmes are needed. We estimated prevalence, vaccine impact and need for antiviral treatment in Blantyre, Malawi to inform an effective public health response. METHODS: We conducted a household study in Blantyre in 2016-2018. We selected individuals from a census using random sampling and estimated age-sex-standardised HBsAg seroprevalence. Impact of infant hepatitis B vaccination, which began in 2002, was estimated by binomial log-linear regression comparing individuals born before and after vaccine implementation. In HBsAg-positive adults, eligibility for antiviral therapy was assessed. RESULTS: Of 97,386 censused individuals, 6,073 (median age 18 years; 56.7% female) were sampled. HBsAg seroprevalence was 5.1% (95% CI 4.3-6.1) among adults and 0.3% (0.1-0.6) among children born after vaccine introduction. Estimated vaccine impact was 95.8% (70.3-99.4). Of HBsAg-positive adults, 26% were HIV-positive. Among HIV-negative individuals, 3%, 6% and 9% were eligible for hepatitis B treatment by WHO, European and American hepatology association criteria, respectively. CONCLUSIONS: Infant HBV vaccination has been highly effective in reducing HBsAg prevalence in urban Malawi. Up to 9% of HBsAg-positive HIV-negative adults are eligible, but have an unmet need, for antiviral therapy

Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children.

BACKGROUND: Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy. METHODS: Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only. RESULTS: Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used. CONCLUSION: The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs

Use and limitations of malaria rapid diagnostic testing by community health workers in war-torn Democratic Republic of Congo

<p>Abstract</p> <p>Background</p> <p>Accurate and practical malaria diagnostics, such as immunochromatographic rapid diagnostic tests (RDTs), have the potential to avert unnecessary treatments and save lives. Volunteer community health workers (CHWs) represent a potentially valuable human resource for expanding this technology to where it is most needed, remote rural communities in sub-Saharan Africa with limited health facilities and personnel. This study reports on a training programme for CHWs to incorporate RDTs into their management strategy for febrile children in the Democratic Republic of Congo, a tropical African setting ravaged by human conflict.</p> <p>Methods</p> <p>Prospective cohort study, satisfaction questionnaire and decision analysis.</p> <p>Results</p> <p>Twelve CHWs were trained to safely and accurately perform and interpret RDTs, then successfully implemented rapid diagnostic testing in their remote community in a cohort of 357 febrile children. CHWs were uniformly positive in evaluating RDTs for their utility and ease of use. However, high malaria prevalence in this cohort (93% by RDTs, 88% by light microscopy) limited the cost-effectiveness of RDTs compared to presumptive treatment of all febrile children, as evidenced by findings from a simplified decision analysis.</p> <p>Conclusions</p> <p>CHWs can safely and effectively use RDTs in their management of febrile children; however, cost-effectiveness of RDTs is limited in zones of high malaria prevalence.</p

The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum

<p>Abstract</p> <p>Background</p> <p>Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating <it>Plasmodium falciparum </it>malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested.</p> <p>Methods</p> <p>A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, <it>P</it>. <it>falciparum</it>-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety.</p> <p>Results</p> <p>Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7–94.7) vs. AS+AQ = 313/340 (95% CI: 88.6–94.7). Non-inferiority was demonstrated at two-sided α = 0.05: Δ (AS+AQ – AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Δ = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances.</p> <p>Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (<it>p </it>= 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients.</p> <p>Conclusion</p> <p>Fixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating <it>P. falciparum </it>malaria with continued safety monitoring.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN07576538</p

Transcriptional Regulation of BMP2 Expression by the PTH-CREB Signaling Pathway in Osteoblasts

Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. Together, these results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts

Malaria is an uncommon cause of adult sepsis in south-western Uganda

Malaria is often considered a cause of adult sepsis in malaria endemic areas. However, diagnostic limitations can make distinction between malaria and other infections challenging. Therefore, the objective of this study was to determine the relative contribution of malaria to adult sepsis in south-western Uganda

Multiple Origins and Regional Dispersal of Resistant dhps in African Plasmodium falciparum Malaria

Cally Roper and colleagues analyze the distribution of sulfadoxine resistance mutations and flanking microsatellite loci to trace the emergence and dispersal of drug-resistant Plasmodium falciparum malaria in Africa