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Background and Aims More than 292 million people are living with hepatitis B worldwide and are at risk of death from liver cirrhosis and liver cancer. The World Health Organization (WHO) has set global targets for the elimination of viral hepatitis as a public health threat by 2030. However, current levels of global investment in viral hepatitis elimination programmes are insufficient to achieve these goals. Methods To catalyse political commitment and to encourage domestic- and international-financing, we used published modelling data and key stakeholder interviews to develop an investment framework to demonstrate the return on investment for viral hepatitis elimination. Results The framework utilizes a public health approach to identify evidence-based national activities that reduce viral hepatitis-related morbidity and mortality, as well as international activities and critical enablers that allow countries to achieve maximum impact on health outcomes from investment to achieve WHO 2030 elimination targets. Conclusion Focusing on hepatitis B, this health policy paper employs the investment framework to estimate the substantial economic benefits of investing in the elimination of hepatitis B and demonstrates how such investments could be cost-saving by 2030., Graphical abstract, Highlights • The WHO has set global targets for elimination of hepatitis B by 2030 • To date, global investment in hepatitis B elimination activities has been limited • We have developed a global investment framework for the elimination of hepatitis B to guide domestic and international investment • This Health Policy paper outlines evidence to support the financial returns on investment in hepatitis B elimination, identifies national and international activities to achieve hepatitis B elimination targets and identifies potential funding sources • The goal of this investment framework is to pave the way for countries to build the economic case for investment in national hepatitis B elimination programmes.

WHO has set global targets for the elimination of hepatitis B and hepatitis C as a public health threat by 2030. However, investment in elimination programmes remains low. To help drive political commitment and catalyse domestic and international financing, we have developed a global investment framework for the elimination of hepatitis B and hepatitis C. The global investment framework presented in this Health Policy paper outlines national and international activities that will enable reductions in hepatitis C incidence and mortality, and identifies potential sources of funding and tools to help countries build the economic case for investing in national elimination activities. The goal of this framework is to provide a way for countries, particularly those with minimal resources, to gain the substantial economic benefit and cost savings that come from investing in hepatitis C elimination.

Introduction Ceftazidime–avibactam combines the established anti-pseudomonal cephalosporin, ceftazidime, with the novel non-β-lactam β-lactamase inhibitor, avibactam. Objectives The aim of this study was to evaluate the safety of ceftazidime–avibactam in adults using pooled data from two phase II (NCT00690378, NCT00752219) and five phase III (NCT01499290, NCT01726023, NCT01644643, NCT01808093 and NCT01595438/NCT01599806) clinical studies. Methods Safety data from seven multicentre, randomised, active-comparator studies were pooled by study group at the patient level for descriptive analyses, comprising patients with complicated urinary tract infection (cUTI), including pyelonephritis, complicated intra-abdominal infection (cIAI), or nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), treated with ceftazidime–avibactam ± metronidazole or comparator. Results In total, 4050 patients (ceftazidime–avibactam ± metronidazole, n = 2024; comparator, n = 2026) were included in the pooled analysis. Adverse events (AEs) up to the last study visit occurred in 996 (49.2%) and 965 (47.6%) patients treated with ceftazidime–avibactam ± metronidazole and comparator, respectively. The most common AEs across treatment groups were diarrhoea, nausea, headache, vomiting and pyrexia. There were few discontinuations due to AEs (2.5% and 1.7% for ceftazidime–avibactam ± metronidazole and comparators, respectively). Overall rates of serious AEs were 8.7% for ceftazidime–avibactam ± metronidazole and 7.2% for comparators; respective rates of AEs with an outcome of death were 2.0% and 1.8%. AEs considered causally related to the study drug or procedures occurred in 10.7% and 9.6% of patients treated with ceftazidime–avibactam ± metronidazole and comparators; the most common drug-related AEs in both groups were diarrhoea, headache, nausea and increased alanine aminotransferase. No impact to the safety profile of ceftazidime–avibactam ± metronidazole was found with regard to intrinsic factors, such as age or renal function at baseline, or extrinsic factors, such as geographical origin. Potentially clinically significant changes in laboratory parameters were infrequent with no trends or safety concerns identified. Conclusion The observed safety profile of ceftazidime–avibactam across infection types is consistent with the established safety profile of ceftazidime monotherapy and no new safety findings were identified. This analysis supports the use of ceftazidime–avibactam as a treatment option in adults with cUTI, cIAI and NP, including VAP. Electronic supplementary material The online version of this article (10.1007/s40264-020-00934-3) contains supplementary material, which is available to authorized users.

Delayed-onset muscle soreness (DOMS) is a very common condition in athletes and individuals not accustomed to physical activity that occurs after moderate/high-intensity exercise sessions. The activation of microglial Toll-like receptor 4 (TLR4) in the spinal cord has been described to be important for the induction and maintenance of persistent pain. Based on that, we hypothesize that 70 kilodalton heat-shock protein (Hsp70), a mediator released by exercise, could activate microglial TLR4 in the spinal cord, releasing proinflammatory cytokines and contributing to the start of DOMS. In fact, we found that the knockout of TLR4, myeloid differentiation primary response 88 (MyD88), interleukin-6 (IL-6), or both tumor necrosis factor-α (TNF-α) receptor 1 and TNF-α receptor 2 in mice prevented the development of DOMS following acute aerobic exercise in contrast to the findings in male C57BL/6 wild-type mice. Furthermore, DOMS in exercised wild-type mice was also prevented after pre-treatment with microglia inhibitor, TLR4 antagonist, and anti-Hsp70 antibody. During exercise-induced DOMS, Hsp70 mRNA, TLR4 mRNA, and protein levels, as well as Iba-1 (a microglial marker), IL-6, and TNF-α protein levels, were increased in the muscle and/or spinal cord. Together, these findings suggest that Hsp70 released during exercise-induced DOMS activates the microglial TLR4/IL-6/TNF-α pathway in the spinal cord. Thus, the blockade of TLR4 activation may be a new strategy to prevent the development of DOMS before intense exercise.

Objective::Prices of antiretroviral (ARV) drugs in lower income countries have decreased substantially over the past two decades, helping to facilitate greatly expanded access to antiretroviral therapy (ART). However, ART coverage in many parts of the world remains low. We investigate the extent of epidemiological benefits that might be expected if ARV drug prices decline further.Design:A modeling study using data from seven countries in West and Central Africa (Cameroon, Democratic Republic of the Congo, Côte d'Ivoire, Niger, Nigeria, Senegal, and Togo).Methods:We investigated how the timing of ARV cost reductions could affect the impact and compared three different possible investment strategies: reinvesting in ART, reinvesting in the HIV response according to historical allocations, and reinvesting with the aim of minimizing HIV incidence and mortality.Results:If ARV drug prices fell by 37% relative to 2018 levels (i.e. following continued trend declines), we calculate ART unit costs could decrease by ∼20% (holding other cost components constant). If this could be achieved by 2020 and the savings were reinvested into ART, we estimate that an additional 8% of HIV infections and 11% of HIV-related deaths could be averted over 2020-2030 across the seven countries. Slightly greater gains could be attained if funds were reinvested in ART in combination with primary prevention. Delays in the year of introduction of ARV price reductions would reduce the impact by about 1% per year.Conclusion:ARV price reductions could free up funds that - if strategically invested - would help countries move closer toward the elimination of HIV.

Bronchoalveolar lavage (BAL) is a key clinical and research tool in lung transplantation (LTx). However, BAL collection and processing are not standardized across LTx centers. This International Society for Heart and Lung Transplantation-supported consensus document on BAL standardization aims to clarify definitions and propose common approaches to improve clinical and research practice standards. The following 9 areas are covered: (1) bronchoscopy procedure and BAL collection, (2) sample handling, (3) sample processing for microbiology, (4) cytology, (5) research, (6) microbiome, (7) sample inventory/tracking, (8) donor bronchoscopy, and (9) pediatric considerations. This consensus document aims to harmonize clinical and research practices for BAL collection and processing in LTx. The overarching goal is to enhance standardization and multicenter collaboration within the international LTx community and enable improvement and development of new BAL-based diagnostics. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:39 issue:11 pages:1171-1190 ispartof: location:United States status: published

Emergence of SARS-CoV-2 with high transmission and immune evasion potential, the so-called variants of concern (VOC), is a major concern. We describe the early genomic epidemiology of SARS-CoV-2 recovered from vaccinated health care professionals (HCP). Our postvaccination COVID-19 symptoms-based surveillance program among HCPs in a 17-hospital network identified all vaccinated HCPs who tested positive for COVID-19 after routine screening or after self-reporting. From 1 January 2021 to 30 April 2021, 23,687 HCPs received either mRNA-1273 or BNT162b2 mRNA vaccine. All available postvaccination SARS-CoV-2 samples and a random collection from nonvaccinated patients during the similar time frame were subjected to VOC screening and whole-genome sequencing (WGS). Sixty-two percent (23,697/37,500) of HCPs received at least one vaccine dose, with 60% (22,458) fully vaccinated. We detected 138 (0.58%, 138/23,697) COVID-19 cases, 105 among partially vaccinated and 33 (0.15%, 33/22,458) among fully vaccinated. Five partially vaccinated required hospitalization, four with supplemental oxygen. VOC screening from 16 fully vaccinated HCPs identified 6 (38%) harboring N501Y and 1 (6%) with E484K polymorphisms; percentage of concurrent nonvaccinated samples was 37% (523/1,404) and 20% (284/1,394), respectively. There was an upward trend from January to April for E484K/Q (3% to 26%) and N501Y (1% to 49%). WGS analysis from vaccinated and nonvaccinated individuals indicated highly congruent phylogenies. We did not detect an increased frequency of any receptor-binding domain (RBD)/N-terminal domain (NTD) polymorphism between groups (P > 0.05). Our results support robust protection by vaccination, particularly among recipients of both doses. Despite VOCs accounting for over 40% of SARS-CoV-2 from fully vaccinated individuals, the genomic diversity appears to proportionally represent VOCs among nonvaccinated populations. IMPORTANCE A number of highly effective vaccines have been developed and deployed to combat the COVID-19 pandemic. The emergence and epidemiological dominance of SARS-CoV-2 mutants with high transmission potential and immune evasion properties, the so-called variants of concern (VOC), continue to be a major concern. Whether these VOCs alter the efficacy of the administered vaccines is of great concern and a critical question to study. We describe the initial genomic epidemiology of SARS-CoV-2 recovered from partial/fully vaccinated health care professionals and probe specifically for VOC enrichment. Our findings support the high level of protection provided by full vaccination despite a steep increase in the prevalence of polymorphisms associated with increased transmission potential (N501Y) and immune evasion (E484K) in the nonvaccinated population. Thus, we do not find evidence of VOC enrichment among vaccinated groups. Overall, the genomic diversity of SARS-CoV-2 recovered postvaccination appears to proportionally represent the observed viral diversity within the community.

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Rationale: Current spirometry quality grading for individuals 7 years and older include within test repeatability thresholds up to 250mls, which may be inappropriately wide for children. Objectives...

Aim Inflammation provides favourable microenvironment for cancer development. An enhanced COX-2 gene expression is a key inflammatory mediator of cancers and the drug that inhibits it, helps to manage cancer effectively and increases survival rate. The objective is to analyse the inflammatory changes and COX-2 gene expression in benzo (a) pyrene induced mice and to evaluate the regulatory effect of all trans retinoic acid. Materials and methods The body and organ weights were recorded in B(a)P induced mice. The haematological parameters and serum inflammatory markers of carcinogenesis were tested. The H & E stained liver and lung tissues were examined for histopathologic changes. The COX-2 gene expression was analysed by RT-PCR and qPCR in lung and liver. Key findings The decreased body weight, increased organ weights and the damages in liver and lung were observed in B(a)P induced mice and were prevented significantly upon ATRA treatment. The lowered Hb, RBC and lymphocytes and an enhanced WBC, monocytes and neutrophils observed in B(a)P group were significantly reversed in treated group. A drastic increase in cancer associated inflammatory markers observed in B(a)P induced mice were significantly (P ≤ 0.001) reduced in treated mice. The RT-PCR product density of COX-2 gene was very high in B(a)P group (lung-0.43 ± 0.06; liver-0.39 ± 0.04) significantly lower in treated group (lung-0.12 ± 0.03; liver-0.08 ± 0.03) with a significant difference in RQ values (B(a)P lung-18.46 ± 0.04, liver-12.46 ± 0.08; treated lung-5.93 ± 0.07, liver-2.92 ± 0.10). Significance The ATRA has decreased the inflammatory condition with downregulation of COX-2 gene expression and thereby prevented carcinogenesis during early stage of B(a)P induced cancer development.

Antimicrobial drugs play an important, often central, role in the therapeutic management of mature horses and foals with a variety of illnesses, including those requiring critical care. Antimicrobial use must be based on rational principles involving thorough patient evaluation and sound clinical judgment that indicate a high likelihood that the patient has a bacterial infection and that antimicrobials are indicated to promote recovery. The aim of antimicrobial treatment is to inflict an insult on infecting bacteria sufficient to kill the organism or render it susceptible to inactivation by natural host defenses or the local microenvironment without adversely affecting the patient.

Emergence of SARS-CoV-2 with high transmission and immune evasion potential, the so-called Variants of Concern (VOC), is a major concern. We describe the early genomic epidemiology of SARS-CoV-2 recovered from vaccinated healthcare professionals (HCP). Our post-vaccination COVID-19 symptoms-based surveillance program among HCPs in a 17-hospital network, identified all vaccinated HCP who tested positive for COVID-19 after routine screening or after self-reporting. From 01/01/2021 to 04/30/2021, 23,687 HCP received either mRNA-1273 or BNT162b2 mRNA vaccine. All available post-vaccination SARS-CoV-2 samples and a random collection from non-vaccinated patients during the similar timeframe were subjected to VOC screening and whole genome sequencing (WGS). 62% (23,697/37,500) of HCPs received at least one vaccine dose, with 95% (22,458) fully vaccinated. We detected 138 (0.58%, 138/23,697) COVID-19 cases, 105 among partially vaccinated and 33 (0.15%, 33/22,458) among fully vaccinated. Five partially vaccinated required hospitalization, four with supplemental oxygen. VOC screening from 16 fully vaccinated HCPs identified 6 (38%) harboring N501Y and 1 (6%) with E484K polymorphisms; concurrent non-vaccinated samples was 37% (523/1404) and 20% (284/1394), respectively. There was an upward trend from January to April for E484K/Q (3% to 26%) and N501Y (1% to 49%). WGS analysis from vaccinated and non-vaccinated individuals indicated highly congruent phylogenies. We did not detect an increased frequency of any RBD/NTD polymorphism between groups (P>0.05). Our results support robust protection by vaccination, particularly among recipients of both doses. Despite VOCs accounting for over 40% of SARS-CoV-2 from fully vaccinated individuals, the genomic diversity appears to proportionally represent those among non-vaccinated populations.IMPORTANCEA number of highly effective vaccines have been developed and deployed to combat the COVID-19 pandemic. The emergence and epidemiological dominance of SARS-CoV-2 mutants, with high transmission potential and immune evasion properties, the so-called Variants of Concern (VOC), continues to be a major concern. Whether these VOCs alter the efficacy of the administered vaccines is of great concern, and a critical question to study. We describe the initial genomic epidemiology of SARS-CoV-2 recovered from vaccinated healthcare professionals and probe specifically for VOC enrichment. Our findings support the high-level of protection provided by full vaccination despite a steep increase in the prevalence of polymorphisms associated with increased transmission potential (N501Y) and immune evasion (E484K) in the non-vaccinated population. Thus, we do not find evidence of VOC enrichment among vaccinated groups. Overall, the genomic diversity of SARS-CoV-2 recovered post-vaccination appears to proportionally represent the observed viral diversity within the community.

Gallstone disease is extremely prevalent in the western society with laparoscopic cholecystectomy (LC) being the standard treatment for patients with symptomatic gallstones. The prevalence of common bile duct (CBD) stones with concomitant gallstones increases with age from 8–15% in patients

Viral hepatitis is a leading cause of morbidity and mortality worldwide, but has long been neglected by national and international policymakers. Recent modelling studies suggest that investing in the global elimination of viral hepatitis is feasible and cost‐effective. In 2016, all 194 member states of the World Health Organization endorsed the goal to eliminate viral hepatitis as a public health threat by 2030, but complex systemic and social realities hamper implementation efforts. This paper presents eight case studies from a diverse range of countries that have invested in responses to viral hepatitis and adopted innovative approaches to tackle their respective epidemics. Based on an investment framework developed to build a global investment case for the elimination of viral hepatitis by 2030, national activities and key enablers are highlighted that showcase the feasibility and impact of concerted hepatitis responses across a range of settings, with different levels of available resources and infrastructural development. These case studies demonstrate the utility of taking a multipronged, public health approach to: (a) evidence‐gathering and planning; (b) implementation; and (c) integration of viral hepatitis services into the Agenda for Sustainable Development. They provide models for planning, investment and implementation strategies for other countries facing similar challenges and resource constraints.

Background The South Eastern Trust established an Ambulatory Stroke Team (AST) in October 2017. This consisted of Stroke Nurses and a Specialty doctor with Stroke consultant support. During the initial pilot the AST team worked Monday – Friday 9-5pm. The majority of assessments took place in the emergency department. The overall aims were to improve length of stay for TIAs / stroke mimics and improve the percentage of strokes being admitted directly to the Stroke Unit. Methods Using quality improvement methodology we worked through several Plan, Do, Study, Act (PDSA) cycles. The most significant intervention was the introduction of a protected direct to stroke unit bed. A database was kept of all patients seen, including final diagnoses and patients discharged after assessment, preventing admission and saving bed days. Results A 6 month period was analysed from April to September 2018. 312 patients were reviewed - 159 (51%) stroke mimics, 108 (35%) strokes and 45 (14%) TIAs. 54 patients were identified for early discharge and appropriate follow-up. Bed days saved was estimated at 110 days. Direct to stroke unit percentage improved from 30% in October 2017 when the AST was introduced to 82% in January 2019. Conclusion A dedicated Ambulatory Stroke Team can prevent hospital admissions and save bed days due to rapid identification and specialist assessment of suspected TIAs and strokes. Multidisciplinary team working as part of a quality improvement project can improve the percentage of strokes admitted directly to the stroke unit.

Background The introduction of highly effective direct-acting antiviral (DAA) therapy for hepatitis C has led to calls to eliminate it as a public health threat through treatment-as-prevention. Recent studies suggest it is possible to develop a vaccine to prevent hepatitis C. Using a mathematical model, we examined the potential impact of a hepatitis C vaccine on the feasibility and cost of achieving the global WHO elimination target of an 80% reduction in incidence by 2030 in the era of DAA treatment. Methods The model was calibrated to 167 countries and included two population groups (people who inject drugs (PWID) and the general community), features of the care cascade, and the coverage of health systems to deliver services. Projections were made for 2018–2030. Results The optimal incidence reduction strategy was to implement test and treat programmes among PWID, and in settings with high levels of community transmission undertake screening and treatment of the general population. With a vaccine available, the optimal strategy was to include vaccination within test and treat programmes, in addition to vaccinating adolescents in settings with high levels of community transmission. Of the 167 countries modelled, between 0 and 48 could achieve an 80% reduction in incidence without a vaccine. This increased to 15–113 countries if a 75% efficacious vaccine with a 10-year duration of protection were available. If a vaccination course cost US$200, vaccine use reduced the cost of elimination for 66 countries (40%) by an aggregate of US$7.4 (US$6.6–8.2) billion. For a US$50 per course vaccine, this increased to a US$9.8 (US$8.7–10.8) billion cost reduction across 78 countries (47%). Conclusions These findings strongly support the case for hepatitis C vaccine development as an urgent public health need, to ensure hepatitis C elimination is achievable and at substantially reduced costs for a majority of countries.

Background Post-stroke lower limb spasticity (PSLLS) has a prevalence of 28–37%. PSLLS can cause difficulty in walking and reduce quality of life (QOL). Post stroke spasticity impairs the ability to intervene to improve walking ability. Botulinum Toxin A (BT) is an effective intervention for focal spasticity, but its use is currently restricted in many countries by their reimbursement system stating that the evidence for improvement in walking and quality of life (QOL) is not robust for treatment in the lower limb. This randomized control trial (RCT) will investigate the effectiveness of BT in modifying spasticity, and improving functioning (mobility, walking, activities of daily living (ADL’s) and QOL. Methods/design A double-blind placebo-controlled trial injection will assess the effect of BT compared with a placebo (normal saline) in a sample of n = 94 patients. Following treatment of spasticity measured by Modified Ashworth Scale (MAS), the primary outcome of gait velocity will be measured by i) Gait Rite (Electronic Walkway); ii) walking by 2 Min Walk Test; iii) balance by Berg Balance Scale; mobility by iv) Timed Up and Go (TUG); v) lower limb function by ABILICO; vi) patient related goal by Goal Attainment Scale (GAS); vii) QOL by SF 12 (Rand version); viii) activities of daily living by the Functional Autonomy Measurement System (SMAF). There will be an associated health economic analysis. Discussion The study methodology is based on our systematic review 2026 studies, which concluded the evidence for improving mobility following use of BT to reduce spasticity was not robust. The results of this study could establish the use of BT in improving gait and lower limb function in PSLLS. This study could provide the evidence needed for reimbursement schemes to consider and changes to its funding policy for BT in PSLLS. Trial registration The trial is registered with the Australia New Zealand Clinical Trails Registry (ANZCTR)-ANZCTRN12617001603303. Registered 07/12/2017.

BACKGROUND Differentiated care has been proposed to improve HIV treatment outcomes. In June 2016, South Africa's National Department of Health in collaboration with researchers began an evaluation of its National Adherence Guidelines for Chronic Diseases (AGL) which was being rolled-out by NDOH to public sector health facilities. METHODS The evaluation has a cluster-randomized design with 12 intervention and 12 control facilities in 4 provinces. Follow up was by passive surveillance using clinical records. Enrollment occurred between June-December 2016. Our primary outcome was receipt of ART through Adherence Clubs (AC) within the first 4 months after AC eligibility. We compared crude results, used baseline covariate adjustment and difference-in-differences approaches to assess effects of ACs. RESULTS We enrolled 275 patients from ACs and 294 control arm patients. About 57% were

Summary Background Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding Cancer Research UK.

Author(s): Wilson, David; Laoteppitaks, Chaiya; Chandra, Shruti | Abstract: Introduction: Medical students pursuing an emergency medicine (EM) residency are advised to obtain at least two Standardized Letters of Evaluation (SLOE). Students often complete one rotation at their home institution and at least one “away” rotation at a program separate from their home institution. The SLOE was introduced as an objective evaluation tool. The aim of this study was to determine whether there was a difference in scores between home rotation and away rotation SLOEs.Methods: We retrospectively reviewed the SLOEs of all applicants to an urban, academic EM residency program. For each SLOE, we calculated a composite score from rankings in seven “Qualifications for EM” (CS7), and converted comparative rank score (CRS) and estimated rank list position (ERP) to percentile scores. The CS7, CRS, and ERP on the home rotation SLOE were compared to those of the away SLOE using a paired t-test.Results: An evaluation of 721 applicants with at least one home SLOE and one away SLOE demonstrated a significant increase in the ERP of home rotators (P = 0.003). The data did not demonstrate a statistically significant difference in the CS7 (P = 0.69), or CRS (P = 0.97).Conclusion: Our study demonstrated that the only difference in SLOEs is that students are likely to be given a slightly higher estimated placement on the rank order list on a home SLOE. We hope this will help residency leadership with reviewing applications.

Background Cystic fibrosis (CF) pulmonary exacerbations (PEx) are associated with a significant drop in pulmonary function. The clinical value of measuring bronchodilator (BD) responsiveness during treatment for PEx to monitor or predict recovery of lung function is unclear. Methods A retrospective analysis of spirometry with BD response testing obtained during hospital admissions for PEx in pediatric CF patients. Repeated events were included for patients with BD testing during multiple admissions. Results 249 spirometries with BD testing in 102 patients were completed around day 7 (day 4-10) of hospital admission for treatment of CF PEx. Median (IQR) forced expiratory volume in one second (FEV1 ) was 70.6% predicted (58.1, 84.6) prior to the PEx event (best FEV1 in 6 months prior to admission), 54.4% (41.5, 66.9) at admission, 62.3% (48.4, 74.7) around day 7 of admission and 67.1% predicted (53.8, 78.2) at end of treatment. BD response around day 7 correlated poorly with FEV1 prior to PEx (r=-0.16, p=0.02), and did not correlate with recovery to baseline FEV1 at end of treatment (r=0.08, p=0.22). Only 23/249 (9%) individual tests had a BD response in FEV1 of ≥12 % and 200 ml. BD response was not related to age or severity of lung disease and led to an immediate change in clinical management in only 4 cases. Conclusions Significant BD response in CF patients treated for PEx is rare, shows poor correlation with baseline pulmonary function and does not correlate with recovery of FEV1 with treatment. These data suggest that routine testing for BD response is not indicated during PEx. This article is protected by copyright. All rights reserved.

Initial global-level estimates reported in June 2020 by the World Health Organization suggested that levels of disruption to TB service delivery could be as high as 25%-50% and result in an additional 6·3 million cases of tuberculosis (TB) and an additional 1·4 million TB-related deaths attributable to COVID-19 between 2020 and 2025. Quarterly epidemiological estimates and programmatic TB data capturing disruption levels to each TB service were collected by National TB Programmes in Indonesia, Kyrgyzstan, Malawi, Mozambique, and Peru. Data from 2019, for a pre-COVID-19 baseline, and throughout 2020, together with the NTP’s COVID-19 response plans, were used within Optima TB models to project TB incidence and deaths over five years because of COVID-19-related disruptions, and the extent to which those impacts may be mitigated through proposed catch-up strategies in each country. Countries reported disruptions of up to 64% to demand-driven TB diagnosis. However, TB service availability disruptions were shorter and less severe, with TB treatment experiencing levels of disruption of up to 21%. We predicted that under the worse-case scenario cumulative new latent TB infections, new active TB infections, and TB-related deaths could increase by up to 23%, 11%, and 20%, respectively, by 2024. However, three of the five countries were on track to mitigate these increases to 3% or less by maintaining TB services in 2021 and 2022 and by implementing proposed catch-up strategies. Indonesia was already experiencing the worse-case scenario, which could lead to 270,000 additional active TB infections and 36,000 additional TB-related deaths by the end of 2024. The COVID-19 pandemic is projected to negatively affect progress towards 2035 End TB targets, especially in countries already off-track. Findings highlight both successful TB service delivery adaptions in 2020 and the need to proactively maintain TB service availability despite potential future waves of more transmissible COVID-19 variants.

Introduction: Catheter ablation has become the cornerstone for the treatment of drug-refractory paroxysmal atrial fibrillation. Two main forms of energy are used: cryoablation (CB) and radiofrequency (RF). Multiple studies have compared the effectiveness/safety curve between these two; among which is the FIRE AND ICE and the FREEZE AF trials which showed non-inferiority between these two technologies. Despite the remarkable success achieved at controlling arrythmias, complications as high as 16.3% have been reported in both technologies. Objectives: The main purpose of this meta-analysis is to compare the incidence of esophageal and myocardial injuries among patients undergoing radiofrequency ablation vs cryoablation for the treatment of atrial fibrillation or atrial flutter (AF). Methods/Results: We searched Pubmed/Embase, Medline and Cochrane from inception to April 2020 for studies that met our predetermined inclusion and exclusion criteria. All studies comparing RFA to CBA and reporting the incidence of life-threatening complications (esophageal injuries and perforation/tamponade) were included in our analysis. To limit confounding variables and significant heterogeneity between studies, we selected only randomized-control trials and propensity-matched observational studies. A total of 2748 patients were identified. Overall analyses show that RFA has significantly higher life-threatening complications than CBA (OR = 2.79, 95% CI: 1.41-5.52; p=0.003). Conclusion: The present systematic review and meta-analysis demonstrates that RFA has 3 times more life-threatening complications than CBA. As previous studies have already shown similar degree of freedom from AF between these two ablation technologies, CBA appears to be more advantageous overall.

Background Hepatitis C is highly prevalent among prisoners. The simplicity of direct-acting antiviral (DAA) treatment for hepatitis C makes it possible to use novel models of care to increase treatment uptake within prisons. We estimate the average non-drug cost of initiating a prisoner on treatment using real world data from the State-wide Hepatitis Program (SHP) in Victoria, Australia – a coordinated nurse-led model of care. Methods Data were considered from prisoners presenting to the SHP (following antibody-positive diagnosis) during the evaluation period, November 2015 to December 2016. All costs associated with the SHP were estimated, including staffing salaries, medical tests, pharmacy costs and overhead costs. DAA costs were excluded as in Australia an unlimited number are available, covered by a federal government risk-sharing agreement with pharmaceutical companies. The average non-drug cost of treatment initiation through the SHP was compared to equivalent costs from primary and hospital-based models of care in the community. Results The total non-drug cost accumulated by prisoners in the SHP was AUD$749,470 (uncertainty range: AUD$728,905-794,111). 659/803 were PCR positive, 424/659 had sentences long enough to be eligible for treatment, and 416/424 were initiated on treatment, resulting in an average non-drug cost of AUD$1,802 (95% CI: AUD$1799-1841) per prisoner initiated. A protocol change allowing prisoners with short sentences to start treatment reduced the average non-drug cost to AUD$1263 (95% CI: AUD$1263-1287) per prisoner initiating treatment – 11% and 56% cheaper than estimated equivalent costs in primary (AUD$1654) and hospital-based (AUD$2847) models of care in the community, respectively. Conclusion Delivering hepatitis C treatment in prison using a nurse-led model of care is cheaper than delivering treatment in the community. These findings provide an economic rationale for implementing coordinated prison-based hepatitis C treatment programs.

Background Eswatini continues to have the highest prevalence of HIV in the world, and one of the highest HIV incidences among adult populations (aged 15–49). This analysis reports on both key elements of study design/protocol and baseline results from an impact evaluation of an intervention incentivizing (i) initiation, enrolment, attendance or completion of some form of education, and (ii) lower risk sexual behaviour. Methods The impact evaluation employs a two by two factorial design in which participants are enrolled in either the incentive for education arm (‘education treatment arm’ providing a conditional cash incentive) or the control arm (‘education control arm’). In each of these arms, 50% of participants were randomized to also be eligible for selection – three times a year – to participate in a conditional raffle conditional on testing negative for curable STIs (syphilis and Trichomonas vaginalis). Results Baseline recruitment and screening occurred in 2016 when a total of 6055 individuals were screened of which 4863 participated in the baseline survey, and 4819 individuals were randomized into one of the study arms. The baseline prevalence of HIV, Trichomonas vaginalis, and syphilis among adolescent girls and young women 8.20% (397/4840), 3.31% (150/4533) and 0.17% (8/4830) respectively. Conclusions An educational cash incentive and raffle incentive impact evaluation that addresses adolescent girls and young women who are in-education and out-of-education has the potential to reduce HIV risk in adolescent girls and young women in Eswatini. Trial registration Name of the registry: Pan African Clinical Trials Registry. Trial registration number: PACTR201811609257043. Date of registration: May 11, 2018 ‘Retrospectively registered’. URL of trial registry record: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=4685

Background Infant pulmonary function testing using the raised volume rapid thoracoabdominal compression (RVRTC) technique requires sedation and is time consuming. Many cystic fibrosis (CF) centers do not have access to equipment and the utility of routine testing remains to be determined. We aimed to assess whether RVRTC tests performed during infancy predict spirometry at early school age. Methods The RVRTC-based forced expiratory flow measures in infants were compared to the first adequately performed spirometry at school age. All tests were carried out during routine clinic visits and expressed as age related z-scores; only test occasions where patients were considered stable were included in the analysis. Results 47 patients had useable infant RVRTC as well as matching school age spirometry data. There was weak correlation between infant FEV0.5 and early school age FEV1 (R = 0.29, p = 0.05). Four infants had significantly low zFEV0.5 (zFEV0.5 Conclusion Infant RVRTC measures were not predictive of pulmonary function in early school age, likely due to the high proportion of measures of forced expiratory flows within the normal range at both time points.

Background and Objectives: Pre-donation screening of potential blood donors is critical for ensuring the safety of the donor blood supply, and donor deferral as a result of risk factors is practised worldwide. This systematic review was conducted in the context of an expert review convened by the Australian Red Cross Lifeblood in 2013 to consider Lifeblood’s injecting drug use (IDU)-related policies and aimed to identify studies assessing interventions to improve compliance with deferral criteria in blood donation settings. Materials and Methods: MEDLINE/PubMed, OVID Medline, OVID Embase, LILACS, and the Cochrane Library (CENTRAL and DARE) databases were searched for studies conducted within blood donation settings that examined interventions to increase blood donor compliance with deferral criteria. Observational and experimental studies from all geographical areas were considered. Results: Ten studies were identified that tested at least one intervention to improve blood donor compliance with deferral criteria, including computerized interviews or questionnaires, direct and indirect oral questioning, educational materials, and a combination of a tickbox questionnaire and a personal donor interview. High-quality evidence from a single study was provided for the effectiveness of a computerized interview in improving detection of HIV risk behaviour. Low-quality evidence for the effectiveness of computerized interviews was provided by 3 additional studies. Two studies reported a moderate effect of direct questioning in increasing donor deferral, but the quality of the evidence was low. Conclusion: This review identified several interventions to improve donor compliance that have been tested in blood donation settings and provided evidence for the effectiveness of computerized interviews in improving detection of risk factors.

ObjectivesTo assess the risks associated with relaxing coronavirus disease 2019 (COVID-19)-related physical distancing restrictions and lockdown policies during a period of low viral transmission.DesignNetwork-based viral transmission risks in households, schools, workplaces, and a variety of community spaces and activities were simulated in an agent-based model, Covasim.SettingThe model was calibrated for a baseline scenario reflecting the epidemiological and policy environment in Victoria during March–May 2020, a period of low community viral transmission.InterventionPolicy changes for easing COVID-19-related restrictions from May 2020 were simulated in the context of interventions that included testing, contact tracing (including with a smartphone app), and quarantine.Main outcome measureIncrease in detected COVID-19 cases following relaxation of restrictions.ResultsPolicy changes that facilitate contact of individuals with large numbers of unknown people (eg, opening bars, increased public transport use) were associated with the greatest risk of COVID-19 case numbers increasing; changes leading to smaller, structured gatherings with known contacts (eg, small social gatherings, opening schools) were associated with lower risks. In our model, the rise in case numbers following some policy changes was notable only two months after their implementation.ConclusionsRemoving several COVID-19-related restrictions within a short period of time should be undertaken with care, as the consequences may not be apparent for more than two months. Our findings support continuation of work from home policies (to reduce public transport use) and strategies that mitigate the risk associated with re-opening of social venues.

AimsWe assessed COVID-19 epidemic risks associated with relaxing a set of physical distancing restrictions in the state of Victoria, Australia – a setting with low community transmission – in line with a national framework that aims to balance sequential policy relaxations with longer-term public health and economic need.MethodsAn agent-based model, Covasim, was calibrated to the local COVID-19 epidemiological and policy environment. Contact networks were modelled to capture transmission risks in households, schools and workplaces, and a variety of community spaces (e.g. public transport, parks, bars, cafes/restaurants) and activities (e.g. community or professional sports, large events). Policy changes that could prevent or reduce transmission in specific locations (e.g. opening/closing businesses) were modelled in the context of interventions that included testing, contact tracing (including via a smartphone app), and quarantine.ResultsPolicy changes leading to the gathering of large, unstructured groups with unknown individuals (e.g. bars opening, increased public transport use) posed the greatest risk, while policy changes leading to smaller, structured gatherings with known individuals (e.g. small social gatherings) posed least risk. In the model, epidemic impact following some policy changes took more than two months to occur. Model outcomes support continuation of working from home policies to reduce public transport use, and risk mitigation strategies in the context of social venues opening, such as >30% population-uptake of a contact-tracing app, physical distancing policies within venues reducing transmissibility by >40%, or patron identification records being kept to enable >60% contact tracing.ConclusionsIn a low transmission setting, care should be taken to avoid lifting sequential COVID-19 policy restrictions within short time periods, as it could take more than two months to detect the consequences of any changes. These findings have implications for other settings with low community transmission where governments are beginning to lift restrictions.

Introduction In 2014, the South African government adopted a differentiated service delivery (DSD) model in its “National Adherence Guidelines for Chronic Diseases (HIV, TB and NCDs)” (AGL) to strengthen the HIV care cascade. We describe the barriers and facilitators of the AGL implementation as experienced by various stakeholders in eight intervention and control sites across four districts. Methods Embedded within a cluster‐randomized evaluation of the AGL, we conducted 48 in‐depth interviews (IDIs) with healthcare providers, 16 IDIs with Department of Health and implementing partners and 24 focus group discussions (FGDs) with three HIV patient groups: new, stable and those not stable on treatment or not adhering to care. IDIs were conducted from August 2016 to August 2017; FGDs were conducted in January to February 2017. Content analysis was guided by the Consolidated Framework for Implementation Research. Findings were triangulated among respondent types to elicit barriers and facilitators to implementation. Results New HIV patients found counselling helpful but intervention respondents reported sub‐optimal counselling and privacy concerns as barriers to initiation. Providers felt insufficiently trained for this intervention and were confused by the simultaneous rollout of the Universal Test and Treat strategy. For stable patients, repeat prescription collection strategies (RPCS) were generally well received. Patients and providers concurred that RPCS reduced congestion and waiting times at clinics. There was confusion though, among providers and implementers, around implementation of RPCS interventions. For patients not stable on treatment, enhanced counselling and tracing patients lost‐to‐follow‐up were perceived as beneficial to adherence behaviours but faced logistical challenges. All providers faced difficulties accessing data and identifying patients in need of tracing. Congestion at clinics and staff attitude were perceived as barriers preventing patients returning to care. Conclusions Implementation of DSD models at scale is complex but this evaluation identified several positive aspects of AGL implementation. The positive perception of RPCS interventions and challenges managing patients not stable on treatment aligned with results from the larger evaluation. While some implementation challenges may resolve with experience, ensuring providers and implementers have the necessary training, tools and resources to operationalize AGL effectively is critical to the overall success of South Africa’s HIV control strategy.

This case report describes a case of severe hemorrhagic tonsillitis in a nine month-old child who suffered significant amount of blood loss and was emergently taken to operating room for control of hemorrhage. The child was brought to emergency room by mom after noticing blood around child's mouth and nose and a subsequent episode of hematemesis having awoken from sleep. Initial impression was bleeding secondary to epistaxis however a thorough bedside otolaryngology exam including flexible rhinolaryngoscopy ruled this out. Rapid pooling of blood in oropharynx, continued hemorrhage with significant blood loss and recent history of hematemesis prompted emergent intervention in operating room for endoscopy for control of hemorrhage including esophagogastroduodenoscopy (EGD). Bleeding was identified from a blood vessel at left lower tonsil pole. Although there is a description in literature of such cases, these are uncommon in the pediatric population and none has been described in a patient this young requiring emergent operative intervention. This case report discusses the diagnostic and decision making dilemma in an infant in setting of ongoing active hemorrhage and the role of multidisciplinary team management.

Examine literature for evidence of changes in button battery (BB) research over time including: amount and rate of literature output, levels of evidence, and the location of the research.Literature review of all peer-reviewed button battery literature available online through Pubmed and Embase was performed. Inclusion criteria were applied to ensure relevance. Publications were grouped into 4 time periods. Various study characteristics were compared between groups.A total of 255 original research studies were reviewed. A significant increase in study number was found with a 664% increase comparing 2009-2018 and 1977-1988 (p 0.001) and a 187% increase comparing 2009-2018 and all previous years. Average author number significantly increased over the study period (range: 2.8 to 4.4; p 0.001). Case report or case series were consistently the most common type of study design (range: 56.5% to 84.0%). Level of evidence has remained at 4-5 for the majority of studies (range: 87% to 92.1%). First author specialty remained stable over time, with non-otolaryngologist surgeons being the most common authors, followed by pediatricians and otolaryngologists (28.8%, 18.9%, 18.5%, respectively). Location of research has diversified, with US publications falling from 50% to 29.5% of all studies when comparing 1977-1988 to 2009-2018 time periods.Button battery ingestion in the pediatric population has been an important topic of discussion among various medical specialties due to a rise in morbidity and mortality surrounding these ingestions. Despite the increase in number of studies and authors, the strength of these studies has remained largely unchanged.

Background Diabetes is one of the leading causes of poor health and high care costs in Ukraine. An estimated 3 million adults live with the condition, placing diabetes in the top ten causes of years lived with disability. To prevent diabetes complications and alleviate the financial burden of diabetes care on patients, the Ukrainian government reimburses diabetes medication and provides glucose monitoring, but there are significant gaps in the care continuum. We estimate the costs of providing diabetes care and the most cost-effective ways to address these gaps in the Poltava region of Ukraine.Methods We gathered data on the unit costs of diabetes interventions in Poltava region in 2017 and estimated expenditure on diabetes care. We then applied the Cascade Analysis Tool, a model for analyzing and optimizing health service implementation, to estimate the optimal combination of facility-based and outreach screening and investigate how additional funding could best be allocated to improve glucose control outcomes.Results Of the ~40000 adults in diabetes care, only ~25% achieved sustained glucose control. Monitoring costs were higher for those who did not: by 10% for patients receiving non-pharmacological treatment, by 61% for insulin patients, and twice as high for patients prescribed oral treatment. Investments in initiatives to improve treatment adherence (e.g. medication copayment schemes, enhanced adherence counseling) would address barriers along the care continuum and we estimate such expenditures may be recouped by reductions in patient monitoring costs. Improvements in case detection are also needed, with only around two-thirds of estimated cases having been diagnosed. Outreach screening campaigns could play a significant role: depending on how well-targeted and scalable such campaigns are, we estimate that 10–46% of all screening could be conducted via outreach, at a cost per positive patient identified of US$7.12–9.63.Conclusions Investments to improve case detection and treatment adherence are the most efficient interventions for improved diabetes control in Poltava region. Quantitative tools such as the Cascade Analysis Tool provide essential decision support for targeting investment into services which close the gaps in implementation.

As loss from HIV care is an ongoing challenge globally, interventions are needed for patients who don't achieve or maintain ART stability. The 2015 South African National Adherence Guidelines (AGL) for Chronic Diseases include two interventions targeted at unstable patients: early tracing of patients who miss visits (TRIC) and enhanced adherence counselling (EAC).As part of a cluster-randomised evaluation at 12 intervention and 12 control clinics in four provinces, intervention sites implemented the AGL interventions, while control sites retained standard care. We report on outcomes of EAC for patients with an elevated viral load (400 copies/ml) and for TRIC patients who missed a visit by5 days. We estimated risk differences (RD) of 3 and 12-month viral resuppression (400 copies/ml) and 12-month retention with cluster adjustment using generalised estimating equations and controlled for imbalances using difference-in-differences compared to all eligible in 2015, prior to intervention roll-out.For EAC, we had 358 intervention and 505 control site patients (61% female, median ART initiation CD4 count 154 cells/μl). We found no difference between arms in 3-month resuppression (RD: -1.7%; 95%CI: -4.3% to 0.9%), but20% of patients had a repeat viral load within 3 months (19.8% intervention, 13.5% control). Including the entire clinic population eligible for EAC with a repeat viral load at all evaluation sites (n = 934), intervention sites showed a small increase in 3-month resuppression (28% vs. 25%, RD 3.0%; 95%CI: -2.7% to 8.8%). Adjusting for baseline differences increased the RD to 8.1% (95% CI: -0.1% to 17.2%). However, we found no differences in 12-month suppression (RD: 1.5%; 95% CI: -14.1% to 17.1% but suppression was low overall at 40%) or retention (RD: 2.8%; 95% CI: -7.5% to 13.2%). For TRIC, we enrolled 155 at intervention sites and 248 at control sites (44%40 years, 67% female, median CD4 count 212 cells/μl). We found no difference between groups in return to care by 12 months (RD: -6.8%; 95% CI: -17.7% to 4.8%). During the study period, control sites continued to use tracing within standard care, however, potentially masking intervention effects.Enhanced adherence counselling showed no benefit over 12 months. Implementation of the tracing intervention under the new guidelines was similar to the standard of care. Interventions that aim to return unstable patients to care should incorporate active monitoring to determine if the interventions are effective.

Singultus or hiccups (HU) is a common, usually temporary, event. Its potentially serious consequences are often overlooked. This review explores published evidence describing HU burden (clinical, economic, and quality of life [QoL] consequences) across patient populations. Literature review identified 81 articles (including 57 individual case reports). We extracted relevant information to better understand the burden of HU and to identify knowledge gaps for future study. HU are physiologic events that can complicate existing medical conditions and treatments regardless of duration. Relatively short episodes can have devastating consequences in patients who have pre-existing conditions. HU appear to impact physical and psychological health, diminish QoL, increase healthcare resource use, and increase costs. A better understanding of HU burden is needed.

The authors report a case of a premature male neonate born at 25.3 weeks gestational age weighing 605 grams with septo-optic dysplasia (SOD) and a heterozygous mutation in TUBA1A c.715A>C, a critical gene for microtubules, who developed asymmetric and aggressive posterior retinopathy of prematurity (ROP). This report presents a novel mutation associated with SOD and proposes that optic nerve hypoplasia may have potentiated a severe ROP phenotype. [ Ophthalmic Surg Lasers Imaging Retina . 2018;49:629–632.]

ObjectivesA new molecular test for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) (GeneXpert CT/NG) has been demonstrated to be as accurate as conventional nucleic acid amplification tests (NAAT), but performance has not been evaluated in routine primary care, performed at the point of care by clinicians. We aimed to examine its diagnostic performance when used by clinicians in remote community health services in Australia with high prevalences of CT and NG infection. The trial was registered with the Australian and New Zealand Clinical Trials Registry (#12613000808741)MethodsAt 12 health services, training was provided to 99 clinicians in the use of the GeneXpert CT/NG assay who tested specimens from all patients undergoing STI screening. Specimens were also sent in parallel for conventional laboratory-based NAATs and the concordance of results was evaluated.ResultsClinicians conducted 2486 tests: CT concordance was 99.4% (95% CI 99.1 to 99.7) with a positive concordance of 98.6% (95% CI 95.9 to 99.7) and negative concordance of 99.5% (95% CI 99.1 to 99.8); NG concordance was 99.9% (95% CI 99.7 to 100.0) with a positive concordance of 100.0% (95% CI 97.5 to 100.0) and negative concordance of 99.9% (95% CI 99.7 to 100.0).ConclusionsIn this first study reporting routine point-of-care use of GeneXpert CT/NG by primary care clinicians, we found excellent concordance with conventional NAATs. The use of the GeneXpert CT/NG at the point of care could potentially transform management and control of these infections in many endemic settings, including low/middle-income countries.

Background Cardiac resynchronization therapy (CRT) using biventricular pacing (BVP) is effective in patients with heart failure, bundle branch block (BBB), or right ventricular pacing. Permanent His-bundle pacing (HBP) has been reported as an alternative option for CRT. Objective The purpose of this study was to assess the feasibility and outcomes of HBP in CRT eligible or failed patients. Methods HBP was attempted as a rescue strategy in patients with failed left ventricular lead or nonresponse to BVP (group I), or as a primary strategy in patients with AV block, BBB, or high ventricular pacing burden as an alternative to BVP (group II) in patients with indications for CRT. Implant characteristics, New York Heart Association functional class, and echocardiographic data were assessed in follow-up. Results HBP was successful in 95 of 106 patients (90%): 30 in group I and 65 in group II. Mean age was 71 ± 12 years and 30% were female, with BBB in 45%, paced rhythm in 39%, and AV block in 16%. His capture and BBB correction thresholds were 1.4 ± 0.9 V and 2.0 ± 1.2 V at 1 ms, respectively. During mean follow-up of 14 months, both groups demonstrated significant narrowing of QRS from 157 ± 33 ms to 117 ± 18 ms (P = .0001), increase in left ventricular ejection fraction from 30% ± 10% to 43% ± 13% (P = .0001), and improvement in New York Heart Association functional class from 2.8 ± 0.5 to 1.8 ± 0.6 (P = .0001) with HBP. Lead-related complications occurred in 7 patients. Conclusion Permanent HBP is a promising alternative for CRT. HBP may be considered as a rescue strategy for failed BVP and may be a reasonable primary alternative to BVP for CRT.

Approximately 85% of tuberculosis (TB) related deaths occur in low- and middle-income countries where health resources are scarce. Effective priority setting is required to maximise the impact of limited budgets. The Optima TB tool has been developed to support analytical capacity and inform evidence-based priority setting processes for TB health benefits package design. This paper outlines the Optima TB framework and how it was applied in Belarus, an upper-middle income country in Eastern Europe with a relatively high burden of TB. Optima TB is a population-based disease transmission model, with programmatic cost functions and an optimisation algorithm. Modelled populations include age-differentiated general populations and higher-risk populations such as people living with HIV. Populations and prospective interventions are defined in consultation with local stakeholders. In partnership with the latter, demographic, epidemiological, programmatic, as well as cost and spending data for these populations and interventions are then collated. An optimisation analysis of TB spending was conducted in Belarus, using program objectives and constraints defined in collaboration with local stakeholders, which included experts, decision makers, funders and organisations involved in service delivery, support and technical assistance. These analyses show that it is possible to improve health impact by redistributing current TB spending in Belarus. Specifically, shifting funding from inpatient- to outpatient-focused care models, and from mass screening to active case finding strategies, could reduce TB prevalence and mortality by up to 45% and 50%, respectively, by 2035. In addition, an optimised allocation of TB spending could lead to a reduction in drug-resistant TB infections by 40% over this period. This would support progress towards national TB targets without additional financial resources. The case study in Belarus demonstrates how reallocations of spending across existing and new interventions could have a substantial impact on TB outcomes. This highlights the potential for Optima TB and similar modelling tools to support evidence-based priority setting., Author summary Tuberculosis (TB) remains a leading global cause of death and morbidity, and 85% of deaths occur in countries where resources for TB care and control are limited. Many countries cannot finance all TB interventions or technologies, which means difficult decisions on what to prioritise and publically finance. Modelling tools can help decision-makers set priorities based on evidence, in a systematic and transparent way. This study presents Optima TB, a tool that estimates which allocations of spending across interventions will most likely maximise specified objectives—such as minimising TB deaths, prevalence and incidence. In partnership with local decision-makers and stakeholders, Optima TB was applied in Belarus. Recommendations from the model findings include focussing investment on outpatient rather than inpatient care and actively finding people with TB (e.g. through contact tracing) rather than mass testing of the population. The recommended reallocations of spending could reduce TB prevalence and deaths by up to 45% and 50%, respectively, by 2035 for the same amount of spending. Key stakeholders were engaged throughout the analysis and findings and uncertainty around the results were clearly communicated with decision-makers. The timeliness of the results helped inform national dialogue on TB care reform, among other key policy discussions.

Potential Australian blood donors are deferred indefinitely if they report a history of injecting drug use (IDU), or for 12 months if they report having engaged in sexual activity with someone who might have ever injected. Given incremental improvements in blood safety, this study sought to examine whether Australia's IDU-related eligibility criteria reflected current scientific evidence, were consistent with international best practice and, if current IDU-related policies were to be changed, how this should happen.An expert committee was formed to review relevant literature with a focus on issues including: the epidemiology of IDU in Australia and key transfusion-transmissible infections (TTIs) among Australian people who inject drugs (PWID); and, 'non-compliance' among PWID regarding IDU-related blood donation guidelines. International policies relating to blood donation and IDU were also reviewed. Modelling with available data estimated the risk of TTIs remaining undetected if the Blood Service's IDU-related guidelines were changed.Very few (1%) Australians engage in IDU, and IDU risk practices are reported by only a minority of PWID. However, the prevalence of HCV remains high among PWID, and IDU remains a key transmission route for various TTIs. Insufficient data were available to inform appropriate estimates of cessation and relapse among Australian PWID. Modelling findings indicated that the risk of not detecting HIV becomes greater than the reference group at a threshold of non-admission of being an active PWID of around 1.8% (0.5-5.1%). Excluding Japan, all Organisation for the Economic Co-operation and Development member countries permanently exclude individuals with a history of IDU from donating.Numerous research gaps meant that the study's expert Review Committee was unable to recommend altering Australia's current IDU-related blood donation guidelines. However, having identified critical knowledge gaps and future areas of research, the review made important steps toward changing the criteria.

Background The high burden of malaria and limited funding means there is a necessity to maximize the allocative efficiency of malaria control programmes. Quantitative tools are urgently needed to guide budget allocation decisions. Methods A geospatial epidemic model was coupled with costing data and an optimization algorithm to estimate the optimal allocation of budgeted and projected funds across all malaria intervention approaches. Interventions included long-lasting insecticide-treated nets (LLINs), indoor residual spraying (IRS), intermittent presumptive treatment during pregnancy (IPTp), seasonal mass chemoprevention in children (SMC), larval source management (LSM), mass drug administration (MDA), and behavioural change communication (BCC). The model was applied to six geopolitical regions of Nigeria in isolation and also the nation as a whole to minimize incidence and malaria-attributable mortality. Results Allocative efficiency gains could avert approximately 84,000 deaths or 15.7 million cases of malaria in Nigeria over 5 years. With an additional US$300 million available, approximately 134,000 deaths or 37.3 million cases of malaria could be prevented over 5 years. Priority funding should go to LLINs, IPTp and BCC programmes, and SMC should be expanded in seasonal areas. To minimize mortality, treatment expansion is critical and prioritized over some LLIN funding, while to minimize incidence, LLIN funding remained a priority. For areas with lower rainfall, LSM is prioritized over IRS but MDA is not recommended unless all other programmes are established. Conclusions Substantial reductions in malaria morbidity and mortality can be made by optimal targeting of investments to the right malaria interventions in the right areas. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-2019-1) contains supplementary material, which is available to authorized users.

BACKGROUND AND OBJECTIVE: To report the visual and anatomical outcomes and microbiologic spectrum of culture-positive endophthalmitis in open globe injuries (OGIs) with or without intraocular foreign bodies (IOFBs). PATIENTS AND METHODS: A retrospective, interventional case series of OGIs (n = 718) treated between 2004 and 2015. Patients underwent a management protocol for OGI, including systemic broad-spectrum antibiotics, on presentation. RESULTS: Culture-positive cases of endophthalmitis after open globe repair occurred in 2.1% of eyes (n = 15 of 718 eyes); two eyes had evidence of endophthalmitis on presentation. The most common organism was Staphylococcus species (five of 17 eyes). An IOFB was present in 6.8% of eyes (n = 49 of 718 eyes). All of these eyes received prophylactic intravitreal antimicrobials. In eyes with IOFB, the rate of culture-positive endophthalmitis after initial globe repair was 8.1% (n = 4 of 49 eyes) versus 1.6% (n = 11 of 669 eyes) in eyes without IOFB ( P < .01). CONCLUSION: Culture-positive endophthalmitis was identified after OGIs more often in eyes with a concurrent IOFB. [ Ophthalmic Surg Lasers Imaging Retina . 2017;48:632–637.]

Purpose: In this era of rising antimicrobial resistance, slowly refilling antibiotic development pipelines, and an aging population, we need to ensure that randomized clinical trials (RCTs) determine the added benefit of new antibiotic agents effectively and in a valid way, especially for severely ill patients. Unfortunately, universally accepted endpoints for the evaluation of new drugs in severe infections are lacking. Methods: We review and discuss the current practices and challenges regarding endpoints in RCTs in this field and propose novel approaches. Results: Usual endpoints actually recommended for drug development suffer from important flaws. Mortality requires large sample size and only partly related to the infectious process. Clinical cure rate is highly subjective in critically ill patients where symptoms may be related to other intercurrent events. Currently, composite endpoints, hierarchical nested designs, and competing risks analysis seem to be the most promising new tools for designing and analyzing clinical trials in this area, although they require further validation. Conclusion: Regulatory authorities, pharmaceutical companies, and clinicians need to agree on the most appropriate clinical endpoints for severe infections to ensure efficient approval of new, effective antibiotic agents.

The present study was initiated to investigate levels and predictors of wellbeing among inhabitants of intentional communities (ICs). An anonymous, Internet-based questionnaire was distributed to US and Canadian ICs. Responses were obtained from 913 members. Wellbeing was measured by the widely used satisfaction with life scale (SWLS). Hierarchical linear regression analyses were run to test the predictive validity of Social support, Identity fusion, Meaning in life, Community satisfaction and Life change, and Religious activity above and beyond demographic variables and personality traits. Mean scores on the SWLS were estimated to 5.27 and 5.47 (1–7 scale) for men and women, respectively. The full model explained 41.4% of the variance for men and 38.2% for women. Personality explained 13.4 (men) and 14.4% (women) of the variation, while demographic variables only had a minor impact. Overall, presence of Meaning in life and Social support were the most important predictors. The IC inhabitants reported wellbeing on par with the highest scores previously published. The findings support the contention that sustainability, in the form of a communal lifestyle of low ecological footprint, may be promoted without forfeiting wellbeing.

AIDS was first publicly reported on 5th June 1981 in the Morbidity and Mortality Weekly Report(MMWR) of the US Centers for Disease Control (CDC). Doctors in New York and San Francisco wereseeing clusters of previously extremely rare diseases such as pneumocystis carinii, and Kaposi’s sarcoma. These infections manifested in exceptionally serious forms, initially, within a narrowly defined riskgroup—young, homosexual men, and lead to death with a short period. Soon it was clear these illnesseswere occurring in other definable groups: haemophiliacs, blood transfusion recipients, and injecting drug users (IDUs). By 1982 cases were seen in the partners and infants of those infected. This reports of cases from Europe, Australia, New Zealand, a number of African countries, Brazil, and Mexico. In Zambia a significant rise in cases of Kaposi’s sarcoma was recorded. In Kinshasa, Zaire there was an upsurge in patients with cryptococcosis, an unusual fungal infection. The Ugandan Ministry of Health was receiving reports of increased and unexpected deaths among young people in Lake Victoria fishing villages. The name ‘Acquired Immunodeficiency Syndrome’ (AIDS) was agreed in Washington in July 1982. Even when the syndrome had been identified and named it was not clear what its cause was, how it spread, and what treatments could be developed. In 1983 the virus was identified by the Institute Pasteur in France and called ‘Lymphadenopathy-Associated Virus’ or LAV. In 1987 the name ‘Human Immunodeficiency Virus’ (HIV) was confirmed by the International Committee on Taxonomy of Viruses. The author warned of the potential devastation AIDS would wreak across Africa, but this went unheard. their watched with dismay as colleagues and friends sickened and died, and the political leaders initially ignored what was to come. In this editorial authors look at the best of times – where things went well; and the worst of times – where the challenges lie.

Background Health resources are limited, which means spending should be focused on the people, places and programs that matter most. Choosing the mix of programs to maximize a health outcome is termed allocative efficiency. Here, we extend the methodology of allocative efficiency to answer the question of how resources should be distributed among different geographic regions. Methods We describe a novel geographical optimization algorithm, which has been implemented as an extension to the Optima HIV model. This algorithm identifies an optimal funding of services and programs across regions, such as multiple countries or multiple districts within a country. The algorithm consists of three steps: (1) calibrating the model to each region, (2) determining the optimal allocation for each region across a range of different budget levels, and (3) finding the budget level in each region that minimizes the outcome (such as reducing new HIV infections and/or HIV-related deaths), subject to the constraint of fixed total budget across all regions. As a case study, we applied this method to determine an illustrative allocation of HIV program funding across three representative oblasts (regions) in Ukraine (Mykolayiv, Poltava, and Zhytomyr) to minimize the number of new HIV infections. Results Geographical optimization was found to identify solutions with better outcomes than would be possible by considering region-specific allocations alone. In the case of Ukraine, prior to optimization (i.e. with status quo spending), a total of 244,000 HIV-related disability-adjusted life years (DALYs) were estimated to occur from 2016 to 2030 across the three oblasts. With optimization within (but not between) oblasts, this was estimated to be reduced to 181,000. With geographical optimization (i.e., allowing reallocation of funds between oblasts), this was estimated to be further reduced to 173,000. Conclusions With the increasing availability of region- and even facility-level data, geographical optimization is likely to play an increasingly important role in health economic decision making. Although the largest gains are typically due to reallocating resources to the most effective interventions, especially treatment, further gains can be achieved by optimally reallocating resources between regions. Finally, the methods described here are not restricted to geographical optimization, and can be applied to other problems where competing resources need to be allocated with constraints, such as between diseases.

Introduction In response to suboptimal adherence and retention, South Africa’s National Department of Health developed and implemented National Adherence Guidelines for Chronic Diseases. We evaluated the effect of a package of adherence interventions beginning in January 2016 and report on the impact of Fast‐Track Treatment Initiation Counselling (FTIC) on ART initiation, adherence and retention. Methods We conducted a cluster‐randomized mixed‐methods evaluation in 4 provinces at 12 intervention sites which implemented FTIC and 12 control facilities providing standard of care. Follow‐up was by passive surveillance using clinical records. We included data on subjects eligible for FTIC between 08 Jan 2016 and 07 December 2016. We adjusted for pre‐intervention differences using difference‐in‐differences (DiD) analyses controlling for site‐level clustering. Results We enrolled 362 intervention and 368 control arm patients. Thirty‐day ART initiation was 83% in the intervention and 82% in the control arm (RD 0.5%; 95% CI: −5.0% to 6.0%). After adjusting for baseline ART initiation differences and covariates using DiD we found a 6% increase in ART initiation associated with FTIC (RD 6.3%; 95% CI: −0.6% to 13.3%). We found a small decrease in viral suppression within 18 months (RD −2.8%; 95% CI: −9.8% to 4.2%) with no difference after adjustment (RD: −1.9%; 95% CI: −9.1% to 5.4%) or when considering only those with a viral load recorded (84% intervention vs. 86% control). We found reduced crude 6‐month retention in intervention sites (RD −7.2%; 95% CI: −14.0% to −0.4%). However, differences attenuated by 12 months (RD: −3.6%; 95% CI: −11.1% to 3.9%). Qualitative data showed FTIC counselling was perceived as beneficial by patients and providers. Conclusions We saw a short‐term ART‐initiation benefit to FTIC (particularly in districts where initiation prior to intervention was lower), with no reductions but also no improvement in longer‐term retention and viral suppression. This may be due to lack of fidelity to implementation and delivery of those components that support retention and adherence. FTIC must continue to be implemented alongside other interventions to achieve the 90‐90‐90 cascade and fidelity to post‐initiation counselling sessions must be monitored to determine impact on longer‐term outcomes. Understanding the cost‐benefit and role of FTIC may then be warranted.

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.