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Magnetic resonance-guided focused ultrasound (MRgFUS) is being increasingly utilized in the treatment of movement disorders such as essential tremor (ET) and Parkinson's disease (PD). Whilst skull density ratio (SDR) has previously been correlated with achieving lesional temperature rises, other patient factors such as brain and cerebrospinal fluid (CSF) volume have not previously been investigated. We aimed to investigate the effect of brain and CSF volumes on lesional temperature rises, as well as the effect of brain and CSF volumes and SDR on post-treatment lesion sizes. Fifty-four consecutive patients were studied with patient and treatment-related variables collected along with post-treatment lesion sizes. Linear regression analysis identified that SDR alone was associated with lesional temperatures. Both SDR and brain atrophy were associated with post-treatment lesion sizes on linear regression analysis. On multiple linear regression analysis SDR was significantly associated with post-treatment lesion size, and the association between brain atrophy and lesion sizes approached significance, a finding that warrants further investigation.

Lung cancer is the leading cancer according to the World Health Organization (WHO), resulting in highest death rate worldwide due to the high level of metastasis. Hence, the drugs that protect from metastasis either as an adjuvant or a primary therapeutic agent may help to reduce the death rate. In this study, All Trans Retinoic Acid (ATRA) was tested for its action against metastatic lodging of B16F10 melanoma cells in the lung and liver of the C57BL/6 mouse model. Serum, lung and liver were evaluated biochemically for the cancer associated changes. Metastatic cancer development was confirmed by tumor nodule formation and histopathological analysis. RAR-β protein expression was analyzed by immunohistochemistry and histopathology. ATRA treated mice showed a percentage of inhibition on metastatic tumor growth in lung and liver and a corresponding protection against pathological changes in these organs. Cholesterol and γ-Glutamyl Transferase (GGT) levels found in cancer induced mice were reduced in the ATRA treated group. As compared to the normal group, lung tissue from cell line induced cancer control group had less RAR-β protein expression while the ATRA treated group showed enhanced RAR-β protein expression. This indicates that the anti-metastasis effects of ATRA might have shown the induction of RAR-β expression and subsequent molecular signaling pathways to regulate the homeostasis of biochemical changes. This study demonstrated the capability of ATRA to prevent the establishment of metastasis by the melanoma cell line into the lung and liver of experimental mice.

Extreme work environments are inherently stressful and involve challenging working and living conditions. In contexts ranging from space exploration to disaster response, people must sustain performance under pressure, and function with limited resources. In this paper we develop the concept of endurance for extreme work environments, which we define as the capacity to sustain performance at high levels for safe and effective operations over extended durations (e.g., a mission, operation, deployment, or expedition). We integrate diverse streams of literature (e.g., work stress, recovery, and sleep) to describe endurance in terms of short- and long-term energy management processes as individuals interact with their work-life system (i.e. work, non-work, and sleep environment). We conclude with theoretical and practical implications for a better understanding of endurance, such as considering multiple time perspectives, and the role that researchers, practitioners, and organizations can play in optimizing endurance in the field.

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.

Background The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP – fremanezumab, galcanezumab and eptinezumab – and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature. Methods To gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays. Results Erenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY1 receptor, a CGRP receptor family member. Both erenumab and telcagepant antagonized amylin-induced cAMP signaling at the AMY1 receptor while fremanezumab did not affect amylin responses. Conclusion The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.

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.

Major gains in reducing the burden of hepatitis C are now possible because of the discovery of a cure. The prevention of premature deaths and increased workforce participation among people who are cured are likely to provide substantial indirect economic benefits. We developed an investment case for hepatitis C for the six WHO world regions, which, to our knowledge, is the first to consider both indirect and direct economic benefits in this context. Scaling up of testing and treatment to reach the 2030 WHO hepatitis C elimination targets was estimated to prevent 2·1 million (95% credible interval 1·3-3·2 million) hepatitis C-related deaths and 10 million (4-14 million) new hepatitis C virus infections globally between 2018 and 2030. This elimination strategy was estimated to cost US$41·5 billion (33·1-48·7 billion) in testing, treatment, and health care between 2018 and 2030 ($23·4 billion more than the status quo scenario of no testing or treatment scale up), with a global average of $885 (654-1189) per disability-adjusted life-year averted at 2030. Compared with the status quo scenario, the elimination scenario generated $46·1 billion (35·9-53·8 billion) in cumulative productivity gains by 2030. These indirect costs made elimination cost-saving by 2027, with a net economic benefit of $22·7 billion (17·1-27·9 billion) by 2030. This model shows that countries might be underestimating the true burden of hepatitis C and will benefit from investing in elimination.

Purpose This paper aims to explore the reasons for and the subsequent longer-term impact of the closure of the Barlinnie Special Unit (BSU). Design/methodology/approach The paper is both descriptive, providing an overview of the work of the BSU, and conceptual in that it argues that the limits of “prisoner rehabilitation” are observed in the closure of the BSU, which sounds a warning for other penal therapeutic communities and what it means to operate effectively. Findings The BSU which assisted long-term, difficult and violent prisoners moderate their prison behaviour and then to live non-offending lives, lost the confidence of government ministers and officials, as well as senior prison managers and, seemingly, the public, so closed after being in operation for 21 years. The impact of this has been that the Scottish Prison Service has not introduced, or attempted to introduce, a similar regime for managing and treating violent and disruptive prisoners. Practical implications There are important lessons to be learned from the BSU experience for all who manage and work in specialist, prison therapeutic units or within prison therapeutic regimes. This includes balancing the therapeutic elements of the regime, which may involve engaging in practices which are outside the norm for custodial establishments, with those establishments’ security and operational requirements, so as to not to create a disconnect between addressing offending behaviour and maintaining expected standards of wider prison conduct. Originality/value While there have been previous evaluations of the BSU, the longer-term impact has neither been previously considered and nor has the unit’s closure been considered from a penal philosophical perspective.

Although controversial, due to its reported effectiveness in attenuating bleeding associated with exercise-induced pulmonary hemorrhage (EIPH), furosemide is currently a permitted race day medication in most North American racing jurisdictions. The objective of this study was to assess the efficacy of furosemide in reducing the presence and severity of EIPH when administered 24 hr prior to strenuous treadmill exercise. Eight exercised Thoroughbred horses received saline or 250 mg of furosemide either 4 or 24 hr prior to high-speed treadmill exercise in a balanced 3-way cross-over design. Blood samples were collected for determination of furosemide, lactate, hemoglobin, blood gas, and electrolyte concentrations. Heart rate and pulmonary arterial pressure were measured throughout the run and endoscopic examination and bronchoalveolar lavage (BAL) performed. Horses were assigned an EIPH score and the number of red blood cells in BAL fluid determined. Although not significantly different, endoscopic EIPH scores were lower in the 4-hr versus the 24-hr and saline groups. RBC counts were not significantly different between the treatment groups. Pulmonary arterial pressures were significantly increased at higher speeds; however, there were no significant differences between dose groups when controlling for speed. A small sample size and unknown bleeding history warrant a larger-scale study.

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 Despite the crucial role of educators in encourage students' academic learning, addressing educator stress inside the classroom remains a significant challenge in the educational context. Mindfulness Meditation training (MM) has been recommended as an environmental enrichment strategy in schools to help teachers cope with stress and cultivating a state of awareness in daily life. Although studies have shown that MM can improve immune system dynamics the biological mechanism underlying glutathione metabolism in a healthy human is unclear Objective The purpose of this study was to determine whether MM training benefits psychological and behavioral response, immunological functions and glutathione metabolism in service healthy female teachers from public schools Methods We randomly assigned 76 teachers to an 8-week Mindfulness-Based Health Program for Educators (MBHPEduca) or Neuroscience for Education program (Neuro-Educa; active control group). Using the quality of life as our primary outcome, perceived stress, negative affectivity, and resilience as our secondary outcome, and pro-inflammatory cytokines and glutathione levels as our third outcome at baseline and post-intervention that occurred in public schools. Blood samples were collected for the measurement of three proinflammatory markers, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) and three GSH metabolism, including Cysteine (Cys), Homocysteine (HCys) and GSH were conducted at pre-and post-intervention, with selfreported assessments over time. Treatment effects were analyzed using generalized estimating equations (GEE) with to intention to treat Results We observed statistically significant improvements to the MBHP-Educa group compared to active control in perceived stress, resilience, positive and negative affect, and quality of life after 8-weeks MM (p ​, Highlights • Mindfulness training enhanced resilience and decreased teachers' perceived stress. • Mindfulness training enhanced teachers' perception in all aspects of quality of life. • Mindfulness training increased glutathione plasma levels and decreased teachers' IL-6 serum levels.

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.

Humans increasingly use automated decision aids. However, environmental uncertainty means that automated advice can be incorrect, creating the potential for humans to act on incorrect advice or to disregard correct advice. We present a quantitative model of the cognitive process by which humans use automation when deciding whether aircraft would violate requirements for minimum separation. The model closely fitted the performance of 24 participants, who each made 2,400 conflict-detection decisions (conflict vs. nonconflict), either manually (with no assistance) or with the assistance of 90% reliable automation. When the decision aid was correct, conflict-detection accuracy improved, but when the decision aid was incorrect, accuracy and response time were impaired. The model indicated that participants integrated advice into their decision process by inhibiting evidence accumulation toward the task response that was incongruent with that advice, thereby ensuring that decisions could not be made solely on automated advice without first sampling information from the task environment.

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...

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.

A substantial number of changes to the composition of the herpetofauna of the Mexican state of Oaxaca, including taxonomic additions and deletions, have occurred in the five years since our original assessment of this region. These changes now establish a herpetofauna of 480 species for the state. A number of taxonomic and nomenclatural changes involving the Oaxacan herpetofauna also are discussed. Updated patterns of physiographic distribution, endemism, and conservation status of the members of the state herpetofauna are examined.

Summary Background Hepatitis C elimination may be possible with broad uptake of direct-acting antiviral treatments (DAAs). In 2016 the Australian government committed A$1.2 billion for five years of unlimited DAAs (March 2016 to February 2021) in a risk-sharing agreement with pharmaceutical companies. We assess the impact, cost-effectiveness and net economic benefits likely to be realised from this investment. Methods Mathematical modelling to project outcomes for 2016-2030 included: (S1) a counter-factual scenario (testing/treatment maintained at pre-2016 levels); (S2) the current status-quo (testing/treatment as actually occurred 2016-2019, with trends maintained to 2030); and (S3) elimination scenario (S2 plus testing/treatment rates increased between 2021-2030 to achieve the WHO elimination targets). Findings S1 resulted in 68,800 new hepatitis C infections and 18,540 hepatitis C-related deaths over 2016-2030. The total health system cost (HCV testing, treatment, disease management) was A$3.01 billion and the cost of lost productivity due to absenteeism, presenteeism and premature deaths was A$26.14 billion. S2 averted 15,700 (23%) new infections and 8,500 (46%) deaths by 2030, with a total health system cost of A$3.48 billion, A$472 million more than S1 (A$1.65 billion more in testing/treatment but A$1.20 billion less in disease costs; A$5,752 per QALY gained from a health systems perspective). Productivity loss over 2016-2030 was A$19.96 billion, A$6.17 less than S1, making S2 cost-saving from a societal perspective by 2022 with a net economic benefit of A$5.70 billion by 2030. S3 averted an additional 10,000 infections and 930 deaths compared with S2 and increased the longer-term economic benefit. Interpretation Five years of unrestricted access to DAAs in Australia has led to significant health benefits and is likely to become cost-saving from a societal perspective by 2022. Funding Burnet Institute

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.

PurposeThe purpose of this study was to elucidate the association between helminth infections, dietary parameters and cognitive performance, as well as the predictors of undernutrition among school-age children (SAC) living in helminth-endemic fishing and farming communities in Ghana.Design/methodology/approachThis was a cross sectional study involving 164 (9 to 12 years old) SAC from fishing (n = 84) and farming (n = 80) communities of the Kwahu Afram Plains South District of the Eastern Region of Ghana, using structured questionnaires and anthropometric and biochemical assessments.FindingsOverall, 51.2% of the children were males, with no significant gender difference between the communities (p = 0.88). Average age of the children was 10.5 ± 1.25 years, with no significant difference between the farming and fishing communities (p = 0.90). About 53.1% of all children were anemic, with no significant differences between farming versus fishing communities (p = 0.87). Helminth-infected children were significantly anemic (p = 0.03). Mean serum zinc level of all children was 13.1 ± 4.57 µmol/L, with zinc deficiency being significantly higher in children in the farming community (p p = 0.001) and girls (p = 0.117). There was no significant difference in the Raven’s Colored Progressive Matrices cognitive test scores between the two communities (p = 0.79). Predictors of anemia were helminthiasis and pica behavior.Originality/valueThese findings are relevant and have the prospect of guiding the development of intervention programs in addressing the persistent problem of nutritional and cognitive deficits among SAC.

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.

Acute management of a severely burned patient is an infrequent and stressful situation that requires medical knowledge as well as immediate coordinated action. Many adverse events in health care result from issues related to the application of 'non-technical' skills such as communication, teamwork, leadership and decision making rather than lack of medical knowledge. Training in these skills is known as Crisis Resource Management (CRM) training. In order to create well-prepared burn teams, it is critical to teach CRM principles through high-fidelity simulation (HFS). While CRM teaches foundational non-technical skills, HFS incorporates lifelike, whole-body, fully-responsive mannequins in order to provide a realistic emergency situation. The aim of the study is to describe the development of a novel high-fidelity simulation course called "SIMBurns: High Fidelity Simulation Program for Emergency Burn Management" that uses CRM as its foundation and is focused on management of burn injuries. The course was designed by a panel of simulation and burns experts from Meyer Children's Hospital in Italy and Birmingham Children's Hospital in the U.K. Simulation Program experts were certified by Boston Children's Hospital's Simulation Program. In this paper, we describe the course's design, development, structure, and participant's assessment of the course. Since the creation of the SIMBurns course in 2013, 9 courses have been conducted and 101 participants have attended the course. The course was well-received and its "Overall Satisfaction" was rated at 4.8/5. The primary objective in the SIMBurns course - to teach teamwork and CRM skills to medical staff involved in emergency burn care - was also met at 4.8/5. Participants felt that the course developed their ability to interact with other team members, further improved their understanding of how to appropriately use resources, emphasized the importance of role clarity and developed their communication skills. Additional quantitative and qualitative analyses obtained from participants were also reviewed after each course. The SIMBurns course aims to contribute to the education of those in healthcare in order to improve patient safety and to continue advancing the education of our emergency burn care teams.

BackgroundWe previously observed that the nine-member family of autotransported polymorphic membrane proteins (Pmps) ofChlamydia trachomatisis variably expressed in cell culture. Additionally,C. trachomatis-infected patients display variable Pmp-specific serum antibody profiles indirectly suggesting expression of unique Pmp profiles is an adaptive response to host-specific stimuli during infection. Here, we propose that the host response to Pmps and other outer surface proteins may correlate with disease severity.MethodsThis study tests this hypothesis using an ELISA that measures serum IgG antibodies specific for the nineC. trachomatisPmp subtypes and four immunodominant antigens (MOMP, OmcB, GroEL, ClpP) in 265 participants of theChlamydiaAdolescent/Young Adult Reproductive Management (CHARM) cohort.ResultsMoreC. trachomatis-infected females displayed high Pmp-specific antibody levels (cut-off Indexes) than males (35.9-40.7% of femalesvs. 24.2-30.0% of males), with statistical significance for PmpC, F and H (PC. trachomatis-infected females with a clinical diagnosis of pelvic inflammatory disease (PID) and those without. However, a statistically significant association between high levels of OmcB-specific antibody and a PID diagnosis (PConclusionsUsing antibody levels as an indirect measure of antigen expression, our results suggest that gender- and/or site-specific (cervix in femalesvs. urethra in males) stimuli controlpmpexpression in infected patients. They also support the possible existence of immune biomarkers of chlamydial infection associated with disease and underline the need for high resolution screening in human serum.

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

Mapping-by-sequencing strategies combine next-generation sequencing (NGS) with classical linkage analysis, allowing rapid identification of the causal mutations of the phenotypes exhibited by mutants isolated in a genetic screen. Computer programs that analyze NGS data obtained from a mapping population of individuals derived from a mutant of interest to identify a causal mutation are available; however, the installation and usage of such programs requires bioinformatic skills, modifying or combining pieces of existing software, or purchasing licenses. To ease this process, we developed Easymap, an open-source program that simplifies the data analysis workflows from raw NGS reads to candidate mutations. Easymap can perform bulked segregant mapping of point mutations induced by ethyl methanesulfonate (EMS) with DNA-seq or RNA-seq datasets, as well as tagged-sequence mapping for large insertions, such as transposons or T-DNAs. The mapping analyses implemented in Easymap have been validated with experimental and simulated datasets from different plant and animal model species. Easymap was designed to be accessible to all users regardless of their bioinformatics skills by implementing a user-friendly graphical interface, a simple universal installation script, and detailed mapping reports, including informative images and complementary data for assessment of the mapping results. Easymap is available at http://genetics.edu.umh.es/resources/easymap; its Quickstart Installation Guide details the recommended procedure for installation.

Summary Background Most studies assessing the HIV care cascade have typically been cross-sectional analyses, which do not capture the transition time to subsequent stages. We aimed to assess the longitudinal HIV cascade of care in Australia, and changes over time in transition times and associated factors. Methods In this longitudinal cohort study, we included linked data for gay and bisexual men (GBM) with a new HIV diagnosis who attended clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance in New South Wales and Victoria between Jan 1, 2012, and Dec 31, 2019. We assessed three cascade transition periods: diagnosis to linkage to care (stage 1 transition); linkage to care to antiretroviral therapy (ART) initiation (stage 2 transition); and ART initiation to virological suppression (viral load ≤200 copies per mL; stage 3 transition). We also calculated the probability of remaining virologically suppressed after the first recorded viral load of less than 200 copies per mL. We used the Kaplan-Meier method to estimate transition times and cumulative probability of stage transition. Findings We included 2196 GBM newly diagnosed with HIV between 2012 and 2019 contributing 6747 person-years of follow-up in our analysis. Median time from HIV diagnosis to linkage to care (stage 1 transition) was 2 days (IQR 1–3). Median time from linkage to care to ART initiation (stage 2 transition) was 33 days (30–35). Median time from ART initiation to first recorded virological suppression (stage 3 transition) was 49 days (47–52). The cumulative probability of ART initiation within 90 days of linkage to care increased from 36·9% (95% CI 32·9–40·6) in the 2012–13 calendar period to 94·1% (91·2–96·0) in the 2018–19 calendar period and cumulative probability of virological suppression within 90 days of ART initiation increased from 54·3% (48·8–59·3) in the 2012–13 calendar period to 82·9% (78·4–86·4) in the 2018–19 calendar period. 91·6% (90·1–93·1) of GBM remained virologically supressed up to 2 years after their first recorded virological suppression event. Interpretation In countries with high cross-sectional cascade estimates such as Australia, the impact of treatment as prevention is better estimated using longitudinal cascade analyses. Funding National Health and Medical Research Council Australia.

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.

Background Countries are increasingly defining health benefits packages (HBPs) as a way of progressing towards Universal Health Coverage (UHC). Resources for health are commonly constrained, so it is imperative to allocate funds as efficiently as possible. We conducted allocative efficiency analyses using the Health Interventions Prioritization tool (HIPtool) to estimate the cost and impact of potential HBPs in three countries. These analyses explore the usefulness of allocative efficiency analysis and HIPtool in particular, in contributing to priority setting discussions. Methods and findings HIPtool is an open-access and open-source allocative efficiency modelling tool. It is preloaded with publicly available data, including data on the 218 cost-effective interventions comprising the Essential UHC package identified in the 3rd Edition of Disease Control Priorities, and global burden of disease data from the Institute for Health Metrics and Evaluation. For these analyses, the data were adapted to the health systems of Armenia, Côte d’Ivoire and Zimbabwe. Local data replaced global data where possible. Optimized resource allocations were then estimated using the optimization algorithm. In Armenia, optimized spending on UHC interventions could avert 26% more disability-adjusted life years (DALYs), but even highly cost-effective interventions are not funded without an increase in the current health budget. In Côte d’Ivoire, surgical interventions, maternal and child health and health promotion interventions are scaled up under optimized spending with an estimated 22% increase in DALYs averted–mostly at the primary care level. In Zimbabwe, the estimated gain was even higher at 49% of additional DALYs averted through optimized spending. Conclusions HIPtool applications can assist discussions around spending prioritization, HBP design and primary health care transformation. The analyses provided actionable policy recommendations regarding spending allocations across specific delivery platforms, disease programs and interventions. Resource constraints exacerbated by the COVID-19 pandemic increase the need for formal planning of resource allocation to maximize health benefits.

This chapter will focus on the following areas which are GDPR, data breaches, digital identity theft, and digital identity schemes. The chapter will explore each subject in detail and then examine the correlation between the four whereby cybersecurity is deemed to be the common factor. Whilst there have been numerous studies on each subject in silo, this study presents the first unique opportunity to correlate the four post GDPR. Furthermore the study sets out to understand the effectiveness of cybersecurity controls of organisations that provision services in this era, whereby a survey has correlated professionals’ attitudes to GDPR compliance and good cybersecurity practice. The study aims to influence investment decisions of executive boards with regard to their investment spend on cyber defences through the introduction of an OKR framework to effect cyber effective defences in the GDPR era.

Advances in remote sensing technology have led to the capture of massive amounts of data. Increased image resolution, more frequent revisit times, and additional spectral channels have created an explosion in the amount of data that is available to provide analyses and intelligence across domains, including agriculture. However, the processing of this data comes with a cost in terms of computation time and money, both of which must be considered when the goal of an algorithm is to provide real-time intelligence to improve efficiencies. Specifically, we seek to identify nutrient deficient areas from remotely sensed data to alert farmers to regions that require attention; detection of nutrient deficient areas is a key task in precision agriculture as farmers must quickly respond to struggling areas to protect their harvests. Past methods have focused on pixel-level classification (i.e. semantic segmentation) of the field to achieve these tasks, often using deep learning models with tens-of-millions of parameters. In contrast, we propose a much lighter graph-based method to perform node-based classification. We first use Simple Linear Iterative Cluster (SLIC) to produce superpixels across the field. Then, to perform segmentation across the non-Euclidean domain of superpixels, we lever-age a Graph Convolutional Neural Network (GCN). This model has 4-orders-of-magnitude fewer parameters than a CNN model and trains in a matter of minutes.

Objectives Evidence-informed priority setting, in particular cost-effectiveness analysis (CEA), can help target resources better to achieve universal health coverage. Central to the application of CEA is the use of a cost-effectiveness threshold. We add to the literature by looking at what thresholds have been used in published CEA and the proportion of interventions found to be cost-effective, by type of threshold. Methods We identified CEA studies in low- and middle-income countries from the Global Health Cost-Effectiveness Analysis Registry that were published between January 1, 2015, and January 6, 2020. We extracted data on the country of focus, type of interventions under consideration, funder, threshold used, and recommendations. Results A total of 230 studies with a total 713 interventions were included in this review; 1 to 3× gross domestic product (GDP) per capita was the most common type of threshold used in judging cost-effectiveness (84.3%). Approximately a third of studies (34.2%) using 1 to 3× GDP per capita applied a threshold at 3× GDP per capita. We have found that no study used locally developed thresholds. We found that 79.3% of interventions received a recommendation as “cost-effective” and that 85.9% of studies had at least 1 intervention that was considered cost-effective. The use of 1 to 3× GDP per capita led to a higher proportion of study interventions being judged as cost-effective compared with other types of thresholds. Conclusions Despite the wide concerns about the use of 1 to 3× GDP per capita, this threshold is still widely used in the literature. Using this threshold leads to more interventions being recommended as “cost-effective.” This study further explore alternatives to the 1 to 3× GDP as a decision rule.

Mobile application (app) platforms have the potential to advance sexual and reproductive health (SRH). Yet there is a dearth of knowledge regarding global perspectives from healthcare providers on how SRH mobile apps are being leveraged in their healthcare practice. In 2019 the World Health Organization (WHO) developed a consolidated guideline on self-care interventions for SRH. To inform this guideline, we conducted a global values and preferences survey. This study aimed to (a) understand the awareness, access, and uptake of SRH mobile apps; (b) examine how many healthcare provider (HCP) participants provided linkages, referrals and information to clients regarding SRH mobile apps; and (c) among HCP, assess how many felt confident and informed regarding SRH mobile apps. We hosted a cross-sectional web-based survey on the WHO Department of Reproductive Health and Research website and shared the survey with SRHR listservs. There were 825 survey participants, 360 whom identified as healthcare providers (HCP). Approximately one-third of HCP participants had provided a referral/information to their clients about sexual or reproductive health apps. While 40.8% of HCP felt confident and informed about sexual health apps, half (47.4%) reported needing more information, and 15.6% expressed interest in receiving training to use in practice. While 42.6% of HCPs felt confident and informed about reproductive health apps, 45.7% needed more information, and 15.1% were interested in further training. There was also an open-ended question for HCP to share their thoughts about self-care SRH interventions. Specifically regarding SRH apps, HCP responses revealed the importance of considering: (a) security and confidentiality; (b) potential benefits of SRH apps for underserved groups (i.e. youth, rural communities); (c) community engagement; (d) health benefits; and (e) and online training for HCP on SRH mobile apps. Findings signal interest and opportunities for training and engaging HCP in using mobile apps to advance SRH.

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.

Crop monitoring and yield prediction are central to management decisions for farmers. One key task is counting the number of kernels on an ear of corn to estimate yield in a field. As ears of corn can easily have 400–900 kernels, manual counting is unrealistic; traditionally, growers have approximated the number of kernels on an ear of corn through a mixture of counting and estimation. With the success of deep learning, these human estimates can now be replaced with more accurate machine learning models, many of which are efficient enough to run on a mobile device. Although a conceptually simple task, the counting and localization of hundreds of instances in an image is challenging for many image detection algorithms which struggle when objects are small in size and large in number. We compare different detection-based frameworks, Faster R-CNN, YOLO, and density-estimation approaches for on-ear corn kernel counting and localization. In addition to the YOLOv5 model which is accurate and edge-deployable, our density-estimation approach produces high-quality results, is lightweight enough for edge deployment, and maintains its computational efficiency independent of the number of kernels in the image. Additionally, we seek to standardize and broaden this line of work through the release of a challenging dataset with high-quality, multi-class segmentation masks. This dataset firstly enables quantitative comparison of approaches within the kernel counting application space and secondly promotes further research in transfer learning and domain adaptation, large count segmentation methods, and edge deployment methods.

Two horses that consumed well water with high fluoride content exhibited clinical signs of chronic dental and skeletal fluoride toxicosis and were later euthanized and autopsied. Both horses had degenerative disease of multiple joints and multiple dental defects. Elevated fluoride concentrations were found in bone and tooth samples of both horses, well water, and feed. Microscopically, abnormalities were noted in bone and tooth samples, and consisted mostly of foci of cement necrosis and hypercementosis. Horses exhibiting bilateral, highly symmetrical dental and/or skeletal lesions, with chronic lameness, should be evaluated for the possible presence of fluoride toxicosis.

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