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Introduction: The efficacy of secondary cytoreductive surgery (SCS) in recurrent ovarian cancer remains controversial, necessitating meticulous preoperative planning. While 3D imaging has transformed surgical approaches in various disciplines, its application in gynaecologic oncology is nascent. This study introduces a novel investigation employing preoperative 3D modeling in SCS preparation., Methods: A retrospective analysis was undertaken at a university affiliated tertiary medical center, examining patients who underwent SCS for recurrent ovarian cancer between 2017 and 2022. Patients were stratified into two cohorts: those with pre-operative CT-based 3D imaging (Group A) and those without (Group B). Demographic profiles, clinical data, and surgical outcomes were compared between the groups., Results: Among the 76 identified patients, 18 were deemed suitable for surgery, with 7 in Group A undergoing preoperative 3D modeling. Demographics encompassing age and performance status were consistent across both groups, while Serous histology was more prominent in Group B. Although operative metrics and collaborative endeavors exhibited no statistically significant variance, the attainment of optimal debulking with no residual disease (R0) was substantially higher in Group A (100%) compared to Group B (54%), with a significance level of P = 0.05., Conclusion: CT-based 3D modeling in the preoperative phase of secondary cytoreductive surgery for ovarian cancer shows potential for enhancing surgical planning. While this pioneering research highlights the potential benefits of integrating 3D imaging into gynaecologic oncology, the limitations of this retrospective study imply that these findings are primarily hypothesis-generating. Further prospective studies are necessary to validate impact., (Copyright © 2024. Published by Elsevier Inc.)

In T-cell acute lymphoblastic leukemia (T-ALL), more than 50% of cases display autoactivation of Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar of Cannabis that induces apoptosis by preventing Notch1 maturation in leukemia cells. Here, we isolated three cannabinoids from this chemovar that synergistically mimic the effects of the whole extract. Two were previously known, cannabidiol (CBD) and cannabidivarin (CBDV), whereas the third cannabinoid, which we termed 331-18A, was identified and fully characterized in this study. We demonstrated that these cannabinoids act through cannabinoid receptor type 2 and TRPV1 to activate the integrated stress response pathway by depleting intracellular Ca 2+ . This is followed by increased mRNA and protein expression of ATF4, CHOP, and CHAC1, which is hindered by inhibiting the upstream initiation factor eIF2α. The increased abundance of CHAC1 prevents Notch1 maturation, thereby reducing the levels of the active Notch1 intracellular domain, and consequently decreasing cell viability and increasing apoptosis. Treatment with the three isolated molecules resulted in reduced tumor size and weight in vivo and slowed leukemia progression in mice models. Altogether, this study elucidated the mechanism of action of three distinct cannabinoids in modulating the Notch1 pathway, and constitutes an important step in the establishment of a new therapy for treating NOTCH1 -mutated diseases and cancers such as T-ALL., Competing Interests: EB, AG, SP, PB No competing interests declared, DM A patent pertaining to the results of the paper has been applied for the use of cannabinoids in the treatment of Notch-related diseases. This patent PCT/IL2021/051352 was licensed to Cavnox Ltd. to test the combination of the molecules in human clinical trials, (© 2023, Besser et al.)

Background: Endomyocardial biopsy (EMB)-based traditional microscopy remains the gold standard for the detection of cardiac allograft rejection, despite its limitation of inherent subjectivity leading to inter-reader variability. Alternative techniques now exist to surveil for allograft injury and classify rejection. Donor-derived cell-free DNA (dd-cfDNA) testing is now a validated blood-based assay used to surveil for allograft injury. The molecular microscope diagnostic system (MMDx) utilizes intragraft rejection-associated transcripts (RATs) to classify allograft rejection and identify injury. The use of dd-cfDNA and MMDx together provides objective molecular insight into allograft injury and rejection. The aim of this study was to measure the diagnostic agreement between dd-cfDNA and MMDx and assess the relationship between dd-cfDNA and MMDx-derived RATs, which may provide further insight into the pathophysiology of allograft rejection and injury., Methods: This is a retrospective observational study of 156 EMB evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood before EMB (up to 9 days). Diagnostic agreement between traditional histopathology, MMDx, and dd-cfDNA (threshold of 0.20%) was compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated., Results: MMDx characterized allograft tissue as no rejection (62.8%), antibody-mediated rejection (ABMR) (26.9%), T-cell-mediated rejection (TCMR) (5.8%), and mixed ABMR/TCMR (4.5%). For the diagnosis of any type of rejection (TCMR, ABMR, and mixed rejection), there was substantial agreement between MMDx and dd-cfDNA (76.3% agreement). All transcript clusters (group of gene sets designated by MMDx) and individual transcripts considered abnormal from MMDx had significantly elevated dd-cfDNA. In addition, a positive correlation between dd-cfDNA levels and certain MMDx-derived RATs was observed. Tissue transcript clusters were correlated with dd-cfDNA scores, including DSAST, GRIT, HT1, QCMAT, and S4. For individual transcripts, tissue ROBO4 was significantly correlated with dd-cfDNA in both nonrejection and rejection as assessed by MMDx., Conclusions: Collectively, we have shown substantial diagnostic agreement between dd-cfDNA and MMDx. Furthermore, based on the findings presented, we postulate a common pathway between the release of dd-cfDNA and expression of ROBO4 (a vascular endothelial-specific gene that stabilizes the vasculature) in the setting of antibody-mediated rejection, which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to acute cellular rejection., (Copyright © 2024. Published by Elsevier Inc.)

Mescaline, among the earliest identified natural hallucinogens, holds great potential in psychotherapy treatment. Nonetheless, despite the existence of a postulated biosynthetic pathway for more than half a century, the specific enzymes involved in this process are yet to be identified. In this study, we investigated the cactus Lophophora williamsii (Peyote), the largest known natural producer of the phenethylamine mescaline. We employed a multi-faceted approach, combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling, enzymatic assays, molecular modeling, and pathway engineering for pathway elucidation. We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway, and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates, likely modulating mescaline levels in Peyote. Finally, we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells, providing novel insights into several challenges hindering complete heterologous mescaline production. Taken together, our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline, safeguarding this valuable natural resource for future generations., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

The oxygen evolution reaction is the bottleneck to energy-efficient water-based electrolysis for the production of hydrogen and other solar fuels. In proton exchange membrane water electrolysis (PEMWE), precious metals have generally been necessary for the stable catalysis of this reaction. In this work, we report that delamination of cobalt tungstate enables high activity and durability through the stabilization of oxide and water-hydroxide networks of the lattice defects in acid. The resulting catalysts achieve lower overpotentials, a current density of 1.8 amperes per square centimeter at 2 volts, and stable operation up to 1 ampere per square centimeter in a PEMWE system at industrial conditions (80°C) at 1.77 volts; a threefold improvement in activity; and stable operation at 1 ampere per square centimeter over the course of 600 hours.

Background: The challenges of evidence-informed decision-making in a public health emergency have never been so notable as during the COVID-19 pandemic. Questions about the decision-making process, including what forms of evidence were used, and how evidence informed-or did not inform-policy have been debated., Methods: We examined decision-makers' observations on evidence-use in early COVID-19 policy-making in British Columbia (BC), Canada through a qualitative case study. From July 2021- January 2022, we conducted 18 semi-structured key informant interviews with BC elected officials, provincial and regional-level health officials, and civil society actors involved in the public health response. The questions focused on: (1) the use of evidence in policy-making; (2) the interface between researchers and policy-makers; and (3) key challenges perceived by respondents as barriers to applying evidence to COVID-19 policy decisions. Data were analyzed thematically, using a constant comparative method. Framework analysis was also employed to generate analytic insights across stakeholder perspectives., Results: Overall, while many actors' impressions were that BC's early COVID-19 policy response was evidence-informed, an overarching theme was a lack of clarity and uncertainty as to what evidence was used and how it flowed into decision-making processes. Perspectives diverged on the relationship between 'government' and public health expertise, and whether or not public health actors had an independent voice in articulating evidence to inform pandemic governance. Respondents perceived a lack of coordination and continuity across data sources, and a lack of explicit guidelines on evidence-use in the decision-making process, which resulted in a sense of fragmentation. The tension between the processes involved in research and the need for rapid decision-making was perceived as a barrier to using evidence to inform policy., Conclusions: Areas to be considered in planning for future emergencies include: information flow between policy-makers and researchers, coordination of data collection and use, and transparency as to how decisions are made-all of which reflect a need to improve communication. Based on our findings, clear mechanisms and processes for channeling varied forms of evidence into decision-making need to be identified, and doing so will strengthen preparedness for future public health crises., (© 2024. The Author(s).)

Background: The purpose of the study is to investigate the relationship between blood and tissue-derived rejection-related transcripts from blood gene expression profiling (GEP) and molecular microscope in the setting of allograft rejection in heart transplant., Methods: All heart transplant patients from August 2021 to May 2022 with both circulating blood GEP (AlloMap) and endomyocardial biopsy with molecular microscope diagnostic system (MMDx) within 4 weeks were included (N = 173 samples). We obtained individual blood GEP-based messenger RNA transcript expression levels of the 11 target genes from CareDx. Student's t-test was performed to compare blood GEP transcript expression levels between no rejection and rejection as assessed by MMDx. A Scatter plot with Spearman correlation analysis was performed to compare the relationship between transcript expression levels from AlloMap and MMDx, with and without allograft rejection., Results: There were 52 samples (30.1%) with antibody-mediated rejection (ABMR) and 15 samples (8.7%) with T-cell-mediated rejection (TCMR), as assessed by MMDx. Expression of one of the blood ITGA4 (Integrin alpha 4) expression level was elevated in ABMR, compared to no ABMR (4,607.5 vs 4,217.5; p = 0.019). Most tissue rejection-associated transcript expression levels were elevated in ABMR, and tissue ROBO4 expression correlated with the blood ITGA4 expression with moderate or greater effect size in all samples (Spearman's R = 0.31; p < 0.001). There was also a positive correlation between blood ITGA4 and tissue ROBO4 expression in samples without ABMR (Spearman's R = 0.33; p < 0.001), but no correlation between blood ITGA4 and tissue ROBO4 expression in samples with ABMR (Spearman's R = 0.009; p = 0.513)., Conclusions: Circulating blood ITGA4 expression is elevated in antibody-mediated rejection (AMR) and correlates with myocardial expression of ROBO4. The knowledge of individual transcript expression levels in blood and in tissue may provide insights into various disease processes in heart transplant patients. Taken together, the results of our study reveal an overlap between 2 objective post-heart transplant rejection surveillance methods, identify potential novel markers for ABMR, and reveal the need for a deeper understanding of molecular mechanisms underlying allograft rejection., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: This study sought to examine how public health organizational structures affected decision-making and provides recommendations to strengthen future public health crisis preparedness. Methods: The Institutions-Politics-Organizations-Governance (IPOG) framework and an organizational lens was applied to the analysis of COVID-19 governance within British Columbia (BC). Organizational charts detailing the structure of public health systems were compiled using available data and supplemented with data collected through key informant interviews. Results: In response to the COVID-19 pandemic, BC initiated several changes in its public health organization. BC's COVID-19 response attempted to utilize a centralized command structure within a decentralized health system. Four key themes were identified pertaining to the 1) locus of decision-making and action; 2) role of emergency structures; 3) challenges in organizational structure; and 4) balance between authority and participation in decision-making. Conclusion: The organizational adaptations enabled a substantively effective response. However, our findings also illustrate deficiencies in organizational structure in the current public health system. Two recommendations for consideration are: 1) a more formal vertical organizational structure; and 2) developing new mechanisms to link health and general emergency response structures., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2024 Berman, Cheng, Bridget, Brubacher and Ruck.)

Background: Vascular calcifications are a hallmark of atherosclerosis, and in the coronary arteries are routinely used as a prognostic marker. Calcifications of intracranial vessels (ICC) are frequently observed on non-contrast CT (NCCT) and their effect on post-stroke cognitive impairment (PSCI) remains unclear. Our aim was to explore the association of ICC with prospective long-term cognitive function and advanced MRI-measures in a large prospective cohort of cognitively intact mild stroke survivors., Methods: Data from the Tel-Aviv brain acute stroke cohort (TABASCO) study [ClinicalTrials.gov #NCT01926691] were analyzed. This prospective cohort study ( n  = 575) aimed to identify predictors of PSCI, in cognitively intact mild stroke survivors. A quantitative assessment of the intracranial calcium content - The ICC score (ICCS) was calculated semi-automatically on NCCT using a validated calcium quantification application. Participants underwent a 3 T-MRI and prospective comprehensive cognitive clinical and laboratory assessments at enrollment, 6, 12, and 24-months., Results: Data were available for 531 participants (67.4 years, 59.5% males). The incidence of PSCI at two-years doubled in the high ICCS group (26% vs. 13.7%, p  < 0.001). The high ICCS group had significantly greater small-vessel-disease (SVD) tissue changes and reduced microstructural-integrity assessed by Diffusion-Tensor-Imaging (DTI) maps ( p  < 0.05 for all). In multivariate analysis, a higher ICCS was independently associated with brain atrophy manifested by lower normalized white and gray matter, hippocampal and thalamic volumes ( β  = -0.178, β  = -0.2, β  = -0.137, β  = -0.157; p  < 0.05) and independently predicted PSCI (OR 1.83, 95%CI 1.01-3.35)., Conclusion: Our findings suggest that the ICCS, which is a simple and readily available imaging marker on NCCT, is associated with brain atrophy, microstructural damage, the extent of SVD, and may predict PSCI. This finding has implications for identifying individuals at risk for PSCI and implementing targeted interventions to mitigate this risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Seyman, Sadeh-Gonik, Berman, Blum, Shendler, Nathan, Rothschild, Molad, Ben Assayag, Hallevi and the TABASCO prospective cohort study group.)

Competing Interests: Disclosures None.

Modulation of the endocannabinoid system is projected to have therapeutic potential in almost all human diseases. Accordingly, the high demand for novel cannabinoids stimulates the discovery of untapped sources and efficient manufacturing technologies. Here we explored Helichrysum umbraculigerum, an Asteraceae species unrelated to Cannabis sativa that produces Cannabis-type cannabinoids (for example, 4.3% cannabigerolic acid). In contrast to Cannabis, cannabinoids in H. umbraculigerum accumulate in leaves' glandular trichomes rather than in flowers. The integration of de novo whole-genome sequencing data with unambiguous chemical structure annotation, enzymatic assays and pathway reconstitution in Nicotiana benthamiana and in Saccharomyces cerevisiae has uncovered the molecular and chemical features of this plant. Apart from core biosynthetic enzymes, we reveal tailoring ones producing previously unknown cannabinoid metabolites. Orthology analyses demonstrate that cannabinoid synthesis evolved in parallel in H. umbraculigerum and Cannabis. Our discovery provides a currently unexploited source of cannabinoids and tools for engineering in heterologous hosts., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In recent years, the literature on public health interventions and health outcomes in the context of epidemic and pandemic response has grown immensely. However, relatively few of these studies have situated their findings within the institutional, political, organizational and governmental (IPOG) context in which interventions and outcomes exist. This conceptual mapping scoping study synthesized the published literature on the impact of IPOG factors on epidemic and pandemic response and critically examined definitions and uses of the terms IPOG in this literature. This research involved a comprehensive search of four databases across the social, health and biomedical sciences as well as multi-level eligibility screening conducted by two independent reviewers. Data on the temporal, geographic and topical range of studies were extracted, then descriptive statistics were calculated to summarize these data. Hybrid inductive and deductive qualitative analysis of the full-text articles was conducted to critically analyse the definitions and uses of these terms in the literature. The searches retrieved 4918 distinct articles; 65 met the inclusion criteria and were thus reviewed. These articles were published from 2004 to 2022, were mostly written about COVID-19 (61.5%) and most frequently engaged with the concept of governance (36.9%) in relation to epidemic and pandemic response. Emergent themes related to the variable use of the investigated terms, the significant increase in relevant literature published amidst the COVID-19 pandemic, as well as a lack of consistent definitions used across all four terms: institutions, politics, organizations and governance. This study revealed opportunities for health systems researchers to further engage in interdisciplinary work with fields such as law and political science, to become more forthright in defining factors that shape responses to epidemics and pandemics and to develop greater consistency in using these IPOG terms in order to lessen confusion among a rapidly growing body of literature., (© The Author(s) 2022. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Competing Interests: The authors have declared that no competing interests exist.

Background: Third-dose mRNA COVID-19 vaccine is currently recommended in the United States for SOT recipients based in part on data showing diminished immune response, including Ab production, after a two-dose regimen. Data on vaccine response in adolescent and young adult SOT recipients are limited, including no data reported on third-dose responsiveness., Methods: Results of serologic testing in a convenience sample of 28 vaccinated adolescent and young adult HT recipients at a single institution were collected from the medical record and summarized., Results: At a median of 98.5 days (IQR 59-150) after second dose, 17 (61%) had an Ab response. Among 12 who had serology before and after third-dose vaccination, four of seven who were negative prior to third dose became positive at a median of 34 days (IQR 31-39.5) following third dose. No myocarditis, acute rejection, graft dysfunction, graft loss, or deaths were observed., Conclusions: These findings support recommendations for the routine administration of three doses of mRNA vaccines in adolescent and young adult HT recipients and show a potential subpopulation in whom the fourth dose should be contemplated., (© 2022 Wiley Periodicals LLC.)

Background: Research on public health responses to COVID-19 globally has largely focused on understanding the virus' epidemiology, identifying interventions to curb transmission, and assessing the impact of interventions on outcomes. Only recently have studies begun to situate their findings within the institutional, political, or organizational contexts of jurisdictions. Within British Columbia (BC), Canada, the COVID-19 response in early 2020 was deemed highly coordinated and effective overall; however, little is understood as to how these upstream factors influenced policy decisions., Methods: Using a conceptual framework we developed, we are conducting a multidisciplinary jurisdictional case study to explore the influence of institutional (I), political (P), organizational (O), and governance (G) factors on BC's COVID-19 public health response in 2020-2021. A document review (e.g. policy documents, media reports) is being used to (1) characterize relevant institutional and political factors in BC, (2) identify key policy decisions in BC's epidemic progression, (3) create an organizational map of BC's public health system structure, and (4) identify key informants for interviews. Quantitative data (e.g. COVID-19 case, hospitalization, death counts) from publicly accessible sources will be used to construct BC's epidemic curve. Key informant interviews (n = 15-20) will explore governance processes in the COVID-19 response and triangulate data from prior procedures. Qualitative data will be analysed using a hybrid deductive-inductive coding approach and framework analysis. By integrating all of the data streams, our aim is to explore decision-making processes, identify how IPOG factors influenced policy decisions, and underscore implications for decision-making in public health crises in the BC context and elsewhere. Knowledge users within the jurisdiction will be consulted to construct recommendations for future planning and preparedness., Discussion: As the COVID-19 pandemic evolves, governments have initiated retrospective examinations of their policies to identify lessons learned. Our conceptual framework articulates how interrelations between IPOG contextual factors might be applied to such analysis. Through this jurisdictional case study, we aim to contribute findings to strengthen governmental responses and improve preparedness for future health crises. This protocol can be adapted to and applied in other jurisdictions, across subnational jurisdictions, and internationally., (© 2022. The Author(s).)

Abstract: Studies have shown that women are more susceptible to adverse effects (AEs) from conventional drugs. This study aimed to investigate the differences of medical cannabis (MC)-related AEs between women and men in patients with chronic noncancer pain (CNCP). This is a cross-sectional study of adult patients licensed for MC treatment who were also diagnosed as patients with CNCP by a physician. Data included self-reported questionnaires and comprehensive MC treatment information. Simultaneously, identification and quantification of phytocannabinoids and terpenoids from the MC cultivars were performed. Comparative statistics were used to evaluate differences between men and women. Four hundred twenty-nine patients with CNCP (64% males) reported fully on their MC treatment. Subgrouping by sex demonstrated that the weight-adjusted doses were similar between men and women (0.48 [0.33-0.6] gr for men and 0.47 [0.34-0.66] gr for women). Nonetheless, women reported more than men on MC-related AEs. Further analysis revealed that women consumed different MC cultivar combinations than men, with significantly higher monthly doses of the phytocannabinoids CBD and CBC and significantly lower monthly doses of the phytocannabinoid 373-15c and the terpenoid linalool. Our findings demonstrate sex differences in MC-related AEs among patients with CNCP. Women are more susceptible to MC-related AEs, presumably because of both the inherent sex effect and the consumption of specific phytocannabinoid compositions in the MC cultivar(s). The understanding of these differences may be crucial for planning MC treatments with safer phytocannabinoid and terpenoid compositions and to better inform patients of expected AEs., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Medical Cannabis and its major cannabinoids (-)- trans -Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) are gaining momentum for various medical purposes as their therapeutic qualities are becoming better established. However, studies regarding their efficacy are oftentimes inconclusive. This is chiefly because Cannabis is a versatile plant rather than a single drug and its effects do not depend only on the amount of THC and CBD. Hundreds of Cannabis cultivars and hybrids exist worldwide, each with a unique and distinct chemical profile. Most studies focus on THC and CBD, but these are just two of over 140 phytocannabinoids found in the plant in addition to a milieu of terpenoids, flavonoids and other compounds with potential therapeutic activities. Different plants contain a very different array of these metabolites in varying relative ratios, and it is the interplay between these molecules from the plant and the endocannabinoid system in the body that determines the ultimate therapeutic response and associated adverse effects. Here, we discuss how phytocannabinoid profiles differ between plants depending on the chemovar types, review the major factors that affect secondary metabolite accumulation in the plant including the genotype, growth conditions, processing, storage and the delivery route; and highlight how these factors make Cannabis treatment highly complex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Procaccia, Lewitus, Lipson Feder, Shapira, Berman and Meiri.)

Rydberg interactions of trapped alkali-metal atoms are used widely to facilitate quantum gate operations in quantum processors and repeaters. In most laboratory realizations using this protocol, the Rydberg states are repelled by the trapping laser fields, requiring that the fields be turned off during gate operations. Here we create a quasi-two-level system in a regime of Rydberg excitation blockade for a mesoscopic Rb ensemble of several hundred atoms confined in a magic-wavelength optical lattice. We observe many-body Rabi oscillations between the ground and collective Rydberg state. In addition we use Ramsey interference techniques to obtain the light shifts of both the lower and upper states of the collective qubit. Whereas the coupling producing the Rabi oscillations is enhanced by a factor of sqrt[N], there is no corresponding enhancement for the light shifts. We derive an effective two-level model which is in good agreement with our observations. Trapped Rydberg qubits and an effective two-level description are expected to have broad applicability for studies of quantum simulation and networking using collective encoding in ensembles of neutral atoms.

Background: Endomyocardial biopsy (EMB) is costly and discomforting yet remains a key component of surveillance after pediatric heart transplantation (HT). Donor-derived cell-free DNA (dd-cfDNA) has been histologically validated with high negative predictive value, offering an alternative to surveillance EMB (sEMB)., Methods: We implemented an alternative surveillance protocol using commercially available dd-cfDNA assays in place of sEMB after pediatric HT. Recipients ≧7 months post-HT with reassuring clinical assessment were referred for dd-cfDNA. When not elevated above the manufacturers' threshold, sEMB was deferred. Subsequent clinical status and results of follow-up EMB were analyzed., Results: Over 17 months, 58 recipients [34% female, median age at HT 3.1 years (IQR 0.6-10.6)] had dd-cfDNA assessed per protocol. Median age was 14.8 years (8.4-18.3) and time from HT 6.0 years (2.2-11.2). Forty-seven (81%) had non-elevated dd-cfDNA and 11 (19%) were elevated. During a median of 8.7 months (4.2-15), all are alive without allograft loss/new dysfunction. Among those with non-elevated dd-cfDNA, 24 (51%) had subsequent sEMB at 12.1 months (6.9-12.9) with 23 showing no acute rejection (AR): grade 0R/pAMR0 (n = 16); 1R(1A)/pAMR0 (n = 7). One had AR (grade 2R(3A)/pAMR0) on follow-up sEMB after decreased immunosuppression following a diagnosis of PTLD. All 11 with elevated dd-cfDNA had reflex EMB at 19 days (12-32) with AR in 4: grade 1R(1B-2)/pAMR0 (n = 3); 1R(1B)/pAMR2 (n = 1)., Conclusions: dd-cfDNA assessment in place of selected, per-protocol EMB decreased surveillance EMB by 81% in our pediatric HT recipient cohort with no short-term adverse outcomes. Individual center approach to surveillance EMB will influence the utility of these findings., (© 2021 Wiley Periodicals LLC.)

The Ethiopian health system faces persistent inequities in health-care utilization and outcomes, despite continued efforts to expand health service coverage. There is little evidence in the literature describing the status of equity in the quality of healthcare. This paper aims to understand the disparities in quality of antenatal care (ANC) and family planning (FP) among the poor and non-poor communities. We used the 2016 Ethiopia Demographic and Health Survey (DHS) data to compute a Multidimensional Poverty Index (MPI), and the 2014 Service Provision Assessment (SPA) data to assess quality of ANC and FP services-defined as the level of adherence to World Health Organization (WHO) clinical and service guidelines. We merged the two datasets using geographical coordinates, and aggregated service users into facility catchment area clusters using a 2-km radius for urban and 10-km radius for rural facilities. We computed ANC and FP quality and MPI indices for each facility and assigned these to catchment areas. Using the international cutoff point for deprivation (MPI = 33.3%), we evaluated whether the quality of ANC and FP services varies by poor and non-poor catchment areas. We found that most of catchment areas (75.7%) were deprived. While the overall quality of ANC and FP services are low (33% and 34% respectively), we found little variation in the distribution of the quality of these services between poor and non-poor areas, urban and rural settings, or regionally. The short-term focus needs to be on improving the overall quality of services rather than on its distribution.

In the last decades, growing evidence showed the therapeutic capabilities of Cannabis plants. These capabilities were attributed to the specialized secondary metabolites stored in the glandular trichomes of female inflorescences, mainly phytocannabinoids and terpenoids. The accumulation of the metabolites in the flower is versatile and influenced by a largely unknown regulation system, attributed to genetic, developmental and environmental factors. As Cannabis is a dioecious plant, one main factor is fertilization after successful pollination. Fertilized flowers are considerably less potent, likely due to changes in the contents of phytocannabinoids and terpenoids; therefore, this study examined the effect of fertilization on metabolite composition by crossbreeding (-)-Δ 9 - trans -tetrahydrocannabinol (THC)- or cannabidiol (CBD)-rich female plants with different male plants: THC-rich, CBD-rich, or the original female plant induced to develop male pollen sacs. We used advanced analytical methods to assess the phytocannabinoids and terpenoids content, including a newly developed semi-quantitative analysis for terpenoids without analytical standards. We found that fertilization significantly decreased phytocannabinoids content. For terpenoids, the subgroup of monoterpenoids had similar trends to the phytocannabinoids, proposing both are commonly regulated in the plant. The sesquiterpenoids remained unchanged in the THC-rich female and had a trend of decrease in the CBD-rich female. Additionally, specific phytocannabinoids and terpenoids showed an uncommon increase in concentration followed by fertilization with particular male plants. Our results demonstrate that although the profile of phytocannabinoids and their relative ratios were kept, fertilization substantially decreased the concentration of nearly all phytocannabinoids in the plant regardless of the type of fertilizing male. Our findings may point to the functional roles of secondary metabolites in Cannabis ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lipson Feder, Cohen, Shapira, Katzir, Peer, Guberman, Procaccia, Berman, Flaishman and Meiri.)

Background: A simple indicator of technical efficiency, such as productivity of health workers, measured using routine health facility data, can be a practical approach that can inform initiatives to improve efficiency in low- and middle-income countries. This paper presents a proof of concept of using routine information from primary healthcare (PHC) facilities to measure health workers' productivity and its application in three regions of Ethiopia., Methods: In four steps, we constructed a productivity measure of the health workforce of Health Centers (HCs) and demonstrated its practical application: (1) developing an analytical dataset using secondary data from health management information systems (HMIS) and human resource information system (HRIS); (2) principal component analysis and factor analysis to estimate a summary measure of output from five indicators (annual service volume of outpatient visits, family planning, first antenatal care visits, facility-based deliveries by skilled birth attendants, and children [< 1 year] with three pentavalent vaccines); (3) calculating a productivity score by combining the summary measure of outputs and the total number of health workers (input), and (4) implementing regression models to identify the determinant of productivity and ranking HCs based on their adjusted productivity score., Results: We developed an analytical dataset of 1128 HCs; however, significant missing values and outliers were reported in the data. The principal component and factor scores developed from the five output measures were highly consistent (correlation coefficient = 0.98). We considered the factor score as the summary measure of outputs for estimating productivity. A very weak association was observed between the summary measure of output and the total number of staff. The result also highlighted a large variability in productivity across similar health facilities in Ethiopia, represented by the significant dispersion in summary measure of output occurring at similar levels of the health workers., Conclusions: We successfully demonstrated the analytical steps to estimate health worker productivity and its practical application using HMIS and HRIS. The methodology presented in this study can be readily applied in low- and middle-income countries using widely available data-such as DHIS2-that will allow further explorations to understand the causes of technical inefficiencies in the health system., (© 2021. The Author(s).)

Background: Preoperative planning of open laryngotracheal surgery is important for achieving good results. This study examines the surgeon's perception of the importance of using life size 3D printed models of the pediatric airway on surgical decision making., Methods: Life-size three-dimensional models of the upper airway were created based on CT images of children scheduled for laryngotracheal-reconstruction and cricotracheal resection with anastomosis. Five pediatric airway surgeons evaluated the three-dimensional models for determining the surgical approach, incision location and length, graft length, and need for single or double-stage surgery of seven children (median age 4.4 years, M:F ratio 4:3). They rated the importance of the three-dimensional model findings compared to the direct laryngoscopy videos and CT findings for each domain on a validated Likert scale of 1-5., Results: The mean rating for all domains was 3.6 ± 0.63 ("moderately important" to "very important"), and the median rating was 4 ("very important"). There was full agreement between raters for length of incision and length of graft. The between-rater agreement was 0.608 ("good") for surgical approach, 0.585 ("moderate") for incision location, and 0.429 ("moderate") for need for single- or two-stage surgery., Conclusion: Patient-specific three-dimensional printed models of children's upper airways were scored by pediatric airway surgeons as being moderately to very important for preoperative planning of open laryngotracheal surgery. Large-scale, objective outcome studies are warranted to establish the reliability and efficiency of these models., (© 2021. The Author(s).)

Medical cannabis (MC) treatment for chronic pain is increasing, but evidence regarding short- and long-term efficacy and associated adverse effects (AEs) of the different cannabis plant components is limited. Most reports focus on two phytocannabinoids, (-)-Δ 9 -trans-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This study, aimed to identify patterns of phytocannabinoid compositions associated with MC treatment response and with related AEs. Participants in this multicenter prospective cohort were patients with chronic non-cancer pain that were prescribed MC by physicians. Data was collected before MC treatment, at one month (short-term) and at 12 months (long-term). Simultaneously, liquid chromatography mass spectrometry identification and quantification of phytocannabinoids from the cultivars were performed. The monthly dose of each phytocannabinoid for each patient was z-scaled and clustered into ten groups to assess the difference in analgesic treatment response (≥30%/50% pain intensity reduction) and AEs rates. We identified ten clusters that had similar analgesic treatment response rates. However, there were significant differences in AEs rates both at short- and long-term. We identified specific phytocannabinoid compositions that were associated with overall AEs rates (5% compared to 53% at short-term and 44% at long-term) and with specific AEs rates such as MC related central nervous system, gastrointestinal and psychological AEs. To conclude, Evaluating only Δ9-THC or CBD is insufficient to find associations with MC related AEs. Therefore, comprehensive profiling of phytocannabinoids is needed to discover associations to related AEs and help physicians prescribe safer cannabis with less AEs while still relieving pain., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Several studies have reported inadequate levels of quality of care in the Ethiopian health system. Facility characteristics associated with better quality remain unclear. Understanding associations between patient volumes and quality of care could help organize service delivery and potentially improve patient outcomes., Methods: Using data from the routine health management information system (HMIS) and the 2014 Ethiopian Service Provision Assessment survey + we assessed associations between daily total outpatient volumes and quality of services. Quality of care at the facility level was estimated as the average of five measures of provider knowledge (clinical vignettes on malaria and tuberculosis) and competence (observations of family planning, antenatal care and sick child care consultations). We used linear regression models adjusted for several facility-level confounders and region fixed effects with log-transformed patient volume fitted as a linear spline. We repeated analyses for the association between volume of antenatal care visits and quality., Results: Our analysis included 424 facilities including 270 health centers, 45 primary hospitals and 109 general hospitals in Ethiopia. Quality was low across all facilities ranging from only 18 to 56% with a mean score of 38%. Outpatient volume varied from less than one patient per day to 581. We found a small but statistically significant association between volume and quality which appeared non-linear, with an inverted U-shape. Among facilities seeing less than 90.6 outpatients per day, quality increased with greater patient volumes. Among facilities seeing 90.6 or more outpatients per day, quality decreased with greater patient volumes. We found a similar association between volume and quality of antenatal care visits., Conclusions: Health care utilization and quality must be improved throughout the health system in Ethiopia. Our results are suggestive of a potential U-shape association between volume and quality of primary care services. Understanding the links between volume of patients and quality of care may provide insights for organizing service delivery in Ethiopia and similar contexts.

Introduction: Chronic non-cancer pain (CNCP) is one of the most prevalent indications for medical cannabis (MC) treatment globally. In this study, we investigated CNCP parameters in patients during prolonged MC treatment, and assessed the interrelation between CNCP parameters and the chemical composition of MC chemovar used. Methods: A cross-sectional questionnaire-based study was performed in one-month intervals for the duration of six months. Subjects were adult patients licensed for MC treatment who also reported a diagnosis of CNCP by a physician. Data included self-reported questionnaires. MC treatment features included administration route, cultivator, cultivar name and monthly dose. Comparison statistics were used to evaluate differences between the abovementioned parameters and the monthly MC chemovar doses at each time point. Results: 429, 150, 98, 71, 77 and 82 patients reported fully on their MC treatment regimens at six one-month intervals, respectively. Although pain intensities did not change during the study period, analgesic medication consumption rates decreased from 46 to 28% ( p < 0.005) and good Quality of Life (QoL) rates increased from 49 to 62% ( p < 0.05). These changes overlapped with increase in rates of (-)-Δ 9 - trans -tetrahydrocannabinol (THC) and α -pinene high dose consumption. Conclusion: Even though we observed that pain intensities did not improve during the study, QoL did improve and the rate of analgesic medication consumption decreased alongside with increasing rates of high dose THC and α -pinene consumption. Understanding MC treatment composition may shed light on its long-term effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with several of the authors (JA, YV, BY, and DM)., (Copyright © 2021 Aviram, Lewitus, Vysotski, Yellin, Berman, Shapira and Meiri.)

Increasing evidence for the therapeutic potential of Cannabis in numerous pathological and physiological conditions has led to a surge of studies investigating the active compounds in different chemovars and their mechanisms of action, as well as their efficacy and safety. The biological effects of Cannabis have been attributed to phytocannabinoid modulation of the endocannabinoid system. In-vitro and in-vivo studies have shown that pure phytocannabinoids can alter the levels of endocannabinoids and other cannabimimetic lipids. However, it is not yet understood whether whole Cannabis extracts exert variable effects on the endocannabinoid metabolome, and whether these effects vary between tissues. To address these challenges, we have developed and validated a novel analytical approach, termed "cannabinoidomics," for the simultaneous extraction and analysis of both endogenous and plant cannabinoids from different biological matrices. In the methodological development liquid chromatography high resolution tandem mass spectrometry (LC/HRMS/MS) was used to identify 57 phytocannabinoids, 15 major phytocannabinoid metabolites, and 78 endocannabinoids and cannabimimetic lipids in different biological matrices, most of which have no analytical standards. In the validation process, spiked cannabinoids were quantified with acceptable selectivity, repeatability, reproducibility, sensitivity, and accuracy. The power of this analytical method is demonstrated by analysis of serum and four different sections of mouse brains challenged with three different cannabidiol (CBD)-rich extracts. The results demonstrate that variations in the minor phytocannabinoid contents of the different extracts may lead to varied effects on endocannabinoid concentrations, and on the CBD metabolite profile in the peripheral and central systems. We also show that the Cannabis challenge significantly decreases the levels of several endocannabinoids in specific brain sections compared to the control group. This effect is extract-specific and suggests the importance of minor, other-than CBD, phytocannabinoid or non-phytocannabinoid compounds., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Phase matching refers to a process in which atom-field interactions lead to the creation of an output field that propagates coherently through the interaction volume. By studying light scattering from arrays of cold atoms, we show that conditions for phase matching change as the dimensionality of the system decreases. In particular, for a single atomic chain, there is phase-matched reflective scattering in a cone about the symmetry axis of the array that scales as the square of the number of atoms in the chain. For two chains of atoms, the phase-matched reflective scattering can be enhanced or diminished as a result of Bragg scattering. Such scattering can be used for mapping collective states within an array of neutral atoms onto propagating light fields and for establishing quantum links between separated arrays.

The therapeutic use of medical Cannabis is growing, and so is the need for standardized and therapeutically stable Cannabis products for patients. The therapeutic effects of Cannabis largely depend on the content of its pharmacologically active secondary metabolites and their interactions, mainly terpenoids and phytocannabinoids. Once harvested and during storage, these natural compounds may decarboxylate, oxidize, isomerize, react photochemically, evaporate and more. Despite its widespread and increasing use, however, data on the stability of most of the plant's terpenoids and phytocannabinoids during storage is scarce. In this study, we therefore aimed to determine postharvest optimal storage conditions for preserving the composition of naturally biosynthesized secondary metabolites in Cannabis inflorescences and Cannabis extracts. To this end, Cannabis inflorescences (whole versus ground samples) and Cannabis extracts (dissolved in different solvents) from (-)-Δ 9 - trans -tetrahydrocannabinol- or cannabidiol-rich chemovars, were stored in the dark at various temperatures (25, 4, -30 and -80°C), and their phytocannabinoid and terpenoid profiles were analyzed over the course of 1 year. We found that in both Cannabis inflorescences and extracts, a storage temperature of 25°C led to the largest changes in the concentrations of the natural phytocannabinoids over time, making this the most unfavorable temperature compared with all others examined here. Olive oil was found to be the best vehicle for preserving the natural phytocannabinoid composition of the extracts. Terpenoid concentrations were found to decrease rapidly under all storage conditions, but temperatures lower than -20°C and grinding of the inflorescences were the least favorable conditions. Overall, our conclusions point that storage of whole inflorescences and extracts dissolved in olive oil, at 4°C, were the optimal postharvest conditions for Cannabis ., (Copyright © 2020 Milay, Berman, Shapira, Guberman and Meiri.)

Low quality of care is a significant problem for health systems in low-income and middle-income countries (LMICs). Policymakers are increasingly interested in using performance-based financing (PBF), a system-wide provider payment reform, conditioned on both quantity and quality of performance, to improve quality of care. The health system context influences both the design and the implementation of these programmes and thus their effectiveness. This study analyses how context has influenced the design and implementation of PBF in improving the quality of primary care in one particular setting, Cote d'Ivoire, a lower-middle income country with some of the poorest health outcomes in the world. Based on literature, an analytical framework was developed identifying five pathways through which financial incentives can influence the quality of primary care: earmarking, conditioning, provider behaviour, community involvement and management. Guided by this framework, semistructured interviews were conducted with policymakers and providers to diagnose the context and to assess the links between financing and quality of care at the primary care level. PBF in Cote d'Ivoire was found to have increased data availability and quality, facility-wide and disease-specific inputs, provider motivation and management practices in contracted facilities, but had limited success in improving process and outcome measures of quality, as well as community involvement and the provision of non-incentivised services. These limitations were attributable to a centralised health system structure constraining the decision space of health providers; financing and governance challenges across the health sector; and shortcomings with regard to the design of the PBF quality checklist and incentive structures in Cote d'Ivoire. In order to improve the quality of primary care, health sector reforms such as PBF should incorporate the organisational and service delivery context more broadly into their design and implementation, as is the case in other countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Cannabis or its derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects. However, cannabis has potent immunomodulatory properties. To determine if cannabis consumption during immunotherapy affects therapy outcomes, we conducted a prospective observatory study including 102 (68 immunotherapy and 34 immunotherapy plus cannabis) consecutive patients with advanced cancers who initiated immunotherapy. Cannabis consumption correlated with a significant decrease in time to tumor progression and overall survival. On the other hand, the use of cannabis reduced therapy-related immune-related adverse events. We also tested the possibility that cannabis may affect the immune system or the tumor microenvironment through the alteration of the endocannabinoid system. We analyzed a panel of serum endocannabinoids (eCBs) and eCB-like lipids, measuring their levels before and after immunotherapy in both groups. Levels of serum eCBs and eCB-like lipids, before immunotherapy, showed no significant differences between cannabis users to nonusers. Nevertheless, the levels of four eCB and eCB-like compounds were associated with patients' overall survival time. Collectively, cannabis consumption has considerable immunomodulatory effects, and its use among cancer patients needs to be carefully considered due to its potential effects on the immune system, especially during treatment with immunotherapy.

Background: Medical cannabis (MC) treatment for migraine is practically emerging, although sufficient clinical data are not available for this indication. This cross-sectional questionnaire-based study aimed to investigate the associations between phytocannabinoid treatment and migraine frequency., Methods: Participants were migraine patients licensed for MC treatment. Data included self-reported questionnaires and MC treatment features. Patients were retrospectively classified as responders vs. non-responders (≥50% vs. <50% decrease in monthly migraine attacks frequency following MC treatment initiation, respectively). Comparative statistics evaluated differences between these two subgroups., Results: A total of 145 patients (97 females, 67%) with a median MC treatment duration of three years were analyzed. Compared to non-responders, responders ( n = 89, 61%) reported lower current migraine disability and lower negative impact, and lower rates of opioid and triptan consumption. Subgroup analysis demonstrated that responders consumed higher doses of the phytocannabinoid ms&#95;373&#95;15c and lower doses of the phytocannabinoid ms&#95;331&#95;18d (3.40 95% CI (1.10 to 12.00); p < 0.01 and 0.22 95% CI (0.05-0.72); p < 0.05, respectively)., Conclusions: These findings indicate that MC results in long-term reduction of migraine frequency in >60% of treated patients and is associated with less disability and lower antimigraine medication intake. They also point to the MC composition, which may be potentially efficacious in migraine patients., Competing Interests: The authors declare no conflict of interest.

The therapeutic effect of the Cannabis plant largely depends on the presence and specific ratio of a spectrum of phytocannabinoids. Although prescription of medicinal Cannabis for various conditions constantly grows, its consumption is mostly limited to oral or respiratory pathways, impeding its duration of action, bioavailability, and efficacy. Herein, a long-acting formulation in the form of melt-printed polymeric microdepots for full-spectrum cannabidiol (CBD)-rich extract administration is described. When injected subcutaneously in mice, the microdepots facilitate sustained release of the encapsulated extract over a two-week period. The prolonged delivery results in elevated serum levels of multiple, major and minor, phytocannabinoids for over 14 days, compared to Cannabis extract injection. A direct analysis of the microdepots retrieved from the injection site gives rise to an empirical model for the release kinetics of the phytocannabinoids as a function of their physical traits. As a proof of concept, we compare the long-term efficacy of a single administration of the microdepots to a single administration of Cannabis extract in a pentylenetetrazol-induced convulsion model. One week following administration, the microdepots reduce the incidence of tonic-clonic seizures by 40%, increase the survival rate by 50%, and the latency to first tonic-clonic seizures by 170%. These results suggest that a long-term full-spectrum Cannabis delivery system may provide new form of Cannabis administration and treatments.

Background: Continued investment, especially from domestic financing, is needed for Ethiopia to achieve universal health coverage and a sustainable health system over time. Understanding costs of providing health services will assist the government to mobilize adequate resources for health, and to understand future costs of changes in quality of care, service provision scope, and potential decline in external resources. This study assessed costs per unit of service output, "unit costs", for government primary hospitals and health centers, and disease-specific services within each facility., Methods: Quantitative and qualitative data were collected from 25 primary hospitals and 47 health centers across eight of the eleven regions of Ethiopia for 2013/14, and 2014/15 and 2015/16 but only for primary hospitals, and supplemented by other related health and financial institutions records. A top-down costing approach was used to estimate unit costs for each facility by department - inpatient, outpatient, maternal and child health, and delivery. A mixed-method approach was used for the disease-specific unit costs exempt from fees., Results: Health center median unit cost was 146 Ethiopian birr (ETB) (17 PPP$, 2012), the Delivery department had the highest median unit cost (647 ETB; 76 PPP$, 2012) and Outpatient department (OPD) had the lowest (124 ETB; 14 PPP$, 2012). Primary hospital median unit cost was 339 ETB (40 PPP$, 2012), with Inpatient department having the highest median unit cost (1288 ETB; 151 PPP$, 2012), while OPD was the lowest (252 ETB; 29 PPP$, 2012). Drugs and pharmaceutical supplies accounted for most of the costs for both facilities. Among the exempted services offered, tuberculosis and antiretroviral treatment are the costliest with median unit costs from 1091 to 1536 ETB (128-180 PPP$, 2012), with drugs and supplies accounting for almost 90% of the costs., Conclusions: High unit costs of service provision could be indicative of underutilization of the primary health care system, coupled with inefficiencies associated with organization and delivery of health services. Data from this study are being used to assess efficiency and productivity among primary care facilities, facilitate premium setting for health insurance, and improve budgeting and allocating health resources for a more sustainable and effective primary health care system.

Background: As advances in oncological treatment continue to prolong the survival of patients with non-resectable pancreatic ductal adenocarcinoma (PDAC), decision-making regarding palliative surgical bypass in patients with a heavy disease burden turns challenging. Here we present the results of a pancreatic surgery referral center., Methods: Patients that underwent palliative gastrojejunostomy and/or hepaticojejunostomy for advanced, non-resectable PDAC between January 2010 and November 2018 were retrospectively assessed. All patients were taken to a purely palliative surgery with no curative intent. The postoperative course as well as short and long-term outcomes was evaluated in relation to preoperative parameters., Results: Forty-two patients (19 females) underwent palliative bypass. Thirty-one underwent only gastrojejunostomy (22 laparoscopic) and 11 underwent both gastrojejunostomy and hepaticojejunostomy (all by an open approach). Although 34 patients (80.9%) were able to return temporarily to oral intake during the index admission, 15 (35.7%) suffered from a major postoperative complication. Seven patients (16.6%) died from surgery and another seven within the following month. Nine patients (21.4%) never left the hospital following the surgery. Mean length of hospital stay was 18 ± 17 days (range 3-88 days). Mean overall survival was 172.8 ± 179.2 and median survival was 94.5 days. Age, preoperative hypoalbuminemia, sarcopenia, and disseminated disease were associated with palliation failure, defined as inability to regain oral intake, leave the hospital, or early mortality., Conclusions: Although palliative gastrojejunostomy and hepaticojejunostomy may be beneficial for specific patients, severe postoperative morbidity and high mortality rates are still common. Patient selection remains crucial for achieving acceptable outcomes.

Objective: To assess the quality and effective coverage (EC) of family planning (FP) and antenatal care (ANC) services in Ethiopia., Design: Secondary analyses of the 2014 Ethiopia Service Provision Assessment Plus Survey and 2016 Ethiopia Demographic and Health Survey data., Setting and Participants: Women using FP and ANC., Main Outcome Measures: Quality indices are created as a proportion of recommended clinical actions done in observations of ANC and FP visits. We adjust the crude coverage of ANC and of FP by the quality to estimate EC for both services., Results: The crude coverage of FP was 61% and 62% for ANC in Ethiopia in 2016. On average, quality was 35.8% during FP visits and 86% of women received <50% of the recommended clinical actions. When adjusting the crude coverage to account for the quality of service, Ethiopia's FP services EC was 22%. On average, ANC quality was 34% and 81% received <50% of the recommended ANC clinical actions. When adjusting the crude coverage by the service quality, the mean EC of ANC services was 22% in Ethiopia., Conclusions: The quality of both FP and ANC services is low in Ethiopia, with women obtaining only a fraction of the standard clinical actions during their visits. In addition, there is considerable variation in EC across Ethiopia's regions, with variation driven largely by variations in crude coverage. To improve EC, actions are needed to improve the quality of ANC and FP care., (© The Author(s) 2019. Published by Oxford University Press in association with the International Society for Quality in Health Care.)

Hanbury Brown-Twiss interference and stimulated emission, two fundamental processes in atomic physics, have been studied in a wide range of applications in science and technology. We study interference effects that occur when a weak probe is sent through a gas of two-level atoms that are prepared in a singly excited collective (Dicke or "superatom") state and for atoms prepared in a factorized state. We measure the time-integrated second-order correlation function g^{(2)} of the output field as a function of the delay τ between the input probe field and radiation emitted by the atoms and find that, for the Dicke state, g^{(2)} is twice as large for τ=0 as it is for γ&#95;{e}τ≫1 (γ&#95;{e} is an excited state decay rate), while for the product state, this ratio is equal to 3/2. The results agree with those of a theoretical model in which any effects related to stimulated emission are totally neglected-the coincidence counts measured in our experiment arise from Hanbury Brown-Twiss interference between the input field and the field radiated by the atoms.

Standardized donor-derived cell-free DNA (dd-cfDNA) testing has been introduced into clinical use to monitor kidney transplant recipients for rejection. This report describes the performance of this dd-cfDNA assay to detect allograft rejection in samples from heart transplant (HT) recipients undergoing surveillance monitoring across the United States. Venous blood was longitudinally sampled from 740 HT recipients from 26 centers and in a single-center cohort of 33 patients at high risk for antibody-mediated rejection (AMR). Plasma dd-cfDNA was quantified by using targeted amplification and sequencing of a single nucleotide polymorphism panel. The dd-cfDNA levels were correlated to paired events of biopsy-based diagnosis of rejection. The median dd-cfDNA was 0.07% in reference HT recipients (2164 samples) and 0.17% in samples classified as acute rejection (35 samples; P = .005). At a 0.2% threshold, dd-cfDNA had a 44% sensitivity to detect rejection and a 97% negative predictive value. In the cohort at risk for AMR (11 samples), dd-cfDNA levels were elevated 3-fold in AMR compared with patients without AMR (99 samples, P = .004). The standardized dd-cfDNA test identified acute rejection in samples from a broad population of HT recipients. The reported test performance characteristics will guide the next stage of clinical utility studies of the dd-cfDNA assay., (© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Countries have implemented a range of reforms in health financing and provision to advance towards universal health coverage (UHC). These reforms often change the role of a ministry of health (MOH) in traditionally unitary national health service systems. An exploratory comparative case study of four upper middle-income and high-income countries provides insights into how these reforms in pursuit of UHC are likely to affect health governance and the organisational functioning of an MOH accustomed to controlling the financing and delivery of healthcare. These reforms often do not result in simple transfers of responsibility from MOH to other actors in the health system. The resulting configuration of responsibilities and organisational changes within a health system is specific to the capacities within the health system and the sociopolitical context. Formal prescriptions that accompany reform proposals often do not fully represent what actually takes place. An MOH may retain considerable influence in financing and delivery even when reforms appear to formally shift those powers to other organisational units. MOHs have limited ability to independently achieve fundamental system restructuring in health systems that are strongly subject to public sector rules and policies. Our comparative study shows that within these constraints, MOHs can drive organisational change through four mechanisms: establishing a high-level interministerial team to provide political commitment and reduce institutional barriers; establishing an MOH 'change team' to lead implementation of organisational change; securing key components of systemic change through legislation; and leveraging emerging political change windows of opportunity for the introduction of health reforms., Competing Interests: Competing interests: All authors had financial support from the Ministry of Health of Malaysia for the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The therapeutic effect of Cannabis largely depends on the content of its pharmacologically active secondary metabolites, mainly phytocannabinoids, flavonoids, and terpenoids. Recent studies suggest there are therapeutic effects of specific terpenoids as well as synergistic effects with other active compounds in the plant. Although Cannabis contains an overwhelming milieu of terpenoids, only a limited number are currently reported and used for metabolic analysis of Cannabis chemovars. In this study, we report the development and validation of a method for simultaneous quantification of 93 terpenoids in Cannabis air-dried inflorescences and extracts. This method employs the full evaporation technique via a static headspace sampler, followed by gas chromatography-mass spectrometry (SHS-GC/MS/MS). In the validation process, spiked terpenoids were quantified with acceptable repeatability, reproducibility, sensitivity, and accuracy. Three medical Cannabis chemovars were used to study the effect of sample preparation and extraction methods on terpenoid profiles. This method was further applied for studying the terpenoid profiles of 16 different chemovars acquired at different dates. Our results demonstrate that sample preparation methods may significantly impact the chemical fingerprint compared to the nontreated Cannabis . This emphasizes the importance of performing SHS extraction in order to study the natural terpenoid contents of chemovars. We also concluded that most inflorescences expressed relatively unique terpenoid profiles for the most pronounced terpenoids, even when sampled at different dates, although absolute concentrations may vary due to aging. The suggested method offers an ideal tool for terpenoid profiling of Cannabis and sets the scene for more comprehensive works in the future.

The Cannabis plant contains over 100 phytocannabinoids and hundreds of other components. The biological effects and interplay of these Cannabis compounds are not fully understood and yet influence the plant's therapeutic effects. Here we assessed the antitumor effects of whole Cannabis extracts, which contained significant amounts of differing phytocannabinoids, on different cancer lines from various tumor origins. We first utilized our novel electrospray ionization liquid chromatography mass spectrometry method to analyze the phytocannabinoid contents of 124 Cannabis extracts. We then monitored the effects of 12 chosen different Cannabis extracts on 12 cancer cell lines. Our results show that specific Cannabis extracts impaired the survival and proliferation of cancer cell lines as well as induced apoptosis. Our findings showed that pure (-)-Δ 9 - trans -tetrahydrocannabinol (Δ 9 -THC) did not produce the same effects on these cell lines as the whole Cannabis extracts. Furthermore, Cannabis extracts with similar amounts of Δ 9 -THC produced significantly different effects on the survival of specific cancer cells. In addition, we demonstrated that specific Cannabis extracts may selectively and differentially affect cancer cells and differing cancer cell lines from the same organ origin. We also found that cannabimimetic receptors were differentially expressed among various cancer cell lines and suggest that this receptor diversity may contribute to the heterogeneous effects produced by the differing Cannabis extracts on each cell line. Our overall findings indicate that the effect of a Cannabis extract on a specific cancer cell line relies on the extract's composition as well as on certain characteristics of the targeted cells., Competing Interests: CONFLICTS OF INTEREST The authors have no conflict of interest to declare.

Background: In planning for universal health coverage, many countries have been examining their fiscal decentralization policies with the goal of increasing efficiency and equity via "additionalities." The concept of "additionality," when the government of a lower administrative level increases the funding allocated to a particular issue when extra funds are present, is often used in these contexts. Although the definition of "additionality" can be used more broadly, for the purposes of this paper we focus narrowly on the additional allocation of primary healthcare expenditures. This paper explores this idea by examining the impact of central level primary healthcare expenditure, on individual state level contributions to primary healthcare expenditure within 16 Indian states between 2005 and 2013., Methods: In examining 5 main variables, we compared differences between government expenditures, contributions, and revenues for Empowered Action Group (EAG) states, and non-EAG states. EAG states are normally larger states that have weaker public health infrastructure and hence qualify for additional funding. Finally, using a model that captured the quantity of central level primary healthcare expenditure distributions to these states, we measured its impact on each state's own contributions to primary healthcare spending., Results: Our results show that, at the state level, growth in per capita central level primary healthcare expenditure has increased by 110% from 2005-2013, while state's own contributions to primary healthcare expenditure per capita increased by 32%. Further analyses show that a 1% change disbursement from the central level leads to a -0.132%, although not significant, change by states in their own expenditure. The effect for wealthier states is -0.151% and significant and for poorer states the effect is smaller at -0.096% and not significant., Conclusion: This analysis suggests that increases in central level primary healthcare expenditure to states have an inverse relationship with primary healthcare expenditures by the state level. Furthermore, this effect is more pronounced in wealthier Indian states. This finding has policy implications on India's decision to increase block grants to states in place of targeted program expenditures., (© 2019 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

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Background: Benefit Incidence Analysis (BIA) is used to understand the distribution of health care utilization and spending in comparison to income distribution. The results can illustrate how effectively governments allocate limited resources towards meeting the needs of the poor. In analyzing the distribution of public spending on inpatient, outpatient, and deliveries, this paper represents the most recent BIA completed in India., Methods: In order to conduct the BIA statistical analysis for this project, 2014 utilization data from the most recently completed Indian National Sample Survey (NSS) was used. Unit costs were estimated for primary care, hospital inpatient, hospital outpatient, and deliveries. Concentration curves and concentration indices were estimated both at the national and state levels. Analyses were reported for overall utilization, as well as for the gross and net benefits for inpatient, outpatient, and deliveries., Results: According to the results, utilization of government inpatient and delivery services is pro-poor. When gross and net benefits are included in the analysis, services become more equal and less pro-poor. Gross benefits, which are measured with state-level unit costs, are virtually equal for all services. Although there are some pro-poor gross benefits trends for national outpatient services, the results also show that the equality of national gross benefits trends hides a significant disparity across Indian States. While a number of Indian States have outpatient gross benefits that are pro-poor, few show pro-poor benefits for inpatient and delivery services. Net benefits, which considers both unit costs for each respective service, and out-of-pocket (OOP) expenditures, trend similarly to gross benefits. In addition, those who use public facilities spend considerable OOP to supplement government services., Conclusions: This BIA reveals that government spending on public health care has not resulted in significantly pro-poor services. While some progress has been made relative to deliveries and outpatient services, inpatient stays are not pro-poor. In addition, national results mask significant disparities across Indian states.

Background: The use of community health workers (CHWs) has been considered as one of the strategies to address the growing shortage of health workers, predominantly in low-income countries. They are playing a pivotal role in lessening health disparities through improving health outcomes for underserved populations. Yet, little is known about what factors motivate and drive them to continue working as CHWs. In this study, we aimed to examine factors contributing to the motivation of volunteer CHWs (vCHWs) in Ethiopia currently known as one-to-five network leaders (1to5NLs) and explore variations between attributes of social and work-related determinants., Method: We conducted a cross-sectional study in four selected woredas (the second lowest administrative structure in Ethiopia, and similar to a district) of Oromia and Tigray regions and interviewed 786 1to5NLs. The effects of each motivational factor were explored using percentage of respondents who agreed and strongly agreed to each of them and Mann-Whitney U test., Results: Individual, community, and health system factors contributed to the motivation of 1to5NLs in this study. Intrinsic desire to have a good status in the community as a result of their volunteer service (81.86%) followed by a commitment to serve the community (81.61%) and to gain satisfaction by accomplishing something worthwhile to the community (81.61%) were some of the factors motivating 1to5NLs in our study. Despite these motivational items, factors such as lack of career development (51.47%), unclear health development army guideline (59.26%), limited supervision and support (62.32%), and lack of recognition and appreciation of accomplishments (63.22%) were the factors negatively affecting motivation of 1to5NLs. Lack of career development, limited supervision and support, and lack of recognition and appreciation of accomplishments were significantly varied between attributes of educational level, marital status, service year as 1to5NLs, and previous volunteer engagement (at P < 0.05)., Conclusion: Findings of our study indicated that non-financial incentives such as the creation of career development models is the key to motivating and retaining CHWs where they are not receiving stipends. Sustainability of CHW program should consider exploring enhanced innovations to strengthen supportive supervision, development of better mechanisms to publicize the role of CHWs, and improvement of recognition and appreciation schemes for CHWs' efforts and accomplishments.