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Using time-resolved sum-frequency generation spectroscopy, the C—O stretch vibration of carbon monoxide adsorbed on a single-crystal Ru(001) surface is investigated during femtosecond near-IR laser excitation leading to desorption. A large transient redshift, a broadening of the resonance, and a strong decrease in intensity are observed. These originate from coupling of the C—O stretch to low-frequency modes, especially the frustrated rotation, that are highly excited in the desorption process.

A novel type of surface vibrational sum-frequency generation spectroscopy is presented that enables a highly specific measurement of the coupling of molecules on surfaces. With this doubly vibrationally resonant technique, two-dimensional vibrational spectroscopy of molecules on surfaces becomes possible. The technique is demonstrated for the C-O stretch vibration of CO on a ruthenium (001) surface. It allows for the determination of the intermolecular coupling strength of dipole-coupled CO molecules on the surface.

Quantum light-matter interfaces that can reversibly map quantum information between photons and atoms are essential for building future quantum networks. Crystals doped with rare-earth ions (REIs) are an attractive solid-state platform for such light-matter interfaces due to their exceptional optical and spin coherence properties at cryogenic temperatures. Building scalable REI-based technology has proven to be challenging due to the inherently weak coupling of REIs with light. This thesis explores the integration of REIs with nanophotonic resonators to overcome this weak light-matter interaction and enable efficient, scalable quantum light-matter interfaces. Specifically, this work focuses on the development of quantum nanophotonics with ytterbium in yttrium orthovanadate. This thesis begins with an introduction to a nanophotonic platform based on photonic crystal cavities fabricated directly in rare-earth host materials and highlights the initial successes of this platform with neodymium-doped materials. This motivates an examination of the optical and spin coherence properties of 171Yb:YVO4, a REI material that was previously unexplored for quantum technology applications. This material is found to have strong optical transitions compared to other REI-doped materials, a simple energy level structure, and long optical and spin coherence lifetimes. The focus then turns to the detection and coherent manipulation of single ytterbium ions coupled to nanophotonic cavities. The Purcell-enhancement in these cavities enables efficient optical detection and spin initialization of individual ytterbium ions. We identify ions corresponding to different isotopes of ytterbium and show that the coupling of electron and nuclear spin in ytterbium-171 at zero-field gives rise to strong electron-spin-like transitions that are first-order insensitive to magnetic field fluctuations. This allows for coherent microwave control and the observation o

INTRODUCTION: This study estimated the costs and incremental cost per case detected of screening strategies for high-grade cervical intraepithelial neoplasia (CIN2+) in women living with HIV (WLHIV) attending HIV clinics in Burkina Faso. METHODS: The direct healthcare provider costs of screening tests (visual inspection with acetic acid (VIA), VIA combined visual inspection with Lugol's iodine (VIA/VILI), cytology and a rapid HPV DNA test (careHPV)) and confirmatory tests (colposcopy, directed biopsy and systematic four-quadrant (4Q) biopsy) were collected alongside the HPV in Africa Research Partnership (HARP) study. A model was developed for a hypothetical cohort of 1000 WLHIV using data on CIN2+ prevalence and the sensitivity of the screening tests. Costs are reported in USD (2019). RESULTS: The study enrolled 554 WLHIV with median age 36 years (inter-quartile range, 31-41) and CIN2+ prevalence of 5.8%. The average cost per screening test ranged from US$3.2 for VIA to US$24.8 for cytology. Compared to VIA alone, the incremental cost per CIN2+ case detected was US$48 for VIA/VILI and US$814 for careHPV. Despite higher costs, careHPV was more sensitive for CIN2+ cases detected compared to VIA/VILI (97% and 56%, respectively). The cost of colposcopy was US$6.6 per person while directed biopsy was US$33.0 and 4Q biopsy was US$48.0. CONCLUSION: Depending on the willingness to pay for the detection of a case of cervical cancer, decision makers in Burkina Faso can consider a variety of cervical cancer screening strategies for WLHIV. While careHPV is more costly, it has the potential to be cost-effective depending on the willingness to pay threshold. Future research should explore the lifetime costs and benefits of cervical cancer screening to enable comparisons with interventions for other diseases.

Importance: Moving to multigene testing for all women with breast cancer (BC) could identify many more mutation carriers who can benefit from precision prevention. However, the cost-effectiveness of this approach remains unaddressed. Objective(s): To estimate incremental lifetime effects, costs, and cost-effectiveness of multigene testing of all patients with BC compared with the current practice of genetic testing (BRCA) based on family history (FH) or clinical criteria. Design, Setting, and Participant(s): This cost-effectiveness microsimulation modeling study compared lifetime costs and effects of high-risk BRCA1/BRCA2/PALB2 (multigene) testing of all unselected patients with BC (strategy A) with BRCA1/BRCA2 testing based on FH or clinical criteria (strategy B) in United Kingdom (UK) and US populations. Data were obtained from 11836 patients in population-based BC cohorts (regardless of FH) recruited to 4 large research studies. Data were collected and analyzed from January 1, 2018, through June 8, 2019. The time horizon is lifetime. Payer and societal perspectives are presented. Probabilistic and 1-way sensitivity analyses evaluate model uncertainty. Intervention(s): In strategy A, all women with BC underwent BRCA1/BRCA2/PALB2 testing. In strategy B, only women with BC fulfilling FH or clinical criteria underwent BRCA testing. Affected BRCA/PALB2 carriers could undertake contralateral preventive mastectomy; BRCA carriers could choose risk-reducing salpingo-oophorectomy (RRSO). Relatives of mutation carriers underwent cascade testing. Unaffected relative carriers could undergo magnetic resonance imaging or mammography screening, chemoprevention, or risk-reducing mastectomy for BC risk and RRSO for ovarian cancer (OC) risk. Main Outcomes and Measures: Incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-Adjusted life-year (QALY) gained and compared with standard 30 000/QALY and $100000/QALY UK and US thresholds, respectively.

Mucosal-associated invariant T (MAIT) cells typically express a TRAV1-2+ semi-invariant TCRα that enables recognition of bacterial, mycobacterial, and fungal riboflavin metabolites presented by MR1. MAIT cells are associated with immune control of bacterial and mycobacterial infections in murine models. Here, we report that a population of pro-inflammatory TRAV1-2+ CD8+ T cells are present in the airways and lungs of healthy individuals and are enriched in bronchoalveolar fluid of patients with active pulmonary tuberculosis (TB). High-throughput T cell receptor analysis reveals oligoclonal expansions of canonical and donor-unique TRAV1-2+ MAIT-consistent TCRα sequences within this population. Some of these cells demonstrate MR1-restricted mycobacterial reactivity and phenotypes suggestive of MAIT cell identity. These findings demonstrate enrichment of TRAV1-2+ CD8+ T cells with MAIT or MAIT-like features in the airways during active TB and suggest a role for these cells in the human pulmonary immune response to Mycobacterium tuberculosis.

Ontario has comprehensive regulations for mine construction, operation and maintenance, which have been adopted by several operators in the USA. Plants constructed using these regulations have less unplanned downtime and fewer issues with Mine Safety and Health Administration issues in their hoist plants. The Ontario regulations, as they apply to hoist plant operations, are much more specific than the MSHA regulations and outline the requirements for operations, mechanical, electrical, rope, conveyance, and shaft inspections and treat the shaft as an integrated system. The underlying philosophy is that everyone in the workplace is responsible for their own safety and the safety of co-workers. Good inspection practices are critical and the Ontario regulations enforce proper documentation and state that the supervisor in charge of the shaft will ascertain that inspections have been made and all necessary work done. A detailed comparison is presented of the daily checks required by the MHSA and Ontario regulations. Maintenance requirements should be considered during shaft design. Factors to be taken into account when using Ontario regulations include sizing of the hoist plant, access to the ropes, access for maintaining equipment, planning for cameras and recording equipment, and autonomous monitoring of shaft/conveyance., Ontario has comprehensive regulations for mine construction, operation and maintenance, which have been adopted by several operators in the USA. Plants constructed using these regulations have less unplanned downtime and fewer issues with Mine Safety and Health Administration issues in their hoist plants. The Ontario regulations, as they apply to hoist plant operations, are much more specific than the MSHA regulations and outline the requirements for operations, mechanical, electrical, rope, conveyance, and shaft inspections and treat the shaft as an integrated system. The underlying philosophy is that everyone in the workplace is responsible for their own safety and the safety of co-workers. Good inspection practices are critical and the Ontario regulations enforce proper documentation and state that the supervisor in charge of the shaft will ascertain that inspections have been made and all necessary work done. A detailed comparison is presented of the daily checks required by the MHSA and Ontario regulations. Maintenance requirements should be considered during shaft design. Factors to be taken into account when using Ontario regulations include sizing of the hoist plant, access to the ropes, access for maintaining equipment, planning for cameras and recording equipment, and autonomous monitoring of shaft/conveyance.

[This corrects the article DOI: 10.1371/journal.pone.0216855.].

BACKGROUND: In western countries, men who have sex with men (MSM) are most affected by HIV and increasingly likely to engage in risky sexual behaviour. MSM who experience a potential sexual exposure to HIV (PEPSE) and receive a preventative regimen of anti-HIV treatment are at particularly high risk of acquiring HIV and could potentially benefit from targeted risk reduction behavioural interventions such as motivational interviewing (MI). PURPOSE: The aim of this trial was to examine the impact of augmented MI (MI plus information provision and behavioural skills building), over and above routine care, on reducing risky sexual behaviour in MSM prescribed PEPSE. Secondary aims of the research were to examine whether the intervention reduced sexually transmitted infections (STI) and further requests for PEP. METHODS: A parallel-group pragmatic randomised controlled trial was conducted with 175 MSM recruited from five sexual health (SH) clinics in the south east of England. The intervention was two fixed-duration sessions of telephone administered augmented MI. A manual guided the selection of individualised persuasive communication strategies based on underlying change mechanisms specified by the Information, Motivation and Behavioural Skills (IMB) model. Primary outcomes were the number of receptive and active anal intercourse (AI) partners, the use of condoms every time during receptive and active AI and the use of condoms sometimes during receptive and active AI. RESULTS: There were no significant impacts on sexual risk behaviour or any of the psychological measures, and no discernible reduction in requests for repeat PEP or rates of STIs within a year. CONCLUSION: Our behavioural intervention of augmented MI did not affect risky sexual behaviour, rates of further PEP and STIs, and psychological factors, in MSM prescribed PEPSE. TRIAL REGISTRATION NUMBERS: UKCRN ID:11436; ISRCTN00746242.

IMPORTANCE: Moving to multigene testing for all women with breast cancer (BC) could identify many more mutation carriers who can benefit from precision prevention. However, the cost-effectiveness of this approach remains unaddressed. OBJECTIVE: To estimate incremental lifetime effects, costs, and cost-effectiveness of multigene testing of all patients with BC compared with the current practice of genetic testing (BRCA) based on family history (FH) or clinical criteria. DESIGN, SETTING, AND PARTICIPANTS: This cost-effectiveness microsimulation modeling study compared lifetime costs and effects of high-risk BRCA1/BRCA2/PALB2 (multigene) testing of all unselected patients with BC (strategy A) with BRCA1/BRCA2 testing based on FH or clinical criteria (strategy B) in United Kingdom (UK) and US populations. Data were obtained from 11 836 patients in population-based BC cohorts (regardless of FH) recruited to 4 large research studies. Data were collected and analyzed from January 1, 2018, through June 8, 2019. The time horizon is lifetime. Payer and societal perspectives are presented. Probabilistic and 1-way sensitivity analyses evaluate model uncertainty. INTERVENTIONS: In strategy A, all women with BC underwent BRCA1/BRCA2/PALB2 testing. In strategy B, only women with BC fulfilling FH or clinical criteria underwent BRCA testing. Affected BRCA/PALB2 carriers could undertake contralateral preventive mastectomy; BRCA carriers could choose risk-reducing salpingo-oophorectomy (RRSO). Relatives of mutation carriers underwent cascade testing. Unaffected relative carriers could undergo magnetic resonance imaging or mammography screening, chemoprevention, or risk-reducing mastectomy for BC risk and RRSO for ovarian cancer (OC) risk. MAIN OUTCOMES AND MEASURES: Incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained and compared with standard £30 000/QALY and $100 000/QALY UK and US thresholds, respectively. Inci

Introduction Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended-release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-Arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. Methods and analysis The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. Ethics and dissemination Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. Trial registration number NCT02720822; Pre-results.

Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended- release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. NCT02720822; Pre-results.

Metabolism facilitates the elimination, detoxification and excretion in urine or bile (as biotransformation products) of a myriad of structurally diverse drugs and other chemicals. The metabolism of drugs, non-drug xenobiotics and many endogenous compounds is catalyzed by families of drug metabolizing enzymes (DMEs). These include the hemoprotein-containing cytochromes P450, which function predominantly as monooxygenases, and conjugation enzymes that transfer a sugar, sulfate, acetate or glutathione moiety to substrates containing a suitable acceptor functional group. Drug and chemical metabolism, especially the enzymes that catalyse these reactions, has been the research focus of several groups in Australia for over four decades. In this review, we highlight the role of recent and current drug metabolism research in Australia, including elucidation of the structure and function of enzymes from the various DME families, factors that modulate enzyme activity in humans (e.g. drug-drug interactions, gene expression and genetic polymorphism) and the application of in vitro approaches for the prediction of drug metabolism parameters in humans, along with the broader pharmacological/clinical pharmacological and toxicological significance of drug metabolism and DMEs and their relevance to drug discovery and development, and to clinical practice.

© 2016 Pennington et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: There is limited evidence on the costs of Endometrial Cancer (EC) by stage of disease. We estimated the long-term secondary care costs of EC according to stage at diagnosis in an English population-based cohort. Methods: Women participating in UKCTOCS and diagnosed with EC following enrolment (2001-2005) and prior to 31st Dec 2009 were identified to have EC through multiple sources. Survival was calculated through data linkage to death registry. Costs estimates were derived from hospital records accessed from Hospital Episode Statistics (HES) with additional patient level covariates derived from case notes and patient questionnaires. Missing and censored data was imputed using Multiple Imputation. Regression analysis of cost and survival was undertaken. Results: 491 of 641 women with EC were included. Five year total costs were strongly dependent on stage, ranging from £9,475 (diagnosis at stage IA/IB) to £26,080 (diagnosis at stage III). Stage, grade and BMI were the strongest predictors of costs. The majority of costs for stage I/II EC were incurred in the first six months after diagnosis while for stage III / IV considerable costs accrued after the first six months. Conclusions: In addition to survival advantages, there are significant cost savings if patients with EC are detected earlier.

Background & Aims We determined the optimal HCV treatment prioritization strategy for interferon-free (IFN-free) HCV direct-acting antivirals (DAAs) by disease stage and risk status incorporating treatment of people who inject drugs (PWID). Methods A dynamic HCV transmission and progression model compared the cost-effectiveness of treating patients early vs. delaying until cirrhosis for patients with mild or moderate fibrosis, where PWID chronic HCV prevalence was 20, 40 or 60%. Treatment duration was 12 weeks at £3300/wk, to achieve a 95% sustained viral response and was varied by genotype/stage in alternative scenarios. We estimated long-term health costs (in £UK = €1.3 = $1.5) and outcomes as quality adjusted life-years (QALYs) gained using a £20,000 willingness to pay per QALY threshold. We ranked strategies with net monetary benefit (NMB); negative NMB implies delay treatment. Results The most cost-effective group to treat were PWID with moderate fibrosis (mean NMB per early treatment £60,640/£23,968 at 20/40% chronic prevalence, respectively), followed by PWID with mild fibrosis (NMB £59,258 and £19,421, respectively) then ex-PWID/non-PWID with moderate fibrosis (NMB £9,404). Treatment of ex-PWID/non-PWID with mild fibrosis could be delayed (NMB -£3,650). In populations with 60% chronic HCV among PWID it was only cost-effective to prioritize DAAs to ex-PWID/non-PWID with moderate fibrosis. For every one PWID in the 20% chronic HCV setting, 2 new HCV infections were averted. One extra HCV-related death was averted per 13 people with moderate disease treated. Rankings were unchanged with reduced drug costs or varied sustained virological response/duration by genotype/fibrosis stage. Conclusions Treating PWID with moderate or mild HCV with IFN-free DAAs is cost-effective compared to delay until cirrhosis, except when chronic HCV prevalence and reinfection risk is very high.

The variable response to warfarin treatment often has a genetic basis. A protein homology model of human vitamin K epoxide reductase, subunit 1 (VKORC1), was generated to elucidate the mechanism of warfarin resistance observed in a patient with the Val66Met mutation. The VKORC1 homology model comprises four transmembrane (TM) helical domains and a half helical lid domain. Cys132 and Cys135, located in the N-terminal end of TM-4, are linked through a disulfide bond. Two distinct binding sites for warfarin were identified. Site-1, which binds vitamin K epoxide (KO) in a catalytically favorable orientation, shows higher affinity for S-warfarin compared with R-warfarin. Site-2, positioned in the domain occupied by the hydrophobic tail of KO, binds both warfarin enantiomers with similar affinity. Displacement of Arg37 occurs in the Val66Met mutant, blocking access of warfarin (but not KO) to Site-1, consistent with clinical observation of warfarin resistance.

UnlabelledPrisoners have a high prevalence of hepatitis C virus (HCV), but case-finding may not have been cost-effective because treatment often exceeded average prison stay combined with a lack of continuity of care. We assessed the cost-effectiveness of increased HCV case-finding and treatment in UK prisons using short-course therapies. A dynamic HCV transmission model assesses the cost-effectiveness of doubling HCV case-finding (achieved through introducing opt-out HCV testing in UK pilot prisons) and increasing treatment in UK prisons compared to status quo voluntary risk-based testing (6% prison entrants/year), using currently recommended therapies (8-24 weeks) or interferon (IFN)-free direct-acting antivirals (DAAs; 8-12 weeks, 95% sustained virological response, £3300/week). Costs (British pounds, £) and health utilities (quality-adjusted life years) were used to calculate mean incremental cost-effectiveness ratios (ICERs). We assumed 56% referral and 2.5%/25% of referred people who inject drugs (PWID)/ex-PWID treated within 2 months of diagnosis in prison. PWID and ex-PWID or non-PWID are in prison an average 4 and 8 months, respectively. Doubling prison testing rates with existing treatments produces a mean ICER of £19,850/quality-adjusted life years gained compared to current testing/treatment and is 45% likely to be cost-effective under a £20,000 willingness-to-pay threshold. Switching to 8-week to 12-week IFN-free DAAs in prisons could increase cost-effectiveness (ICER £15,090/quality-adjusted life years gained). Excluding prevention benefit decreases cost-effectiveness. If >10% referred PWID are treated in prison (2.5% base case), either treatment could be highly cost-effective (ICER<£13,000). HCV case-finding and IFN-free DAAs could be highly cost-effective if DAA cost is 10% lower or with 8 weeks' duration.ConclusionsIncreased HCV testing in UK prisons (such as through opt-out testing) is borderline cost-effective compared to status quo voluntar

Objective: to study the specific features of metabolism and blood rheological properties in the acute period of ischemic stroke (IS) in patients aged less than 50 years.Subjects and methods. Thirty patients (mean age 45.1±1.1 years) having acute IS were examined. According to its severity, the patients were divided into 3 groups: 1) 8 patients with mild IS; 2) 11 patients with moderate IS; 3) 11 with severe IS. All Group 3 patients were treated at an intensive care unit. A control group comprised 20 healthy individuals (mean age 44.7±1.0 years). In all the patients, fasting blood homocysteine concentrations were measured on an IMMULITE One immunochemiluminescent analyzer (USA). The rheological properties of blood were examined, by measuring its viscosity on a rotary viscometer (Russia) at a shear rate of 10 to 200 sec-1. Fibrinogen concentrations were determined on an ACL-100 coagulograph.Results. The patients who had experienced ischemic stroke at the age of under 50 years were found to have atherogenic dyslipidemia, elevated homocysteine and fibrinogen levels and considerably increased blood viscosity, which correlated with the severity of their condition and the outcome of stroke. The highest values were noted in patients with severe ischemic stroke and a poor outcome.Conclusion. Studies of homocysteine and fibrinogen concentrations and blood viscosity may be used as additional criteria for evaluating the severity of ischemic stroke and predicting its outcome in patients aged less than 50 years., Цель исследования — изучить особенности метаболизма и реологические свойства крови в остром периоде ишемиче-ского инсульта (ИИ) у пациентов в возрасте до 50 лет.Материалы и методы. Обследовано 30 пациентов в остром периоде ИИ (средний возраст 45,1±1,1 лет). По степени тяжести пациентов распределили на три группы: 1-я группа — пациенты с ИИ легкой степени тяжести (n=8), 2-я — пациенты с ИИ средней степени тяжести (n=11), 3-я — пациенты с ИИ тяжелой степени тяжести (n=11). Все пациенты третьей группы находились на лечении в отделении реанимации. Контрольную группу составили 20 здоровых лиц (средний возраст 44,7±1,0 лет). У всех пациентов натощак определяли в крови концентрацию гомоцистеина на иммунохемилюминесцентном анализаторе «IMMULITE One» (США). Показатели липидного обмена (общий холестерин, холестерин липопротеидов различной плотности, тригли-цериды) определяли автоматизированными методами на анализаторе «HITACHI-912». Реологические свойства крови изучали, измеряя ее вязкость на ротационном вискозиметре (Россия) при скоростях сдвига в диапазоне от 10 до 200с-1. Концентрацию фибриногена определяли на коагулографе ACL-100.Результаты. У пациентов, перенесших ишемический инсульт в возрасте до 50 лет, обнаружено наличие атерогенной дислипидемии, а также коррелирующие со степенью тяжестью состояния и исходом инсульта повышенный уровень гомоцистеина, фибриногена и значительное увеличение вязкости крови. Наиболее высокие значения отмечены у больных с ишемическим инсультом тяжелой степени тяжести, с неблагоприятным исходом.Заключение. Исследования концентрации гомоцистеина, фибриногена и вязкости крови могут использоваться в качестве дополнительных критериев при оценке степени тяжести и прогнозирования исхода ишемического инсульта у пациентов в возрасте до 50 лет.

Polytrauma is one of the main causes of death in modern medicine. It is characterized by the particular severity of clinical manifestations and attended by significant impairments of the body’s vital functions, by diagnostic difficulties, and treatment complexity. In Kuzbass, as many as 8 thousand victims annually die from severe injuries. Death rates amount 21—22% in specialized hospitals and up to 60% or more in unspecialized hospitals. On the basis of multidisciplinary medical centers, an effective network of health care facilities (HCF) is being set up to render a specialized medical aid to patients with polytrauma. The application of expensive medical diagnostic and therapeutic technologies reduces the rates of morbidity and disability among patients with polytrauma. A specialized medical aid cannot be rendered to all victims without solving the problems of their transportation to a specialized center. Of the greatest difficulty is the transportation of critically ill patients with polytrauma and unstable hemodynamics when artificial ventilation is used during transportation. The transportation service set up in the Center of Miners’ Health Care in the specialized polytrauma center is engaged in the development of the problems of safe transport of this category of victims. Organizational problems are to collect information on victims, to form a specialized team and to supply the latter with equipment. Therapeutic-and-diagnostic problems are to additionally evaluate the status of victims at the scene (in an unspecialized HCF, if required, in and around the area of an accident), to prepare a patient before transportation; to provide a complete set of intensive therapy during interhospital transportation of patients with polytrauma in relation to the predominant component of a damage. In the authors’ opinion, solution of this group of problems can enhance the efficiency of intensive care during transportation and reduce mortality rates in this category of patients, Политравма является одной из основных причин смертности в современной медицине. Она отличается особой тяжестью клинических проявлений, сопровождается значительными нарушениями жизненно важных функций организма, трудностью диагностики, сложностью лечения. В Кузбассе ежегодно погибает до 8 тыс пострадавших от тяжелых травм. В условиях специализированных стационаров летальность составляет 21—22%, не специализированных ЛПУ — она достигает 60% и более. На базе многопрофильных медицинских центров создается действенная сеть лечебных учреждений для оказания специализированной медицинской помощи пациентам с политравмой. Использование дорогостоящих медицинских диагностических и лечебных технологий позволяет снизить уровень летальности, инвалидности среди пациентов с политравмой. Оказание специализированной медицинской помощи всем пострадавшим невозможно без решения вопросов транспортировки в специализированный центр. Наибольшую сложность представляет транспортировка пациентов с политравмой, находящихся в критическом состоянии, с нестабильной гемодинамикой, с применением во время транспортировки ИВЛ. Созданная в «Центре охраны здоровья шахтеров» при специализированном центре политравмы служба транспортировки занимается разработкой вопросов безопасного транспорта этой категории пострадавших. Организационными: информация о пострадавших, формирование специализированной бригады и её оснащения. Лечебно-диагностическими: дополнительная оценка состояния пострадавших на месте (в неспециализированном ЛПУ, при необходимости — в зоне чрезвычайных происшествий); подготовка пациента перед транспортировкой; обеспечение полного комплекса интенсивной терапии во время межгоспитальной транспортировки у пациентов с политравмой в зависимости от доминирующего компонента повреждения. Решение этих вопросов позволит повысить эффективность интенсивной терапии при проведении транспортировки и снизить летальность у данной категории пациентов.

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There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.This article has not been written or reviewed by Nature editors. Nature accepts no responsibility for the accuracy of the information provided.

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

Objective Estimates of healthcare costs associated with HIV infection would provide valuable insight for evaluating the cost-effectiveness of possible prevention interventions. We evaluate the additional lifetime healthcare cost incurred due to living with HIV. Methods We used a stochastic computer simulation model to project the distribution of lifetime outcomes and costs of men-who-have-sex-with-men (MSM) infected with HIV in 2013 aged 30, over 10,000 simulations. We assumed a resource-rich setting with no loss to follow-up, and that standards and costs of healthcare management remain as now. Results Based on a median (interquartile range) life expectancy of 71.5 (45.0–81.5) years for MSM in such a setting, the estimated mean lifetime cost of treating one person was £360,800 ($567,000 or €480,000). With 3.5% discounting, it was £185,200 ($291,000 or €246,000). The largest proportion (68%) of these costs was attributed to antiretroviral drugs. If patented drugs are replaced by generic versions (at 20% cost of patented prices), estimated mean lifetime costs reduced to £179,000 ($281,000 or €238,000) and £101,200 ($158,900 or €134,600) discounted. Conclusions If 3,000 MSM had been infected in 2013, then future lifetime costs relating to HIV care is likely to be in excess of £1 billion. It is imperative for investment into prevention programmes to be continued or scaled-up in settings with good access to HIV care services. Costs would be reduced considerably with use of generic antiretroviral drugs., OBJECTIVE: Estimates of healthcare costs associated with HIV infection would provide valuable insight for evaluating the cost-effectiveness of possible prevention interventions. We evaluate the additional lifetime healthcare cost incurred due to living with HIV.METHODS: We used a stochastic computer simulation model to project the distribution of lifetime outcomes and costs of men-who-have-sex-with-men (MSM) infected with HIV in 2013 aged 30, over 10,000 simulations. We assumed a resource-rich setting with no loss to follow-up, and that standards and costs of healthcare management remain as now.RESULTS: Based on a median (interquartile range) life expectancy of 71.5 (45.0-81.5) years for MSM in such a setting, the estimated mean lifetime cost of treating one person was £ 360,800 ($567,000 or € 480,000). With 3.5% discounting, it was £ 185,200 ($291,000 or € 246,000). The largest proportion (68%) of these costs was attributed to antiretroviral drugs. If patented drugs are replaced by generic versions (at 20% cost of patented prices), estimated mean lifetime costs reduced to £ 179,000 ($ 281,000 or € 238,000) and £ 101,200 ($ 158,900 or € 134,600) discounted.CONCLUSIONS: If 3,000 MSM had been infected in 2013, then future lifetime costs relating to HIV care is likely to be in excess of £ 1 billion. It is imperative for investment into prevention programmes to be continued or scaled-up in settings with good access to HIV care services. Costs would be reduced considerably with use of generic antiretroviral drugs.

Human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) both cause lifelong persistent infections, but differ in their clinical outcomes. HTLV-1 infection causes a chronic or acute T-lymphocytic malignancy in up to 5% of infected individuals whereas HTLV-2 has not been unequivocally linked to a T-cell malignancy. Virus-driven clonal proliferation of infected cells both in vitro and in vivo has been demonstrated in HTLV-1 infection. However, T-cell clonality in HTLV-2 infection has not been rigorously characterized. In this study we used a high-throughput approach in conjunction with flow cytometric sorting to identify and quantify HTLV-2-infected T-cell clones in 28 individuals with natural infection. We show that while genome-wide integration site preferences in vivo were similar to those found in HTLV-1 infection, expansion of HTLV-2-infected clones did not demonstrate the same significant association with the genomic environment of the integrated provirus. The proviral load in HTLV-2 is almost confined to CD8+ T-cells and is composed of a small number of often highly expanded clones. The HTLV-2 load correlated significantly with the degree of dispersion of the clone frequency distribution, which was highly stable over ∼8 years. These results suggest that there are significant differences in the selection forces that control the clonal expansion of virus-infected cells in HTLV-1 and HTLV-2 infection. In addition, our data demonstrate that strong virus-driven proliferation per se does not predispose to malignant transformation in oncoretroviral infections.

OBJECTIVE:: There has been discussion about whether individuals coinfected with HIV and hepatitis C virus (HCV) or hepatitis B virus (HBV) (∼30% of all people living with HIV) should be prioritized for early HIV antiretroviral therapy (ART). We assess the relative benefits of providing ART at CD4 count below 500 cells/μl or immediate ART to HCV/HIV or HBV/HIV-coinfected adults compared with HIV-monoinfected adults. We evaluate individual outcomes (HIV/liver disease progression) and preventive benefits in a generalized HIV epidemic setting. METHODS:: We modeled disease progression for HIV-monoinfected, HBV/HIV-coinfected, and HCV/HIV-coinfected adults for differing ART eligibility thresholds (CD4+ 350 cells/μl, CD4 +500 cells/μl, immediate ART eligibility upon infection). We report disability-adjusted life-years averted per 100 person-years on ART (DALYaverted/100PYonART) as a measure of the health benefits generated from incremental changes in ART eligibility. Sensitivity analyses explored impact on sexual HIV and vertical HIV, HCV, and HBV transmission. RESULTS:: For HBV/HIV-coinfected adults, a switch to ART initiation at CD4 count below 500 cells/μl from CD4 below 350 cells/μl generates 9% greater health benefits per year on ART (48 DALYaverted/100PYonART) than for HIV-monoinfected adults (44 DALYaverted/100PYonART). Additionally, ART at CD4 below 500 cells/μl could prevent 25% and 32% of vertical transmissions of HIV and HBV, respectively. For HCV/HIV-coinfected adults, ART at CD4 below 500 cells/μl generates 10% fewer health benefits (40 DALYaverted/100PYonART) than for HIV monoinfection, unless ART reduces progression to cirrhosis by more than 70% (33% in base-case). CONCLUSIONS:: The additional therapeutic benefits of ART for HBV-related liver disease results in ART generating more health benefits among HBV/HIV-coinfected adults than HIV-monoinfected individuals, whereas less health benefits are generated amongst HCV/HIV coinfection in a generalized HIV epide

BACKGROUND: To guide future need for cheap resistance tests for use in low income settings, we assessed cost-effectiveness of drug resistance testing as part of monitoring of people on first line ART - with switching from first to second line ART being conditional on NNRTI drug resistance mutations being identified.METHODS: An individual level simulation model of HIV transmission, progression and the effect of ART which accounts for adherence and resistance development was used to compare outcomes of various potential monitoring strategies in a typical low income setting in sub-Saharan Africa. Underlying monitoring strategies considered were based on clinical disease, CD4 count or viral load. Within each we considered a strategy in which no further measures are performed, one with a viral load measure to confirm failure, and one with both a viral load measure and a resistance test. Predicted outcomes were assessed over 2015-2025 in terms of viral suppression, first line failure, switching to second line regimen, death, HIV incidence, disability-adjusted-life-years averted and costs. Potential future low costs of resistance tests ($30) were used.RESULTS: The most effective strategy, in terms of DALYs averted, was one using viral load monitoring without confirmation. The incremental cost-effectiveness ratio for this strategy was $2113 (the same as that for viral load monitoring with confirmation). ART monitoring strategies which involved resistance testing did not emerge as being more effective or cost effective than strategies not using it. The slightly reduced ART costs resulting from use of resistance testing, due to less use of second line regimens, was of similar magnitude to the costs of resistance tests.CONCLUSION: Use of resistance testing at the time of first line failure as part of the decision whether to switch to second line therapy was not cost-effective, even though the test was assumed to be very inexpensive.

With continued roll-out of antiretroviral therapy (ART) in resource-limited settings, evidence is emerging of increasing levels of transmitted drug-resistant HIV. We aimed to compare the effectiveness and cost-effectiveness of different potential public health responses to substantial levels of transmitted drug resistance.

To guide future need for cheap resistance tests for use in low income settings, we assessed cost-effectiveness of drug resistance testing as part of monitoring of people on first line ART - with switching from first to second line ART being conditional on NNRTI drug resistance mutations being identified.

ObjectivesPeople who inject drugs (PWID) are at high risk for acquiring hepatitis C virus (HCV), but many are unaware of their infection. HCV dried blood spot (DBS) testing increases case-finding in addiction services and prisons. We determine the cost-effectiveness of increasing HCV case-finding among PWID by offering DBS testing in specialist addiction services or prisons as compared to using venepuncture.DesignCost-utility analysis using a dynamic HCV transmission model among PWID, including: disease progression, diagnosis, treatment, injecting status, incarceration and addition services contact.Setting uk interventionDBS testing in specialist addiction services or prisons. Intervention impact was determined by a meta-analysis of primary data.Primary and secondary outcome measuresCosts (in UK £, £1=US$1.60) and utilities (quality-adjusted life years, QALYs) were attached to each state and the incremental cost effectiveness ratio (ICER) determined. Multivariate uncertainty and one-way sensitivity analyses were performed.ResultsFor a £20 000 per QALY gained willingness-to-pay threshold, DBS testing in addiction services is cost-effective (ICER of £14 600 per QALY gained). Under the base-case assumption of no continuity of treatment/care when exiting/entering prison, DBS testing in prisons is not cost-effective (ICER of £59 400 per QALY gained). Results are robust to changes in HCV prevalence; increasing PWID treatment rates to those for ex-PWID considerably reduces ICER (£4500 and £30 000 per QALY gained for addiction services and prison, respectively). If continuity of care is >40%, the prison DBS ICER falls below £20 000 per QALY gained.ConclusionsDespite low PWID treatment rates, increasing case-finding can be cost-effective in specialist addiction services, and in prisons if continuity of treatment/care is ensured.

In the field of unmanned vehicle (UV) systems, researchers have been striving to inverse the human-robot ratio such that one operator can control multiple robots. This goal has not yet been accomplished for military applications, despite ongoing research. Research suggests that the human-robot interaction (HRI) that takes place while an operator is in control of one or more UVs needs to be improved before the ratio can be inversed. This literature review covers 53 references to provide an overview of current HRI research dealing with the operation of UVs and to identify the key human factors (HF) issues when conducting research within this area. The literature identifies three key factors in HRI research related to operating UVs for military applications: operator capacity (i.e., the number and type of UVs that a human operator controls or supervises), automation implementation, and interface design. In the literature, HRI is most often measured through the three common metrics of situational awareness (SA), workload, and task performance. In general, research shows that increasing operator capacity increases workload and decreases SA, while the corresponding impact on performance has been shown to be inconsistent. Automation and multimodal interfaces have been shown to alleviate some of the increased workload and decreased SA as operator capacity is increased. However, there is a complex interaction among the three variables. The literature suggests that adaptive automation and adaptive interfaces are promising solutions to accommodate this complex interaction, but further research and empirical studies are necessary before they can be implemented in military operations. Three additional characteristics of military applications also need to be investigated further: one operator in control of mixed UV platforms (i.e., UAVs and UGVs); operators controlling UVs in a mobile environment; and team coordination among multiple operators, each in control of multiple UVs., Text in English; Abstract and Executive Summary in English and French.

Global coverage of infant Haemophilus influenzae type b (Hib) vaccination has increased considerably during the past decade, partly due to GAVI Alliance donations of the vaccine to low-income countries. In settings where large numbers of children receive only one or two vaccine doses rather than the recommended three doses, dose-specific efficacy estimates are needed to predict impact. The objective of this meta-analysis is to determine Hib vaccine efficacy against different clinical outcomes after receiving one, two or three doses of vaccine. Studies were eligible for inclusion if a prospective, controlled design had been used to evaluate commercially available Hib conjugate vaccines. Eight studies were included. Pooled vaccine efficacies against invasive Hib disease after one, two or three doses of vaccine were 59%, 92% and 93%, respectively. The meta-analysis provides robust estimates for use in decision-analytical models designed to predict the impact of Hib vaccine.

BACKGROUND: Post-exposure prophylaxis (PEP) following sexual exposure to HIV has been recommended as a method of preventing HIV infection in the UK. Men who have sex with men (MSM) are the group most affected by HIV in the UK and their sexual risk taking behaviour is reported to be increasing. One-to-one behavioural interventions, such as motivational interviewing (MI) have been recommended to reduce HIV in high risk groups. The Information, Motivation and Behavioral skills (IMB) model has been shown to provide a good basis for understanding and predicting HIV-relevant health behaviour and health behaviour change, however the IMB has yet to be applied to PEP after risky sexual exposure. The primary aim of this trial is to examine the impact of MI augmented with information provision and behavioural skills building (informed by the IMB Model), over and above usual care, on risky sexual behaviour in MSM prescribed PEP after potential sexual exposure. A secondary aim of this research is to examine the impact of the intervention on adherence to PEP. This study will also provide estimates of the cost-effectiveness of the intervention. METHODS: A manualised parallel group randomised controlled trial with economic evaluation will be conducted. The primary outcome is the proportion of risky sexual practices. Secondary outcomes include: i) Levels of adherence to PEP treatment; ii) Number of subsequent courses of PEP; iii) Levels of motivation to avoid risky sexual behaviours; iv) Levels of HIV risk-reduction information/knowledge; v) Levels of risk reduction behavioural skills; vi) Diagnosis of anal gonorrhoea, Chlamydia and/or HIV. 250 participants will be asked to self-complete a questionnaire at four time points during the study (at 0,3,6,12 months). The intervention will consist of a two-session, fixed duration, telephone administered augmented MI intervention based on the IMB model. A newly developed treatment manual will guide the selection of persuasive communication

PR, IFPRI3; ISI; CRP4, PHND; A4NH, CGIAR Research Program on Agriculture for Nutrition and Health (A4NH)

Background: Reducing the excessive accumulation of amyloid β-protein (Aβ) in Alzheimer's disease (AD) is a key objective of most AD therapies. Several studies suggest that pharmacological inhibition of angiotensin-converting enzyme (ACE) or its by-product angiotensin II may delay onset or progression of dementia and it has been suggested that this occurs via regulation of Aβ. Intraneuronal oligomeric accumulation of Aβ is postulated to be one of the earliest pathological events. Thus this study investigated the effect of an ACE-inhibitor, captopril, and two angiotensin II receptor blockers (ARBs), eprosartan and valsartan, on intraneuronal Aβ pathology and oligomeric Aβ levels in a triple transgenic (3xTGAD) mouse model of AD. Methods: Male, adult (3-4 month old) 3xTgAD mice (n=39) were randomly assigned to 4 treatment groups: valsartan (0.17g/l), eprosartan (0.8g/l), captopril (5g/l) or normal drinking water and the drugs given ad libitum for 2 months. Mean arterial blood pressure (MABP) was measured at baseline, at 2 weeks and at 2 months when the mice were sacrificed and the brains hemisected for analysis. One hemisphere was processed for Aβ and amyloid precursor protein (APP) immunohistochemistry and the other for biochemical measurement of oligomeric Aβ and APP. ACE activity was measured in the brain and kidney. Results: MABP was significantly reduced at 2 weeks and 2 months in the ACE-I group (p=0.0006) but was unaltered in the ARB groups compared to vehicle. Neither ACE-I nor ARB treatment altered Aβ and APP immunolabelling or the level of Aβ or APP in brain tissue homogenates. Similarly neither ACE-I nor ARB treatment altered ACE activity in either brain or kidney compared to control tissue. Conclusions: ACE-I or ARB administration over 2 months did not affect APP levels or either intraneuronal Aβ or oligomeric Aβ levels in 3xTGAD mice. While ARBs did not alter MABP, captopril did mediate reductions in MABP in the 3xTGAD mice which appeared to be independent

PR, IFPRI3, PHND

Contains fulltext : 69861.pdf (publisher's version ) (Closed access), Neprilysin, a zinc-metalloendopeptidase, has important roles in the physiology and pathology of many diseases such as hypertension, cancer and Alzheimer's disease. We have developed an immunocapture assay to measure the specific enzyme activity of neprilysin in brain tissue homogenates and cerebrospinal fluid (CSF). The assay uses a neprilysin-specific antibody, previously used in a commercially available ELISA kit, to isolate and immobilise NEP from brain homogenates and CSF, prior to the addition of a fluorogenic peptide substrate (Mca-RPPGFSAFK(Dnp)). This fluorogenic substrate is ordinarily cleaved by multiple enzymes. We have shown that without the immunocapture phase, even under reaction conditions reported to be specific for neprilysin - i.e. in the presence of thiorphan, at pH above 7 - the fluorogenic peptide substrate does not allow neprilysin activity in brain homogenates and CSF to be discriminated from that of other closely related enzymes. The specificity of the immunocapture enzyme activity assay was confirmed by >80% inhibition of substrate cleavage in brain homogenates and CSF in the presence of thiorphan. The assay allows high-throughput analysis and, critically, also ensures a high level of enzyme specificity even when assaying crude tissue homogenates or CSF.

Udgivelsesdato: 2008-Apr-26, BACKGROUND: In lower-income countries, WHO recommends a population-based approach to antiretroviral treatment with standardised regimens and clinical decision making based on clinical status and, where available CD4 cell count, rather than viral load. Our aim was to study the potential consequences of such monitoring strategies, especially in terms of survival and resistance development. METHODS: A validated computer simulation model of HIV infection and the effect of antiretroviral therapy was used to compare survival, use of second-line regimens, and development of resistance that result from different strategies-based on viral load, CD4 cell count, or clinical observation alone-for determining when to switch people starting antiretroviral treatment with the WHO-recommended first-line regimen of stavudine, lamivudine, and nevirapine to second-line antiretroviral treatment. FINDINGS: Over 5 years, the predicted proportion of potential life-years survived was 83% with viral load monitoring (switch when viral load >500 copies per mL), 82% with CD4 cell count monitoring (switch at 50% drop from peak), and 82% with clinical monitoring (switch when two new WHO stage 3 events or a WHO stage 4 event occur). Corresponding values over 20 years were 67%, 64%, and 64%. Findings were robust to variations in model specification in extensive univariable and multivariable sensitivity analyses. Although survival was slightly longer with viral load monitoring, this strategy was not the most cost effective. INTERPRETATION: For patients on the first-line regimen of stavudine, lamivudine, and nevirapine the benefits of viral load or CD4 cell count monitoring over clinical monitoring alone are modest. Development of cheap and robust versions of these assays is important, but widening access to antiretrovirals-with or without laboratory monitoring-is currently the highest priority.

Educational report about the respiratory diseases (asthma, COPD, silicosis, beryllium disease, Black lung disease, and asbestos disease) in the mining industry.