Modelling the impact and cost-effectiveness of non-governmental organizations on HIV and HCV transmission among people who inject drugs in Ukraine

Introduction

People who inject drugs (PWID) in Ukraine have high prevalences of HIV and hepatitis C virus (HCV). Non-governmental organizations (NGOs) provide PWID with needles/syringes, condoms, HIV/HCV testing and linkage to opioid agonist treatment (OAT) and antiretroviral therapy (ART). We estimated their impact and cost-effectiveness among PWID.

Methods

A dynamic HIV and HCV transmission model among PWID was calibrated using data from four national PWID surveys (2011–2017). The model assumed 37–49% coverage of NGOs among community PWID, with NGO contact reducing injecting risk and increasing condom use and recruitment onto OAT and ART. We estimated the historic (1997–2021) and future (2022–2030, compared to no NGO activities from 2022) impact of NGOs in terms of the proportion of HIV/HCV infections averted and changes in HIV/HCV incidence. We estimated the future impact of scaling-up NGOs to 80% coverage with/without scale-up in OAT (5–20%) and ART (64–81%). We estimated the cost per disability-adjusted life-year (DALY) averted of current NGO provision over 2022–2041 compared to NGO activities stopping over 2022–2026, but restarting after that till 2041. We assumed average unit costs of US$80–90 per person-year of NGO contact for PWID.

Results

With existing coverage levels of NGOs, the model projects that NGOs have averted 20.0% (95% credibility interval: 13.3–26.1) and 9.6% (5.1–14.1) of new HIV and HCV infections among PWID over 1997–2021, respectively, and will avert 31.8% (19.6–39.9) and 13.7% (7.5–18.1) of HIV and HCV infections over 2022–2030. With NGO scale-up, HIV and HCV incidence will decrease by 54.2% (43.3–63.8) and 30.2% (20.5–36.2) over 2022–2030, or 86.7% (82.9–89.3) and 39.8% (31.4–44.8) if OAT and ART are also scaled-up. Without NGOs, HIV and HCV incidence will increase by 51.6% (23.6–76.3) and 13.4% (4.8–21.9) over 2022–2030. Current NGO provision over 2022–2026 will avert 102,736 (77,611–137,512) DALYs when tracked until 2041 (discounted 3% annually), and cost US$912 (702–1222) per DALY averted; cost-effective at a willingness-to-pay threshold of US$1548/DALY averted (0.5xGDP).

Conclusions

NGO activities have a crucial preventative impact among PWID in Ukraine which should be scaled-up to help achieve HIV and HCV elimination. Disruptions could have a substantial detrimental impact.     

Thyroid cancer in Ukraine after the Chernobyl accident (in the framework of the Ukraine-US Thyroid Project)

As a result of the accident at the Chernobyl Nuclear Power Plant, millions of residents of Belarus, Russia, and Ukraine were exposed to large doses of radioactive iodine isotopes, mainly I-131. The purpose of the Ukraine-American (UkrAm) and Belarus-American (BelAm) projects are to quantify the risks of thyroid cancer in the framework of a classical cohort study, comprising subjects who were aged under 18 years at the time of the accident, had direct measurements of thyroid I-131 radioactivity taken within two months after the accident, and were residents of three heavily contaminated northern regions of Ukraine (Zhitomir, Kiev, and Chernigov regions). Four two-year screening examination cycles were implemented from 1998 until 2007 to study the risks associated with thyroid cancer due to the iodine exposure caused during the Chernobyl accident. A standardised procedure of clinical examinations included: thyroid palpation, ultrasound examination, blood collection followed by a determination of thyroid hormone levels, urinary iodine content test, and fine-needle aspiration if required. Among the 110 cases of thyroid cancer diagnosed in UkrAm as the result of four screening examinations, 104 cases (94.5%) of papillary carcinomas, five cases (4.6%) of follicular carcinomas, and one case (0.9%) of medullary carcinoma were diagnosed.     

Factors Associated With Study Attrition Among HIV-Infected Risky Drinkers in St. Petersburg,Russia

Background: Participant attrition in HIV longitudinal studies may introduce bias and diminish research quality. The identification of participant characteristics that are predictive of attrition might inform retention strategies. Objective: The study aimed to identify factors associated with attrition among HIV-infected Russian risky drinkers from the secondary HIV prevention HERMITAGE trial. We examined whether current injection drug use (IDU), binge drinking, depressive symptoms, HIV status nondisclosure, stigma, and lifetime history of incarceration were predictors of study attrition. We also explored effect modification due to gender. Methods: Complete loss to follow-up (LTFU), defined as no follow-up visits after baseline, was the primary outcome, and time to first missed visit was the secondary outcome. We used multiple logistic regression models for the primary analysis, and Cox proportional hazards models for the secondary analysis. Results: Of 660 participants, 101 (15.3%) did not return after baseline. No significant associations between independent variables and complete LTFU were observed. Current IDU and HIV status nondisclosure were significantly associated with time to first missed visit (adjusted hazard ratio [AHR], 1.39; 95% CI, 1.03-1.87; AHR, 1.38; 95% CI, 1.03-1.86, respectively). Gender stratified analyses suggested a larger impact of binge drinking among men and history of incarceration among women with time to first missed visit. Conclusions: Although no factors were significantly associated with complete LTFU, current IDU and HIV status nondisclosure were significantly associated with time to first missed visit in HIV-infected Russian risky drinkers. An understanding of these predictors may inform retention efforts in longitudinal studies.     

Application of the LPE-Grown LuAG: Ce Film/YAG Crystal Composite Thermoluminescence Detector for Distinguishing the Components of the Mixed Radiation Field

Single-crystalline films (SCFs) of the LuAG: Ce garnet grown using the liquid-phase epitaxy method onto YAG single-crystal (SC) substrates were investigated for possible applications as composite thermoluminescent (TL) detectors. Such detectors may help to register the different components of ionizing radiation fields with various penetration depths, e.g., heavy charged particles and gamma or beta rays. It was found that the TL signal of LuAG: Ce SCF sufficiently differs from that of the YAG substrate concerning both the temperature and wavelength of emissions. Furthermore, even by analyzing TL glow curves, it was possible to distinguish the difference between weakly and deeply penetrating types of radiation. Within a test involving the exposure of detectors with the mixed alpha/beta radiations, the doses of both components were determined with an accuracy of a few percent.     

Substrate-induced changes in the structural properties of LacY

The lactose permease (LacY) of Escherichia coli, a paradigm for the major facilitator superfamily, catalyzes the coupled stoichiometric translocation of a galactopyranoside and an H⁺ across the cytoplasmic membrane. To catalyze transport, LacY undergoes large conformational changes that allow alternating access of sugar- and H⁺-binding sites to either side of the membrane. Despite strong evidence for an alternating access mechanism, it remains unclear how H⁺- and sugar-binding trigger the cascade of interactions leading to alternating conformational states. Here we used dynamic single-molecule force spectroscopy to investigate how substrate binding induces this phenomenon. Galactoside binding strongly modifies kinetic, energetic, and mechanical properties of the N-terminal 6-helix bundle of LacY, whereas the C-terminal 6-helix bundle remains largely unaffected. Within the N-terminal 6-helix bundle, the properties of helix V, which contains residues critical for sugar binding, change most radically. Particularly, secondary structures forming the N-terminal domain exhibit mechanically brittle properties in the unbound state, but highly flexible conformations in the substrate-bound state with significantly increased lifetimes and energetic stability. Thus, sugar binding tunes the properties of the N-terminal domain to initiate galactoside/H⁺ symport. In contrast to wild-type LacY, the properties of the conformationally restricted mutant Cys154➝Gly do not change upon sugar binding. It is also observed that the single mutation of Cys154➝Gly alters intramolecular interactions so that individual transmembrane helices manifest different properties. The results support a working model of LacY in which substrate binding induces alternating conformational states and provides insight into their specific kinetic, energetic, and mechanical properties.The lactose permease of Escherichia coli (LacY) of the major facilitator superfamily (MFS) (1, 2) catalyzes the coupled stoichiometric translocation of a galactopyranoside and an H⁺ (sugar/H⁺ symport) (3–6). Uphill (i.e., active) symport of galactoside against a concentration gradient is achieved by transduction of free energy released from the downhill movement of H⁺ with the electrochemical H⁺ gradient (Δ$\tilde{\mu }$_H⁺; interior negative and/or alkaline). Conversely, because coupling between sugar and H⁺ is obligatory, downhill galactoside transport from a high to a low sugar concentration is coupled to uphill H⁺ transport with the generation of Δ$\tilde{\mu }$_H+, the polarity of which depends upon the direction of the sugar concentration gradient (7–10).LacY monomers reconstituted into proteoliposomes are functional (11, 12), and X-ray crystal structures reveal 12, mostly irregular, transmembrane α-helices organized into two pseudosymmetrical 6-helix bundles surrounding a large interior hydrophilic cavity open to the cytoplasm (13–16). At the apex of the hydrophilic cavity, which is at the approximate middle of the molecule, the galactoside- and H⁺-binding sites are located. Side chains important for sugar recognition are located in both the N- and the C-terminal 6-helix bundles, whereas those involved in H⁺ binding are largely in the C-terminal 6-helix bundle. Most X-ray structures obtained thus far exhibit a tightly sealed periplasmic side with the sugar-binding site at the apex of the cavity and inaccessible from the periplasm and an open cytoplasmic side (an inward-facing conformation). LacY is structurally highly dynamic, and binding of a galactoside closes the deep inward-facing cavity with opening of a complementary outward-facing cavity (reviewed in refs. 17, 18). Therefore, transport involves a large conformational change that allows alternating access of sugar- and H⁺-binding sites to either side of the cellular membrane, and a recent structure indicates that an occluded intermediate is involved (19). Although structural models of LacY provide insight into the conformational states involved in transport, a crystal structure represents a static structural snapshot, and therefore an understanding of how sugar binding triggers the cascade of events that results in dynamic alternating access remains unclear. Furthermore, because these interactions alter the physical properties of LacY (reviewed in ref. 9), the energetic, kinetic, and mechanical properties of LacY that fulfill different functional roles during transport remain to be characterized.Atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) has been applied to localize and quantify interactions that stabilize structural elements of an increasing number of native membrane proteins (20–25). Because SMFS can be used with membrane proteins embedded in native or synthetic lipid membranes under physiological conditions, the method has been used to assess interactions that change upon substrate binding, insertion of mutations, and assembly or lipid composition of the membrane (26–35). Moreover, when operated in the dynamic mode, dynamic single-molecule force spectroscopy (DFS) localizes and quantifies the kinetic, energetic, and mechanical properties of the structural elements in a membrane protein in a physiologically relevant environment (20, 21).LacY binds galactopyranosides, and 4-nitrophenyl-α-d-galactopyranoside (αNPG) is among the lactose analogs with highest affinity (∼30 µM) (36). In the absence of substrate, LacY preferentially occupies an inward-facing open conformation, and substrate binding causes closing of the inward-facing cavity with opening of a reciprocal outward-facing cavity (reviewed in refs. 17, 18) with an occluded intermediate conformation (19). To understand the structural perturbations and properties associated with these conformations, we describe here the conformational, kinetic, energetic, and mechanical properties of LacY in the apo state and how these properties change upon substrate binding. SMFS and DFS are used to characterize the properties of individual structural segments of LacY and to describe how these regions change properties upon galactoside binding. To understand further how a single point mutation alters LacY, the conformationally restricted LacY mutant C154G (37), which crystallized originally (13), was also investigated. All measurements were conducted with wild-type (WT) or mutant C154G LacY embedded in a phospholipid membrane under physiological conditions. The findings quantify the structural properties of WT LacY, which change drastically upon sugar binding. In contrast, the structural properties of mutant C154G LacY remain largely unaffected by ligand binding.     

Everolimus Plus Exemestane in Postmenopausal Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free Survival Analysis

Introduction

Effective treatments for hormone-receptor-positive (HR⁺) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population.

Methods

BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR⁺ advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints.

Results

Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38–0.54); log-rank P < 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31–0.48); log-rank P < 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, patients with recurrence during or within 12 months of completion of adjuvant therapy, and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials.

Conclusion

The addition of everolimus to exemestane markedly prolonged PFS in patients with HR⁺ advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655.     

Different pools of postsynaptic GABAA receptors mediate inhibition evoked by low‐ and high‐frequency presynaptic stimulation at hippocampal synapses

Patterns of short‐term synaptic plasticity could considerably differ between synapses of the same axon. This may lead to separation of synaptic receptors transmitting either low‐ or high‐frequency signals and, therefore, may have functional consequences for the information transfer in the brain. Here, we estimated a degree of such separation at hippocampal GABAergic synapses using a use‐dependent GABA_A receptor antagonist, picrotoxin, to selectively suppress a pool of GABA_A receptors monosynaptically activated during the low‐frequency stimulation. The relative changes in postsynaptic responses evoked by the high‐frequency stimulation before and after such block were used to estimate the contribution of this GABA_A receptor pool to synaptic transmission at high frequencies. Using this approach, we have shown that IPSCs evoked by low‐frequency (0.2 Hz) stimulation and asynchronous currents evoked by high‐frequency (20–40 Hz) stimulation are mediated by different pools of postsynaptic GABA_A receptors. Thus, our findings suggest that inhibition produced by a single hippocampal interneuron may be selectively routed to different postsynaptic targets depending on the presynaptic discharge frequency. Synapse 68:344–354, 2014 . © 2014 Wiley Periodicals, Inc.     

Critical tests evaluating efficacy of moxidectin against small strongyles in horses from a herd for which reduced activity had been found in field tests in Central Kentucky

Critical tests were performed in 2009 and 2010 in four 2-year-old horses naturally infected with internal parasites. The horses were from a herd (Farm MC) where reduced activity of ivermectin and moxidectin on small strongyles was demonstrated previously from EPG (eggs/gram of feces) data in field tests. Also, in critical tests in horses from the same herd, ivermectin was less effective on immature small strongyles in the lumen of the large intestine than when the drug was first marketed. The main interest in the present critical tests was to determine the efficacy of moxidectin (400 μg/kg) on small strongyles. This was done to try and find indications of why there has been a return of strongyle EPG counts sooner after treatment in field tests than when moxidectin was first commercially available. Removal of adult small strongyles for the four treated horses was >99% to 100%. Efficacy on immature (L₄) small strongyles was 82%, 96%, 98%, and >99% for the individual horses. Identification of small strongyles recovered from two of the horses revealed that three genera and 11 species were present. Specimens of Cylicocyclus ashworthi are reported for the first time in horses in Kentucky although eggs of this species have been identified. Moxidectin, in the present study, was excellent on removing adult small strongyles but was less effective on immatures (L₄) in the intestinal contents. The question as to why moxidectin efficacy on small strongyles has declined in field tests may have been answered at least to a certain extent. It seems that a significant factor is “quick development” of a few remaining immatures in the gut lumen of horses. Also, possible activity may have decreased on encysted stages in the large intestinal lining. In any event, after treatment of some horses with moxidectin, the life cycle of small strongyles is shorter now than at the onset of usage of this compound.     

The mancozeb‐containing carbamate fungicide tattoo induces mild oxidative stress in goldfish brain,liver, and kidney

Tattoo belongs to the group of carbamate fungicides and contains Mancozeb (ethylene(bis)dithiocarbamate) as its main constituent. The toxicity of Mancozeb to living organisms, particularly fish, is not resolved. This work investigated the effects of 96 h of exposure to 3, 5, or 10 mg L^?1 of Tattoo (corresponding to 0.9, 1.5, or 3 mg L^?1 of Mancozeb) on the levels of oxidative stress markers and the antioxidant enzyme system of brain, liver, and kidney of goldfish, Carassius auratus). In liver, Tattoo exposure resulted in increased activities of superoxide dismutase (SOD) by 70%–79%, catalase by 23%–52% and glutathione peroxidase (GPx) by 49%. The content of protein carbonyls (CP) in liver was also enhanced by 92%–125% indicating extensive damage to proteins. Similar increases in CP levels (by 98%–111%) accompanied by reduced glucose‐6‐phosphate dehydrogenase activity (by 13%–15%) was observed in kidney of fish exposed to Tattoo; however, SOD activity increased by 37% in this tissue after treatment with 10 mg L^?1 Tattoo. In brain, a rise in lipid peroxide level (by 29%) took place after exposure to 10 mg L^?1 Tattoo and was accompanied by elevation of high‐molecular mass thiols (by 14%). Tattoo exposure also resulted in a concentration‐dependent decrease in glutathione reductase activity (by 26%–37%) in brain. The data collectively show that exposure of goldfish to 3–10 mg L^?1 of the carbamate fungicide Tattoo resulted in the development of mild oxidative stress and activation of antioxidant defense systems in goldfish tissues. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1227–1235, 2014.