Activity-based costing for HIV, primary care and nutrition services in low- and middle-income countries: A systematic literature review and synthesis

Background This study is a systematic literature review of HIV, nutrition, and primary care activity-based costing (ABC) studies conducted in low- and middle-income countries. ABC studies are critical for understanding the quantities and unit costs of the activities and resources for specific cost functions. The results of ABC studies enable governments, funders, and policymakers to utilize costing results to make efficient, cost-effective decisions on how to allocate scarce resources. Methods We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology for systematic literature reviews. Key search terms included: (1) activity-based costing and time-driven activity-based costing, (2) cost of services, (3) HIV interventions OR (4) primary health care. Terms were searched within article titles and abstracts in PubMed, EconLit, and Scopus. Results 1,884 abstracts were screened and reduced to 57 articles using exclusion criteria. After a full text review, 16 articles were included in the final data synthesis. Findings were used to classify costs into relevant and common inputs for activity-based costing. All costs were converted to unit cost (cost per patient) and inflated to January 2020 USD. The largest unit cost across nutrition services was training (US$194.16 per patient, 34.6$125.41, 71.0%). The largest unit cost for primary care services was human resources (US$84.78, 62.5$176.71, US$135.67 for primary care services, and US$561.68 for nutrition services. The costing results presented suggest that spending on HIV exceeds the actual cost of HIV services. Conclusions This is the first systematic literature review to summarize the costs of HIV, primary care, and nutrition services across activity-based costing studies. While there was a wide variation in the study designs and economic methods, many of the input cost categories were similar. With the increasing number of costing studies in countries around the world, understanding trends in costs by function and service can lead to greater efficiency in the implementation of HIV, primary care, and nutrition programs

Distribution of an Invasive Aquatic Pathogen (Viral Hemorrhagic Septicemia Virus) in the Great Lakes and Its Relationship to Shipping

Viral hemorrhagic septicemia virus (VHSV) is a rhabdovirus found in fish from oceans of the northern hemisphere and freshwaters of Europe. It has caused extensive losses of cultured and wild fish and has become established in the North American Great Lakes. Large die-offs of wild fish in the Great Lakes due to VHSV have alarmed the public and provoked government attention on the introduction and spread of aquatic animal pathogens in freshwaters. We investigated the relations between VHSV dispersion and shipping and boating activity in the Great Lakes by sampling fish and water at sites that were commercial shipping harbors, recreational boating centers, and open shorelines. Fish and water samples were individually analyzed for VHSV using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and cell culture assays. Of 1,221 fish of 17 species, 55 were VHSV positive with highly varied qRT-PCR titers (1 to 5,950,000 N gene copies). The detections of VHSV in fish and water samples were closely associated and the virus was detected in 21 of 30 sites sampled. The occurrence of VHSV was not related to type of site or shipping related invasion hotspots. Our results indicate that VHSV is widely dispersed in the Great Lakes and is both an enzootic and epizootic pathogen. We demonstrate that pathogen distribution information could be developed quickly and is clearly needed for aquatic ecosystem conservation, management of affected populations, and informed regulation of the worldwide trade of aquatic organisms

ADAM8 signaling drives neutrophil migration and ARDS severity

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain

Genotype and Cardiovascular Phenotype Correlations With TBX1 in 1,022 Velo-Cardio-Facial/Digeorge/22q11.2 Deletion Syndrome Patients

Haploinsufficiency of TBX1, encoding a T-box transcription factor, is largely responsible for the physical malformations in velo-cardio-facial /DiGeorge/22q11.2 deletion syndrome (22q11DS) patients. Cardiovascular malformations in these patients are highly variable, raising the question as to whether DNA variations in the TBX1 locus on the remaining allele of 22q11.2 could be responsible. To test this, a large sample size is needed. The TBX1 gene was sequenced in 360 consecutive 22q11DS patients. Rare and common variations were identified. We did not detect enrichment in rare SNP (single nucleotide polymorphism) number in those with or without a congenital heart defect. One exception was that there was increased number of very rare SNPs between those with normal heart anatomy compared to those with right-sided aortic arch or persistent truncus arteriosus, suggesting potentially protective roles in the SNPs for these phenotype-enrichment groups. Nine common SNPs (minor allele frequency, MAF \u3e 0.05) were chosen and used to genotype the entire cohort of 1,022 22q11DS subjects. We did not find a correlation between common SNPs or haplotypes and cardiovascular phenotype. This work demonstrates that common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome

Overt Cleft Palate Phenotype and TBX1 Genotype Correlations in Velo-cardio-facial/DiGeorge/22q11.2 Deletion Syndrome Patients

Velo-cardio-facial syndrome/DiGeorge syndrome, also known as 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, with an estimated incidence of 1/2,000 – 1/4,000 live births. Approximately 9–11% of patients with this disorder have an overt cleft palate (CP), but the genetic factors responsible for CP in the 22q11DS subset are unknown. The TBX1 gene, a member of the T-box transcription factor gene family, lies within the 22q11.2 region that is hemizygous in patients with 22q11DS. Inactivation of one allele of Tbx1 in the mouse does not result in CP, but inactivation of both alleles does. Based on these data, we hypothesized that DNA variants in the remaining allele of TBX1 may confer risk to CP in patients with 22q11DS. To test the hypothesis, we evaluated TBX1 exon sequencing (n = 360) and genotyping data (n = 737) with respect to presence (n = 54) or absence (n = 683) of CP in patients with 22q11DS. Two upstream SNPs (rs4819835 and rs5748410) showed individual evidence for association but they were not significant after correction for multiple testing. Associations were not identified between DNA variants and haplotypes in 22q11DS patients with CP. Overall, this study indicates that common DNA variants in TBX1 may be nominally causative for CP in patients with 22q11DS. This raises the possibility that genes elsewhere on the remaining allele of 22q11.2 or in the genome could be relevant

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study

Objective To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). Methods A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. Results Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. Conclusions Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progressionThis project was funded by The Motor Neurone Disease Association (Malaspina/Apr13/6097) and Barts and The London Charities (468/1714). LG is the Graham Watts Senior Research Fellow, funded by The Brain Research Trust and the European Community’s Seventh Framework Programme (FP7/2007-2013)

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Cell cycle proteins in Alzheimer\u27s disease: Plenty of wheels but no cycle

The unexpected presence of certain control elements of the cell cycle in susceptible neurons in AD not only provides a possible explanation for many of the pathological aspects of the disease, but also suggests a crucial role for temporally ectopic cell cycle dysregulation driving proximal pathophysiology and cell death in AD. This process may be precipitated by alterations in and/or sensitivity of signal transduction pathways that are stimulated by growth factors such as NGF, TGF and bFGF, or inflammatory cytokines, all of which are increased in AD brain. While it has been argued that expression and activation of cell cycle proteins leads to cell cycle progression, DNA replication and cell death via a mitotic catastrophe, we favor a model in which cell cycle proteins that traditionally function at different stages of the cell cycle directly and concurrently participate in regulating gene expression and sprouting, formation of pathologic lesions associated with AD, and cell death mechanisms (Fig. 2). Importantly, these cell cycle protein responses may be susceptible to pharmacological interventions that disrupt cell cycle activation, thereby providing new and exciting potential therapeutic interventions for AD. Future studies should explore the possible utility of cyclin/CDK inhibitors or other agents that directly modify the function of cell cycle proteins in reducing neuronal cell death and impeding NFT formation during AD. In addition, the signal transduction pathways that regulate cell cycle protein activation or re-distribution are also potential targets for therapeutic intervention. Finally, altered function or distribution of cell cycle transcriptional regulators may alter chromatin structure and make the DNA more susceptible to oxidative induced damage, further adding to the degenerative state of the neuron. In conclusion, expression and activation of cell cycle proteins during AD likely occurs as a response to the initiating disease factors and directly participates in neuronal responses and cell death pathways during the disease process. While neurons may exit the GO phase of the cell cycle, progression through stages of the cycle or DNA replication are not necessary for cell cycle proteins to stimulate neuronal death during AD nor function in the phosphorylation of τ and development of NFTs

Educating the Future of Sustainability

The future of global environmental sustainability is contingent upon educating the next generation of environmental stewards. Critical elements of training such an interdisciplinary workforce include mentoring and experiential learning in the areas of science, communication, and leadership. To keep pace with the ever changing and increasingly complex issues of global environmental sustainability, environmental educators must encourage and support the participation and training of a diverse body of students in the environmental sciences. The Rocky Mountain Sustainability and Science Network (RMSSN) is a partnership of over two dozen universities, federal agencies and other organizations designed to help train the next diverse generation of interdisciplinary leaders who are prepared to address issues related to global climate change, environmental sustainability, and the management of public lands and resources using the Rocky Mountains as a laboratory and classroom. Herein, we present the RMSSN as a model for engaging students in the environmental sciences with an emphasis on understanding key elements of sustainability. Our model is based on a foundation of: (1) diversity; (2) tiered mentoring in cohorts; (3) engaging lectures coupled with field experiences on public lands; (4) long term networking; and (5) environmental internships