Characteristics of TPT initiation and completion among people living with HIV.

BACKGROUND: TB preventive treatment (TPT) reduces morbidity and mortality among people living with HIV (PLHIV). Despite the successful scale-up of TPT in Malawi, monitoring and evaluation have been suboptimal. We utilized the Malawi Population-Based HIV Impact Assessment (MPHIA) 2020-2021 survey data to estimate TPT uptake and completion among self-reported HIV-positive persons. METHODS: We estimated the proportion of HIV-positive respondents who had ever undergone TPT, and determined the percentage of those currently on TPT who had completed more than 6 months of treatment. Bivariate and multivariable logistic regression were performed to calculate the odds ratios for factors associated with ever-taking TPT. All variables were self-reported, and the analysis was weighted and accounted for in the survey design. RESULTS: Of the HIV+ respondents, 38.8% (95% CI 36.4-41.3) had ever taken TPT. The adjusted odds of ever taking TPT were 8.0 and 5.2 times as high in the Central and Southern regions, respectively, compared to the Northern region; 1.9 times higher among those in the highest wealth quintile, and 2.1 times higher for those on antiretroviral therapy >10 years. Of those currently taking TPT, 56.2% completed >6 months of TPT. CONCLUSION: These results suggest low TPT uptake and >6 months' completion rates among self-reported HIV+ persons. Initiatives to create demand and strengthen adherence would improve TPT uptake.

CONTEXTE: Le traitement préventif de la TB (TPT) réduit la morbidité et la mortalité chez les personnes vivant avec le VIH (PVVIH). Malgré l'extension réussie du TPT au Malawi, le suivi et l'évaluation n'ont pas été optimaux. Nous avons utilisé les données de l'enquête MPHIA (Malawi Population-Based HIV Impact Assessment) 2020­2021 pour estimer l'adoption et l'achèvement du TPT parmi les personnes se déclarant séropositives. MÉTHODES: Nous avons estimé la proportion de répondants séropositifs qui avaient déjà subi un TPT et déterminé le pourcentage de ceux qui sont actuellement sous TPT et qui ont terminé plus de 6 mois de traitement. Une régression logistique bivariée et multivariable a été effectuée pour calculer les rapports de cotes des facteurs associés au fait d'avoir déjà pris un TPT. Toutes les variables étaient autodéclarées et l'analyse a été pondérée et prise en compte dans la conception de l'enquête. RÉSULTATS: Parmi les répondants séropositifs, 38,8% (IC 95% 36,4­41,3) avaient déjà pris du TPT. Les probabilités ajustées de prise de TPT étaient 8,0 et 5,2 fois plus élevées dans les régions du centre et du sud, respectivement, que dans la région du nord ; 1,9 fois plus élevées chez les personnes appartenant au quintile de richesse le plus élevé, et 2,1 fois plus élevées chez les personnes suivant une thérapie antirétrovirale depuis plus de 10 ans. Parmi ceux qui prennent actuellement un TPT, 56,2% ont terminé >6 mois de TPT. CONCLUSION: Ces résultats suggèrent un faible taux d'utilisation du TPT et des taux d'achèvement de >6 mois parmi les personnes déclarées séropositives. Des initiatives visant à créer une demande et à renforcer l'adhésion permettraient d'améliorer l'utilisation du TPT.

Consideration-of-concept of EvolvRehab-Body for upper limb virtual rehabilitation at home for people late after stroke.

OBJECTIVE: EvolvRehab-Body is a non-immersive virtual rehabilitation system that could provide high-dose, exercise-based upper limb therapy after stroke. This consideration-of-concept study investigated: adherence rate to prescribed repetitions; viability of repeated measures in preparation for a dose-articulation study; and preliminary signal of potential benefit. METHODS: Pre-post and repeated measures with people at least six months after stroke. Twelve-week intervention: exercise-based therapy via EvolvRehab-Body. Pre-post-intervention measures: Wolf Motor Function Test (WMFT); hand grip force. Repeated-during-intervention measures: Motricity Index (MI) and Action Research Arm Test (ARAT). ANALYSIS: adherence rate (%) to set repetitions; percentage of total possible measures collected; pre-to-post-intervention change estimated in relation to published minimally detectable changes of WMFT and hand grip force; and slope of plotted data for MI and ARAT (linear regression). RESULTS: Eight of twelve participants completed the 12-week intervention phase. Adherence: 88% (1710-9377 repetitions performed). Viability repeated measures: 88 of 96 (92%) ARAT and MI scores collected. Preliminary signal of potential benefit was observed in five participants but not always for the same measures. Three participants improved WMFT-time (-7.9 to -27.2 s/item), four improved WMFT-function (0.2-1.1 points/item), and nobody changed grip force. Slope of plotted data over the 12-week intervention ranged from: - 1.42 (p = 0.26) to 1.36 (p = 0.24) points-per-week for MI and - 0.30 (p = 0.40) to 1.71 (p < 0.001) points-per-week for ARAT. CONCLUSION: Findings of good adherence rate in home settings and preliminary signal of benefit for some participants gives support to proceed to a dose-articulation study. These findings cannot inform clinical practice. CONTRIBUTION OF THE PAPER.

Quantitative structure determination of adsorbed formate and surface hydroxyls on Fe3O4(001).

Using the chemically specific techniques of normal incidence X-ray standing waves and photoelectron diffraction, we have investigated the dissociative adsorption of formic acid on the Fe3O4(001) surface, specifically probing the local structures of both the adsorbed formate and resulting surface hydroxyl. Using model independent direct methods, we reinforce the observations of a previous surface X-ray diffraction study that the formate molecule adsorbs with both oxygens atop octahedrally coordinated surface Fe cations and that ∼60% of the formate is adsorbed in the so called tet site. We additionally determine, for the first time, that the surface hydroxyl species are found at the so called int site. This confirms previous DFT predictions and reinforces the pivotal role the surface hydroxyl plays in lifting the subsurface cation vacancy termination of the Fe3O4(001) surface.

Validation of the inverted adsorption structure for free-base tetraphenyl porphyrin on Cu(111).

Utilising normal incidence X-ray standing waves we rigourously scrutinise the "inverted model" as the adsorption structure of free-base tetraphenyl porphyrin on Cu(111). We demonstrate that the iminic N atoms are anchored at near-bridge adsorption sites on the surface displaced laterally by 1.1 ± 0.2 Å in excellent agreement with previously published calculations.

Probing structural changes upon carbon monoxide coordination to single metal adatoms.

In this work, the adsorption height of Ag adatoms on the Fe3O4(001) surface after exposure to CO was determined using normal incidence x-ray standing waves. The Ag adatoms bound to CO (Ag1 CO) are found to be pulled out of the surface to an adsorption height of 1.15 Å ± 0.08 Å, compared to the previously measured height of 0.96 Å ± 0.03 Å for bare Ag adatoms and clusters. Utilizing DFT+vdW+U calculations with the substrate unit cell dimension fixed to the experimental value, the predicted adsorption height for Ag1 CO was 1.16 Å, in remarkably good agreement with the experimental results.

From Molecules to Mechanisms: Functional Proteomics and Its Application to Renal Tubule Physiology.

Classical physiological studies using electrophysiological, biophysical, biochemical, and molecular techniques have created a detailed picture of molecular transport, bioenergetics, contractility and movement, and growth, as well as the regulation of these processes by external stimuli in cells and organisms. Newer systems biology approaches are beginning to provide deeper and broader understanding of these complex biological processes and their dynamic responses to a variety of environmental cues. In the past decade, advances in mass spectrometry-based proteomic technologies have provided invaluable tools to further elucidate these complex cellular processes, thereby confirming, complementing, and advancing common views of physiology. As one notable example, the application of proteomics to study the regulation of kidney function has yielded novel insights into the chemical and physical processes that tightly control body fluids, electrolytes, and metabolites to provide optimal microenvironments for various cellular and organ functions. Here, we systematically review, summarize, and discuss the most significant key findings from functional proteomic studies in renal epithelial physiology. We also identify further improvements in technological and bioinformatics methods that will be essential to advance precision medicine in nephrology.

Direct measurement of Ni incorporation into Fe3O4(001).

The normal incidence X-ray standing wave (NIXSW) technique has been used to follow the evolution of the adsorption geometry of Ni adatoms on the Fe3O4(001)-(√2 × âˆš2)R45° surface as a function of temperature. Two primary surface region sites are identified: a bulk-continuation tetrahedral site and a sub-surface octahedral site, the latter site being preferred at higher annealing temperatures. The ease of incorporation is linked to the presence of subsurface cation vacancies in the (√2 × âˆš2)R45° reconstruction and is consistent with the preference for octahedral coordination observed in the spinel compound NiFe2O4.

AbDesigner3D: a structure-guided tool for peptide-based antibody production.

Summary: We present AbDesigner3D, a new tool for identification of optimal immunizing peptides for antibody production using a peptide-based strategy. AbDesigner3D integrates 3D structural data from the Protein Data Bank (PDB) with UniProt data, which includes basic sequence data, post-translational modification sites, SNP occurrences and more. Other features, such as uniqueness and conservation scores, are calculated based on sequences from UniProt. The 3D visualization capabilities allow an intuitive interface, while an abundance of quantitative output simplifies the process of comparing immunogen peptides. Important quantitative features added in this tool include calculation and display of accessible surface area (ASA) and protein-protein interacting residues (PPIR). The specialized data visualization features of AbDesigner3D will greatly assist users to optimize their choice of immunizing peptides. Availability and implementation: AbDesigner3D is freely available at http://sysbio.chula.ac.th/AbDesigner3D or https://hpcwebapps.cit.nih.gov/AbDesigner3D/. Supplementary information: Supplementary data are available at Bioinformatics online.

p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia.

p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity. In tumor-derived organoid cultures, elimination of both p120 alleles resulted in caspase-3-dependent apoptosis that was blocked by inhibition of Rho kinase (ROCK). With ROCK inhibition, however, p120-ablated organoids exhibited a branching phenotype and a substantial increase in cell proliferation. Access to data from Sleeping Beauty mutagenesis screens afforded an opportunity to directly assess the tumorigenic impact of p120 haploinsufficiency relative to other candidate drivers. Remarkably, p120 ranked third among the 919 drivers identified. Cofactors α-catenin and epithelial cadherin (E-cadherin) were also among the highest scoring candidates, indicating a mechanism at the level of the intact complex that may play an important role at very early stages of of intestinal tumorigenesis while simultaneously restricting outright loss via synthetic lethality.

Quantifying the critical thickness of electron hybridization in spintronics materials.

In the rapidly growing field of spintronics, simultaneous control of electronic and magnetic properties is essential, and the perspective of building novel phases is directly linked to the control of tuning parameters, for example, thickness and doping. Looking at the relevant effects in interface-driven spintronics, the reduced symmetry at a surface and interface corresponds to a severe modification of the overlap of electron orbitals, that is, to a change of electron hybridization. Here we report a chemically and magnetically sensitive depth-dependent analysis of two paradigmatic systems, namely La1-xSrxMnO3 and (Ga,Mn)As. Supported by cluster calculations, we find a crossover between surface and bulk in the electron hybridization/correlation and we identify a spectroscopic fingerprint of bulk metallic character and ferromagnetism versus depth. The critical thickness and the gradient of hybridization are measured, setting an intrinsic limit of 3 and 10 unit cells from the surface, respectively, for (Ga,Mn)As and La1-xSrxMnO3, for fully restoring bulk properties.

Hypercalcemia induces targeted autophagic degradation of aquaporin-2 at the onset of nephrogenic diabetes insipidus.

Hypercalcemia can cause renal dysfunction such as nephrogenic diabetes insipidus (NDI), but the mechanisms underlying hypercalcemia-induced NDI are not well understood. To elucidate the early molecular changes responsible for this disorder, we employed mass spectrometry-based proteomic analysis of inner medullary collecting ducts (IMCD) isolated from parathyroid hormone-treated rats at onset of hypercalcemia-induced NDI. Forty-one proteins, including the water channel aquaporin-2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the downregulated proteins were associated with cytoskeletal protein binding, regulation of actin filament polymerization, and cell-cell junctions. Targeted LC-MS/MS and immunoblot studies confirmed the downregulation of 16 proteins identified in the initial proteomic analysis and in additional experiments using a vitamin D treatment model of hypercalcemia-induced NDI. Evaluation of transcript levels and estimated half-life of the downregulated proteins suggested enhanced protein degradation as the possible regulatory mechanism. Electron microscopy showed defective intercellular junctions and autophagy in the IMCD cells from both vitamin D- and parathyroid hormone-treated rats. A significant increase in the number of autophagosomes was confirmed by immunofluorescence labeling of LC3. Colocalization of LC3 and Lamp1 with aquaporin-2 and other downregulated proteins was found in both models. Immunogold electron microscopy revealed aquaporin-2 in autophagosomes in IMCD cells from both hypercalcemia models. Finally, parathyroid hormone withdrawal reversed the NDI phenotype, accompanied by termination of aquaporin-2 autophagic degradation and normalization of both nonphoshorylated and S256-phosphorylated aquaporin-2 levels. Thus, enhanced autophagic degradation of proteins plays an important role in the initial mechanism of hypercalcemic-induced NDI.

Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome.

BACKGROUND: The AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPARγ activation is known to modulate metabolic syndrome; however a systems-level investigation looking at the protective effects of PPARγ activation as related to the AROS axis has not been performed. The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD-induced metabolic syndrome, in the presence or absence of a PPARγ agonist, Rosiglitazone (RGZ). METHODS: Rats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half. RESULTS: Rats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented. CONCLUSIONS: Our data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by PPARγ modulation.

Creating Excess Electrons at the Anatase TiO2(101) Surface.

Excess electrons facilitate redox reactions at the technologically relevant anatase TiO2(101) surface. The availability of these electrons is related to the defect concentration at the surface. We present two-photon (2PPE, 3.10-3.54 eV) and ultraviolet (UPS, 21.2 & 40.8 eV) photoemission spectroscopy measurements evidencing an increased concentration of excess electrons following electron bombardment at room temperature. Irradiation-induced surface oxygen vacancies are known to migrate into the sub-surface at this temperature, quickly equilibrating the surface defect concentration. Hence, we propose that the irradiated surface is hydroxylated. Peaks in UPS difference spectra are observed centred 8.45, 6.50 and 0.73 eV below the Fermi level, which are associated with the 3σ and 1π hydroxyl molecular orbitals and Ti 3d band gap states, respectively. The higher concentration of excess electrons at the hydroxylated anatase (101) surface may increase the potential for redox reactions.

A machine learning strategy for predicting localization of post-translational modification sites in protein-protein interacting regions.

BACKGROUND: One very important functional domain of proteins is the protein-protein interacting region (PPIR), which forms the binding interface between interacting polypeptide chains. Post-translational modifications (PTMs) that occur in the PPIR can either interfere with or facilitate the interaction between proteins. The ability to predict whether sites of protein modifications are inside or outside of PPIRs would be useful in further elucidating the regulatory mechanisms by which modifications of specific proteins regulate their cellular functions. RESULTS: Using two of the comprehensive databases for protein-protein interaction and protein modification site data (PDB and PhosphoSitePlus, respectively), we created new databases that map PTMs to their locations inside or outside of PPIRs. The mapped PTMs represented only 5 % of all known PTMs. Thus, in order to predict localization within or outside of PPIRs for the vast majority of PTMs, a machine learning strategy was used to generate predictive models from these mapped databases. For the three mapped PTM databases which had sufficient numbers of modification sites for generating models (acetylation, phosphorylation, and ubiquitylation), the resulting models yielded high overall predictive performance as judged by a combined performance score (CPS). Among the multiple properties of amino acids that were used in the classification tasks, hydrophobicity was found to contribute substantially to the performance of the final predictive models. Compared to the other classifiers we also evaluated, the SVM provided the best performance overall. CONCLUSIONS: These models are the first to predict whether PTMs are located inside or outside of PPIRs, as demonstrated by their high predictive performance. The models and data presented here should be useful in prioritizing both known and newly identified PTMs for further studies to determine the functional relationship between specific PTMs and protein-protein interactions. The implemented R package is available online ( http://sysbio.chula.ac.th/PtmPPIR ).

Communication networks beyond the capacity crunch.

This issue of Philosophical Transactions of the Royal Society, Part A represents a summary of the recent discussion meeting 'Communication networks beyond the capacity crunch'. The purpose of the meeting was to establish the nature of the capacity crunch, estimate the time scales associated with it and to begin to find solutions to enable continued growth in a post-crunch era. The meeting confirmed that, in addition to a capacity shortage within a single optical fibre, many other 'crunches' are foreseen in the field of communications, both societal and technical. Technical crunches identified included the nonlinear Shannon limit, wireless spectrum, distribution of 5G signals (front haul and back haul), while societal influences included net neutrality, creative content generation and distribution and latency, and finally energy and cost. The meeting concluded with the observation that these many crunches are genuine and may influence our future use of technology, but encouragingly noted that research and business practice are already moving to alleviate many of the negative consequences.

Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus.

Hypokalemia (low serum potassium level) is a common electrolyte imbalance that can cause a defect in urinary concentrating ability, i.e., nephrogenic diabetes insipidus (NDI), but the molecular mechanism is unknown. We employed proteomic analysis of inner medullary collecting ducts (IMCD) from rats fed with a potassium-free diet for 1 day. IMCD protein quantification was performed by mass spectrometry using a label-free methodology. A total of 131 proteins, including the water channel AQP2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the down-regulated proteins were associated with the biological processes of generation of precursor metabolites and energy, actin cytoskeleton organization, and cell-cell adhesion. Targeted LC-MS/MS and immunoblotting studies further confirmed the down regulation of 18 selected proteins. Electron microscopy showed autophagosomes/autophagolysosomes in the IMCD cells of rats deprived of potassium for only 1 day. An increased number of autophagosomes was also confirmed by immunofluorescence, demonstrating co-localization of LC3 and Lamp1 with AQP2 and several other down-regulated proteins in IMCD cells. AQP2 was also detected in autophagosomes in IMCD cells of potassium-deprived rats by immunogold electron microscopy. Thus, enhanced autophagic degradation of proteins, most notably including AQP2, is an early event in hypokalemia-induced NDI.

Broadband wavelength and angle-resolved scattering characterization for nanophotonics investigations.

The characterization of scattered light is complex and relatively nonstandardized despite being of great importance to many optical technologies. While total scatter can be efficiently measured using integrating-sphere-based techniques, a detailed determination of the full bidirectional scattering distribution function is far more challenging, often requiring complicated and expensive equipment as well as substantial measurement time. Due to this, many research groups rely on simpler, angle-resolved scattering (ARS) measurements, yet these are typically carried out using a single wavelength source, therefore providing limited information. Here, we demonstrate a custom-built broadband angle-resolved optical spectrometer, which utilizes a supercontinuum white light laser source combined with a custom automated goniometer and a Si CCD array spectrometer in order to carry out broad spectral measurements of ARS. The use of a collimated supercontinuum allows for small area measurements that are often crucial for investigation of nanophotonic samples created using expensive fabrication techniques. The system has been tested and calibrated, and accuracy and reproducibility have been verified by integrating wavelength and ARS data over the angular range and comparing to calibrated integrating sphere measurements.

A randomised clinical study to evaluate the efficacy of alcohol-free or alcohol-containing mouthrinses with chlorhexidine on gingival bleeding.

OBJECTIVES: Gingival bleeding following twice-daily use of 0.2% w/v chlorhexidine digluconate mouthrinse with and without alcohol (0.2% CHX-alcohol; 0.2% CHX-alcohol-free, respectively) and brushing with a standard fluoride toothpaste was compared to brushing alone. METHODS: Three hundred and nineteen subjects with mild-to-moderate gingivitis (with ≥16 gradable permanent teeth including four molars, bleeding after brushing and ≥20 bleeding sites) completed this randomised, examiner-blinded, parallel-group study. A prophylaxis was performed at baseline. Gingival Severity Index (GSI; primary objective), Gingival Index (GI) and Plaque Index (PI) were assessed at baseline and after 6 weeks of treatment. Adverse events (AEs) were recorded throughout the study. RESULTS: Between treatment differences at week 6 demonstrated significantly lower GSI for the 0.2% CHX-alcohol and 0.2% CHX-alcohol-free groups compared to brushing alone (primary endpoint; treatment difference -0.061 [95% CI -0.081, -0.041] and -0.070 [95% CI -0.090, -0.050], respectively; both p <0.0001). There were also significant reductions in GI and PI for the 0.2% CHX-alcohol and 0.2% CHX-alcohol-free groups compared to brushing alone (all p <0.0001). The proportion of subjects reporting ≥1 treatment-related adverse events (TRAEs) was 27.8% (0.2% CHX-alcohol), 24.8% (0.2% CHX-alcohol-free) and 3.7% (brushing alone). CONCLUSIONS: Chlorhexidine mouthrinse with or without alcohol as an adjunct to brushing with regular fluoride toothpaste significantly reduces bleeding scores, plaque and gingival inflammation compared to brushing alone. TRAEs are characteristic of those associated with the use of chlorhexidine and are similar for both mouthrinses.

Prolonged school non-attendance in adolescence: a practical approach.

Prolonged school non-attendance in adolescence poses a significant public health concern. Adverse outcomes for adolescents who have missed out on the social and academic benefits of high school include mental health disorders and economic, social and relationship difficulties that may persist into adulthood. Healthcare professionals are often consulted in cases of prolonged school non-attendance. Diagnosis and management of specific physical and mental health problems must be the health professional's initial priority, with the subsequent development of a management plan to assist with school reintegration. Using a specific framework, an understanding of the factors contributing to a young person's school non-attendance can be developed. Intervention leading to a successful return to school has the potential to lower the risk of associated long-term adverse health outcomes.

Understanding the electronic structure of IrO2 using hard-X-ray photoelectron spectroscopy and density-functional theory.

The electronic structure of IrO2 has been investigated using hard x-ray photoelectron spectroscopy and density-functional theory. Excellent agreement is observed between theory and experiment. We show that the electronic structure of IrO2 involves crystal field splitting of the iridium 5d orbitals in a distorted octahedral field. The behavior of IrO2 closely follows the theoretical predictions of Goodenough for conductive rutile-structured oxides [J. B. Goodenough, J. Solid State Chem. 3, 490 (1971).