Evaluation of HIV treatment outcomes with reduced frequency of clinical encounters and antiretroviral treatment refills: A systematic review and meta-analysis

BackgroundGlobal HIV treatment programs have sought to lengthen the interval between clinical encounters for people living with HIV (PLWH) who are established on antiretroviral treatment (ART) to reduce the burden of seeking care and to decongest health facilities. The overall effect of reduced visit frequency on HIV treatment outcomes is however unknown. We conducted a systematic review and meta-analysis to evaluate the effect of implementation strategies that reduce the frequency of clinical appointments and ART refills for PLWH established on ART.Methods and findingsWe searched databases​ between 1 January 2010 and 9 November 2021 to identify randomized controlled trials (RCTs) and observational studies that compared reduced (6- to 12-monthly) clinical consultation or ART refill appointment frequency to 3- to 6-monthly appointments for patients established on ART. We assessed methodological quality and real-world relevance, and used Mantel–Haenszel methods to generate pooled risk ratios (RRs) with 95% confidence intervals for retention, viral suppression, and mortality. We evaluated heterogeneity quantitatively and qualitatively, and overall evidence certainty using GRADE. Searches yielded 3,955 records, resulting in 10 studies (6 RCTs, 3 observational studies, and 1 study contributing observational and RCT data) representing 15 intervention arms with 33,599 adults (≥16 years) in 8 sub-Saharan African countries. Reduced frequency clinical consultations occurred at health facilities, while reduced frequency ART refills were delivered through facility or community pharmacies and adherence groups. Studies were highly pragmatic, except for some study settings and resources used in RCTs. Among studies comparing reduced clinical consultation frequency (6- or 12-monthly) to 3-monthly consultations, there appeared to be no difference in retention (RR 1.01, 95% CI 0.97–1.04, p = 0.682, 8 studies, low certainty), and this finding was consistent across 6- and 12-monthly consultation intervals and delivery strategies. Viral suppression effect estimates were markedly influenced by under-ascertainment of viral load outcomes in intervention arms, resulting in inconclusive evidence. There was similarly insufficient evidence to draw conclusions on mortality (RR 1.12, 95% CI 0.75–1.66, p = 0.592, 6 studies, very low certainty). For ART refill frequency, there appeared to be little to no difference in retention (RR 1.01, 95% CI 0.98–1.06, p = 0.473, 4 RCTs, moderate certainty) or mortality (RR 1.45, 95% CI 0.63–3.35, p = 0.382, 4 RCTs, low certainty) between 6-monthly and 3-monthly visits. Similar to the analysis for clinical consultations, although viral suppression appeared to be better in 3-monthly arms, effect estimates were markedly influence by under-ascertainment of viral load outcomes in intervention arms, resulting in overall inclusive evidence. This systematic review was limited by the small number of studies available to compare 12- versus 6-monthly clinical consultations, insufficient data to compare implementation strategies, and lack of evidence for children, key populations, and low- and middle-income countries outside of sub-Saharan Africa.ConclusionsBased on this synthesis, extending clinical consultation intervals to 6 or 12 months and ART dispensing intervals to 6 months appears to result in similar retention to 3-month intervals, with less robust conclusions for viral suppression and mortality. Future research should ensure complete viral load outcome ascertainment, as well as explore mechanisms of effect, outcomes in other populations, and optimum delivery and monitoring strategies to ensure widespread applicability of reduced frequency visits across settings.

Noelle Le Tourneau and co-workers study HIV outcomes in studies investigating reduced frequency of antiretroviral drug provision and clinical consultations.     

Potential risk zone for anthropogenic mortality of carnivores in Gandaki Province,Nepal

Anthropogenic pressures in human‐dominated landscapes often contribute to wildlife mortality. Carnivores are especially vulnerable to human‐induced mortality due to the perceived threat to livestock and humans. Despite having widespread conservation implications, carnivore mortality data have been largely underutilized within Nepal. This study utilized Maxent to identify high‐risk areas and explore the contribution of habitat attributes associated with carnivore mortality using the casualty database within the Gandaki province of central Nepal. We categorized the risk to carnivore species in three taxonomic groups, Felid, Viverridae, and Herpestidae, and identified a 3704‐km² area within the province at high risk for carnivore casualty. The middle mountains were the riskiest physiographic zone, and the Annapurna Conservation Area represented the largest risk zone among the four protected areas. Agricultural land was the most problematic area in terms of carnivore casualty. The human population was positively associated with high‐risk areas and the number of casualties, whereas protected area cover had a negative association. This study identified that the common leopard was at the highest risk of mortality and therefore would benefit from the implementation of an action plan and species‐specific conservation strategies, especially within identified high‐risk zones. An expansion of protected areas in the middle mountain region would serve to greatly reduce carnivore casualty. Species distribution modeling can be further used with national‐level spatial and temporal mortality data to identify the most prominent casualty times and pinpoint potential casualty locations throughout the country.     

Protoberberine Alkaloids Berberine,Palmatine, and Coralyne Binding to Poly(dT)⋅(Poly(dA)⋅Poly(dT)) Triplex: Comparative Structural Aspects and Energetics Profiles of the Interaction

The interaction of bioactive protoberberine alkaloids berberine, palmatine, and coralyne with the DNA triplex poly(dT)⋅(poly(dA)⋅poly(dT)) was studied using biophysical and calorimetric techniques. All three alkaloids bound the triplex cooperatively. Berberine and palmatine predominantly stabilized the triplex structure, while coralyne stabilized both triplex and duplex structures as inferred from optical thermal melting profiles. Fluorescence quenching, polarization, and viscometric studies hinted at an intercalative mode of binding for the alkaloids to the triplex, coralyne being more strongly intercalated compared to partial intercalation of berberine and palmatine. The overall affinity of coralyne was two order higher (2.29×10⁷ M ⁻¹) than that of berberine (3.43×10⁵ M ⁻¹) and palmatine (2.34×10⁵ M ⁻¹). Isothermal titration calorimetric studies revealed that the binding to the triplex was favored by negative enthalpy change (ΔH=−3.34 kcal/mol) with favorable entropy contribution (TΔS = 4.07 kcal/mol) for berberine, favored by almost equal negative enthalpy (ΔH =−3.88 kcal/mol) and entropy changes (TΔS = 3.37 kcal/mol) for palmatine, but driven by large enthalpy contributions (ΔH =−25.62 kcal/mol and TΔS =−15.21 kcal/mol) for coralyne. These results provide new insights on the binding of isoquinoline alkaloids to the DNA triplex structure.     

A comparative study of two community-based conservation models in Nepal

Conservation areas (CAs) and community forests (CFs) are generally considered to be two successful community-based conservation (CBC) models in Nepal. Nepal’s two CAs are administered by a nongovernmental organization (NGO), and all of its CFs are administered by a government agency (GA). The goal of this research is to compare and contrast these two models using quantitative and qualitative data collected through field research in the Annapurna Conservation Area in the summer of 2007 and adjacent CFs in the fall of 2008. The Conservation Area Management Committee (CAMC) and the Community Forest User Committee (CFUC) are the functional decision-making entities at the local level in CAs and CFs, respectively. We conducted one-on-one semi-structured interviews with 66 executive members of 10 CAMCs and 67 members of 9 CFUCs. While both models appear to have performed well overall, the CA under the direction of the NGO appears to have fared better with regard to (i) developing trust of local constituencies, (ii) garnering favorable attitudes among villagers, (iii) building capacity of executive members, and (iv) improving standards of living. We suggest that the particular accountabilities associated with NGOs may situate them in a better position to cultivate local governance than state entities on their own.     

Xerombrophila crystallifera, a new genus and species in the Helotiales

Xerombrophila, a new member of the Helotiales, is erected for a previously undescribed species that macroscopically resembles genera such as Phaeohelotium or Pezicula. The new species, for which we propose the name X. crystallifera, is characterized by a strong gelatinization of the medullary excipulum as well as the covering layer of the ectal excipulum, by the presence of abundant octahedral crystals, asci with an euamyloid apical ring that resembles the Calycina-type, and paraphyses containing refractive vacuoles. It can also be distinguished from members of both Ombrophila and Phaeohelotium in that it is desiccation-tolerant by surviving several weeks in the dry state. The species appears to be confined to xeric bark of Salix and was exclusively found over waterlogged soil, irrespective of being acidic or calcareous. It is known from various planar and colline areas of temperate Europe, and can be found throughout the year. Phylogenetic analysis of partial LSU sequences positions X. crystallifera as a sister taxon of a clade within the Helotiaceae s.l. that includes Ascocoryne, Chloroscypha, Gelatinodiscus, Neobulgaria and "Sarcoleotia" turficola.     

Identifying Novel Drug Indications through Automated Reasoning

Background

With the large amount of pharmacological and biological knowledge available in literature, finding novel drug indications for existing drugs using in silico approaches has become increasingly feasible. Typical literature-based approaches generate new hypotheses in the form of protein-protein interactions networks by means of linking concepts based on their cooccurrences within abstracts. However, this kind of approaches tends to generate too many hypotheses, and identifying new drug indications from large networks can be a time-consuming process.

Methodology

In this work, we developed a method that acquires the necessary facts from literature and knowledge bases, and identifies new drug indications through automated reasoning. This is achieved by encoding the molecular effects caused by drug-target interactions and links to various diseases and drug mechanism as domain knowledge in AnsProlog, a declarative language that is useful for automated reasoning, including reasoning with incomplete information. Unlike other literature-based approaches, our approach is more fine-grained, especially in identifying indirect relationships for drug indications.

Conclusion/Significance

To evaluate the capability of our approach in inferring novel drug indications, we applied our method to 943 drugs from DrugBank and asked if any of these drugs have potential anti-cancer activities based on information on their targets and molecular interaction types alone. A total of 507 drugs were found to have the potential to be used for cancer treatments. Among the potential anti-cancer drugs, 67 out of 81 drugs (a recall of 82.7%) are indeed known cancer drugs. In addition, 144 out of 289 drugs (a recall of 49.8%) are non-cancer drugs that are currently tested in clinical trials for cancer treatments. These results suggest that our method is able to infer drug indications (original or alternative) based on their molecular targets and interactions alone and has the potential to discover novel drug indications for existing drugs.     

Evaluation of the influence of intermolecular electron-nucleus couplings and intrinsic metal binding sites on the measurement of <Superscript>15</Superscript>N longitudinal paramagnetic relaxation enhancements in proteins by solid-state NMR

Magic-angle spinning solid-state NMR measurements of ¹⁵N longitudinal paramagnetic relaxation enhancements (PREs) in ¹³C,¹⁵N-labeled proteins modified with Cu²⁺-chelating tags can yield multiple long-range electron-nucleus distance restraints up to ~20 Å (Nadaud et al. in J Am Chem Soc 131:8108–8120, 2009). Using the EDTA-Cu²⁺ K28C mutant of B1 immunoglobulin binding domain of protein G (GB1) as a model, we investigate the effects on such measurements of intermolecular electron-nucleus couplings and intrinsic metal binding sites, both of which may potentially complicate the interpretation of PRE data in terms of the intramolecular protein fold. To quantitatively assess the influence of intermolecular ¹⁵N-Cu²⁺ interactions we have determined a nearly complete set of longitudinal ¹⁵N PREs for a series of microcrystalline samples containing ~10, 15 and 25 mol percent of the ¹³C,¹⁵N-labeled EDTA-Cu²⁺-tagged protein diluted in a matrix of diamagnetic natural abundance GB1. The residual intermolecular interactions were found to be minor on the whole and account for only a fraction of the relatively small but systematic deviations observed between the experimental ¹⁵N PREs and corresponding values calculated using protein structural models for residues furthest removed from the EDTA-Cu²⁺ tag. This suggests that these deviations are also caused in part by other factors not related to the protein structure, such as the presence in the protein of intrinsic secondary sites capable of binding Cu²⁺ ions. To probe this issue we performed a Cu²⁺ titration study for K28C-EDTA GB1 monitored by 2D ¹⁵N-¹H solution-state NMR, which revealed that while for Cu²⁺:protein molar ratios of ≤ 1.0 Cu²⁺ binds primarily to the high-affinity EDTA tag, as anticipated, at even slightly super-stoichiometric ratios the Cu²⁺ ions can also associate with side-chains of aspartate and glutamate residues. This in turn is expected to lead to enhanced PREs for residues located in the vicinity of the secondary Cu²⁺ binding sites, and indeed many of these residues were ones found to display the elevated longitudinal ¹⁵N PREs in the solid phase.