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PURPOSE: Brain metastases (BM) remain a significant cause of morbidity and mortality in breast cancer (BC) patients. Specific factors promoting the process of BM and predilection for selected neuro-anatomical regions remain unknown, yet may have major implications for prevention or treatment. Anatomical spatial distributions of BM from BC suggest a predominance of metastases in the hindbrain and cerebellum. Systematic approaches to quantifying BM location or location-based analyses based on molecular subtypes, however, remain largely unavailable. METHODS: We analyzed stereotactic Cartesian coordinates derived from 134 patients undergoing gamma- knife radiosurgery (GKRS) for treatment of 407 breast cancer BMs to quantitatively study BM spatial distribution along principal component axes and by intrinsic molecular subtype (ER, PR, Herceptin). We used kernel density estimators (KDE) to highlight clustering and distribution regions in the brain, and we used the metric of mutual information (MI) to tease out subtle differences in the BM distributions associated with different molecular subtypes of BC. BM location maps according to vascular and anatomical distributions using Cartesian coordinates to aid in systematic classification of tumor locations were additionally developed. RESULTS: We corroborated that BC BMs show a consistent propensity to arise posteriorly and caudally, and that Her2+ tumors are relatively more likely to arise medially rather than laterally. To compare the distributions among varying BC molecular subtypes, the mutual information metric reveal that the ER-PR-Her2+ and ER-PR-Her2- subtypes show the smallest amount of mutual information and are most molecularly distinct. The kernel density contour plots show a propensity for triple negative BC to arise in more superiorly or cranially situated BMs. CONCLUSIONS: We present a novel and shareable workflow for characterizing and comparing spatial distributions of BM which may aid in identifying therapeutic or diagnostic targets and interactions with the tumor microenvironment. Further characterization of these patterns with larger multi-institutional data-sets may have major impacts on treatment or management of cancer patients.

This case examines a rural teaching principal in a small K-12 school in a prairie province. The case examines the work intensification of Mrs. Hayes, whose school has been affected by reductions in student enrolment, staffing, and administrative time. Overwhelmed by myriad responsibilities, the principal feels inadequate as both a teacher and a leader. She is exhausted in her efforts to provide quality learning and extra-curricular opportunities for students, as her workload continues to grow. Teaching activities examine the uniqueness of the rural teaching principal role and possible solutions that may support leaders as they manage work intensification in order to accomplish the responsibilities of this dual role.

BACKGROUND: While it has been suspected that different primary cancers have varying predilections for metastasis in certain brain regions, recent advances in neuroimaging and spatial modeling analytics have facilitated further exploration into this field. METHODS: A systematic electronic database search for studies analyzing the distribution of brain metastases (BMs) from any primary systematic cancer published between January 1990 and July 2020 was conducted using PRISMA guidelines. RESULTS: Two authors independently reviewed 1957 abstracts, 46 of which underwent full-text analysis. A third author arbitrated both lists; 13 studies met inclusion/exclusion criteria. All were retrospective single- or multi-institution database reviews analyzing over 8227 BMs from 2599 patients with breast (8 studies), lung (7 studies), melanoma (5 studies), gastrointestinal (4 studies), renal (3 studies), and prostate (1 study) cancers. Breast, lung, and colorectal cancers tended to metastasize to more posterior/caudal topographic and vascular neuroanatomical regions, particularly the cerebellum, with notable differences based on subtype and receptor expression. HER-2-positive breast cancers were less likely to arise in the frontal lobes or subcortical region, while ER-positive and PR-positive breast metastases were less likely to arise in the occipital lobe or cerebellum. BM from lung adenocarcinoma tended to arise in the frontal lobes and squamous cell carcinoma in the cerebellum. Melanoma metastasized more to the frontal and temporal lobes. CONCLUSION: The observed topographical distribution of BM likely develops based on primary cancer type, molecular subtype, and genetic profile. Further studies analyzing this association and relationships to vascular distribution are merited to potentially improve patient treatment and outcomes.

BackgroundMalaria reactive case detection is the testing and, if positive, treatment of close contacts of index cases. It is included in national malaria control programmes of countries in the Greater Mekong Subregion to accelerate malaria elimination. Yet the value of reactive case detection in the control and elimination of malaria remains controversial because of the low yield, limited evidence for impact, and high demands on resources.MethodsData from the epidemiological assessments of large mass drug administration (MDA) studies in Myanmar, Vietnam, Cambodia and Laos were analysed to explore malaria infection clustering in households. The proportion of malaria positive cases among contacts screened in a hypothetical reactive case detection programme was then determined. The parasite density thresholds for rapid diagnostic test (RDT) detection was assumed to be > 50/µL (50,000/mL), for dried-blood-spot (DBS) based PCR > 5/µL (5000/mL), and for ultrasensitive PCR (uPCR) with a validated limit of detection at 0.0022/µL (22/mL).ResultsAt baseline, before MDA, 1223 Plasmodium infections were detected by uPCR in 693 households. There was clustering of Plasmodium infections. In 637 households with asymptomatic infections 44% (278/637) had more than one member with Plasmodium infections. In the 132 households with symptomatic infections, 65% (86/132) had more than one member with Plasmodium infections. At baseline 4% of households had more than one Plasmodium falciparum infection, but three months after MDA no household had more than one P. falciparum infected member. Reactive case detection using DBS PCR would have detected ten additional cases in six households, and an RDT screen would have detected five additional cases in three households among the 169 households with at least one RDT positive case. This translates to 19 and 9 additional cases identified per 1000 people screened, respectively. Overall, assuming all febrile RDT positive patients would seek treatment and provoke reactive case detection using RDTs, then 1047 of 1052 (99.5%) Plasmodium infections in these communities would have remained undetected.ConclusionReactive case detection in the Greater Mekong subregion is predicted to have a negligible impact on the malaria burden, but it has substantial costs in terms of human and financial resources.

This paper reports on the ways in which teaching principals in rural schools in Alberta, Manitoba, and Saskatchewan, Canada enact instructional leadership within the five leadership domains conceptualized by Robinson, Lloyd, and Rowe (2008). Although participants suggested that they were "not where they wanted to be" in their efforts to enact instructional leadership, their actions demonstrate exemplary practice in this regard. The nature of the discourse perpetuated by leadership groups and teachers' associations that equates instructional leadership with classroom visits only has the effect of decreasing teaching principals' self-efficacy as instructional leaders. We argue for recognition of these leaders' efforts to support learning, and a reconstitution of the role of the teaching principal such that instructional leadership expectations are realistically manageable for leaders in small rural schools.

BackgroundScrub typhus (ST) and murine typhus (MT) are common but poorly understood causes of fever in Laos. We examined the spatial and temporal distribution of ST and MT, with the intent of informing interventions to prevent and control both diseases.Methodology and principle findingsThis study included samples submitted from 2003 to 2017 to Mahosot Hospital, Vientiane, for ST and MT investigation. Serum samples were tested using IgM rapid diagnostic tests. Patient demographic data along with meteorological and environmental data from Laos were analysed. Approximately 17% of patients were positive for either ST (1,337/8,150 patients tested) or MT (1,283/7,552 patients tested). While both diseases occurred in inhabitants from Vientiane Capital, from the univariable analysis MT was positively and ST negatively associated with residence in Vientiane Capital. ST was highly seasonal, with cases two times more likely to occur during the wet season months of July-September compared to the dry season whilst MT peaked in the dry season. Multivariable regression analysis linked ST incidence to fluctuations in relative humidity whereas MT was linked to variation in temperature. Patients with ST infection were more likely to come from villages with higher levels of surface flooding and vegetation in the 16 days leading up to diagnosis.ConclusionsThe data suggest that as cities expand, high risk areas for MT will also expand. With global heating and risks of attendant higher precipitation, these data suggest that the incidence and spatial distribution of both MT and ST will increase.

BackgroundNational Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple sample collection procedures in routine public health procedures.MethodsSamples from symptomatic patients are processed by SpotMalaria, a high-throughput system that produces a comprehensive set of genotypes comprising several drug resistance markers, species markers and a genomic barcode. GenRe-Mekong delivers Genetic Report Cards, a compendium of genotypes and phenotype predictions used to map prevalence of resistance to multiple drugs.ResultsGenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9623 samples from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces, informing decision-making by NMCPs.ConclusionsGenRe-Mekong provides detailed knowledge about drug resistance at a local level, and facilitates data sharing at a regional level, enabling cross-border resistance monitoring and providing the public health community with valuable insights. The project provides a rich open data resource to benefit the entire malaria community.FundingThe GenRe-Mekong project is funded by the Bill and Melinda Gates Foundation (OPP11188166, OPP1204268). Genotyping and sequencing were funded by the Wellcome Trust (098051, 206194, 203141, 090770, 204911, 106698/B/14/Z) and Medical Research Council (G0600718). A proportion of samples were collected with the support of the UK Department for International Development (201900, M006212), and Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

There are two major myths concerning A level exam standards in England. First, the Ancient Myth, which insists that standards were norm-referenced until the 1980s, when they transitioned to being criterion-referenced. Second, the Modern Myth, which insists that standards transitioned again, during the 2010s, to being based upon the comparable outcomes principle. The present paper debunks these myths, arguing that: except for the occasional use of comparable outcomes to bridge qualification reforms, A level standards have always been attainment-referenced; and that this has always been operationalised using a combination of methods, including both examiner judgement of exam performances and statistical expectations of cohort attainment. The paper also argues that what has changed significantly is the degree of confidence that the exam industry has placed in examiner judgement relative to statistical expectations, which has waxed and waned over time. When statistical expectations have prevailed, pass rates have tended to plateau; somewhat implausibly. When examiner judgement has prevailed, pass rates have tended to rise; also somewhat implausibly. These trends have given a false impression of principled transitions, which the paper dispels.

BACKGROUND:Central nervous system (CNS) infections are important contributors to morbidity and mortality and the causative agents for ~50% patients are never identified. The causative agents of some CNS infections have distinct spatial and temporal patterns. METHODOLOGY/PRINCIPAL FINDINGS:Here we present the results of a spatial epidemiological and ecological analysis of CNS infections in Lao PDR (2003-2011). The data came from hospitalizations for suspected CNS infection at Mahosot Hospital in Vientiane. Out of 1,065 patients, 450 were assigned a confirmed diagnosis. While many communities in Lao PDR are in rural and remote locations, most patients in these data came from villages along major roads. Japanese encephalitis virus ((JEV); n = 94) and Cryptococcus spp. (n = 70) were the most common infections. JEV infections peaked in the rainy season and JEV patients came from villages with higher surface flooding during the same month as admission. JEV infections were spatially dispersed throughout rural areas and were most common in children. Cryptococcus spp. infections clustered near Vientiane (an urban area) and among adults. CONCLUSIONS/SIGNIFICANCE:The spatial and temporal patterns identified in this analysis are related to complex environmental, social, and geographic factors. For example, JEV infected patients came from locations with environmental conditions (surface water) that are suitable to support larger mosquito vector populations. Most patients in these data came from villages that are near major roads; likely the result of geographic and financial access to healthcare and also indicating that CNS diseases are underestimated in the region (especially from more remote areas). As Lao PDR is undergoing major developmental and environmental changes, the space-time distributions of the causative agents of CNS infection will also likely change. There is a major need for increased diagnostic abilities; increased access to healthcare, especially for rural populations; and for increased surveillance throughout the nation.

BackgroundMass administrations of antimalarial drugs (MDA) have reduced the incidence and prevalence of P. falciparum infections in a trial in the Greater Mekong Subregion. Here we assess the impact of the MDA on P. vivax infections.MethodsBetween May 2013 and July 2017, four villages in each Myanmar, Vietnam, Cambodia and Lao PDR were selected based on high prevalence of P. falciparum infections. Eight of the 16 villages were randomly assigned to receive MDA consisting of three-monthly rounds of three-day courses of dihydroartemisinin-piperaquine and, except in Cambodia, a single low-dose of primaquine. Cross-sectional surveys were conducted at quarterly intervals to detect Plasmodium infections using ultrasensitive qPCR. The difference in the cumulative incidence between the groups was assessed through a discrete time survival approach, the difference in prevalence through a difference-in-difference analysis, and the difference in the number of participants with a recurrence of P. vivax infection through a mixed-effect logistic regression.Results3,790 (86%) residents in the intervention villages participated in at least one MDA round, of whom 2,520 (57%) participated in three rounds. The prevalence of P. vivax infections fell from 9.31% to 0.89% at month 3 but rebounded by six months to 5.81%. There was no evidence that the intervention reduced the cumulative incidence of P.vivax infections (95% confidence interval [CI] Odds ratio (OR): 0.29 to 1.36). Similarly, there was no evidence of MDA related reduction in the number of participants with at least one recurrent infection (OR: 0.34; 95% CI: 0.08 to 1.42).ConclusionMDA with schizontocidal drugs had a lasting effect on P. falciparum infections but only a transient effect on the prevalence of P. vivax infections. Radical cure with an 8-aminoquinoline will be needed for the rapid elimination of vivax malaria.

BackgroundHow people respond to febrile illness is critical to malaria prevention, control, and ultimately elimination. This article explores factors affecting treatment-seeking behaviour for febrile illnesses in a remote area of Lao PDR.MethodsHousehold heads or their representatives (n = 281) were interviewed using a structured questionnaire. A total of twelve focus group discussions (FGDs) each with eight to ten participants were conducted in four villages. In addition, observations were recorded as field notes (n = 130) and were used to collect information on the local context, including the treatment seeking behaviour and the health services.ResultsAlmost three-quarters (201/281) of respondents reported fever in past two months. Most (92%, 185/201) sought treatment of which 80% (149/185) sought treatment at a health centre. Geographic proximity to a health centre (AOR = 6.5; CI = 1.74-24.25; for those  3.6 km) and previous experience of attending a health centre (AOR = 4.7; CI = 1.2-19.1) were strong predictors of visiting a health centre for febrile symptoms. During FGDs, respondents described seeking treatment from traditional healers and at health centre for mild to moderate illnesses. Respondents also explained how if symptoms, including fever, were severe or persisted after receiving treatment elsewhere, they sought assistance at health centres. Access to local health centres/hospitals was often constrained by a lack of transportation and an ability to meet the direct and indirect costs of a visit.ConclusionIn Nong District, a rural area bordering Vietnam, people seek care from health centres offering allopathic medicine and from spiritual healers. Decisions about where and when to attend health care depended on their economic status, mobility (distance to the health centre, road conditions, availability of transport), symptoms severity and illness recognition. Current and future malaria control/elimination programmes could benefit from greater collaboration with the locally accessible sources of treatments, such as health volunteers and traditional healers.

Elevated CO2 (eCO2) experiments provide critical information to quantify the effects of rising CO2 on vegetation1–6. Many eCO2 experiments suggest that nutrient limitations modulate the local magnitude of the eCO2 effect on plant biomass1,3,5, but the global extent of these limitations has not been empirically quantified, complicating projections of the capacity of plants to take up CO27,8. Here, we present a data-driven global quantification of the eCO2 effect on biomass based on 138 eCO2 experiments. The strength of CO2 fertilization is primarily driven by nitrogen (N) in ~65% of global vegetation and by phosphorus (P) in ~25% of global vegetation, with N- or P-limitation modulated by mycorrhizal association. Our approach suggests that CO2 levels expected by 2100 can potentially enhance plant biomass by 12 ± 3% above current values, equivalent to 59 ± 13 PgC. The global-scale response to eCO2 we derive from experiments is similar to past changes in greenness9 and biomass10 with rising CO2, suggesting that CO2 will continue to stimulate plant biomass in the future despite the constraining effect of soil nutrients. Our research reconciles conflicting evidence on CO2 fertilization across scales and provides an empirical estimate of the biomass sensitivity to eCO2 that may help to constrain climate projections.

BackgroundThe emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People's Democratic Republic, where artemisinin resistance is prevalent.Methods and findingsAfter establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention.ConclusionsAdded to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination.Trial registrationClinicalTrials.gov NCT01872702.

Consumption of wildlife meat drives emerging infectious diseases (1), often amplified by human encroachment into natural areas and changes in land use. Wildlife trade and consumption have been responsible for [...]

There is currently an unmet need in higher education for a structured, pre-emptive programme of support to help students enhance their resilience to stress. This article presents a mixed-methods evaluation of a transferable biopsychosocial resilience intervention for students -- the "Resilience Enhancement Programme for Students" (REP-S). In Study 1, a randomised control trial showed that participating in the intervention was associated with significantly decreased perceived stress, decreased trait neuroticism and enhanced self-esteem over a period of one month. In Study 2, written and focus-group qualitative data from students provided evidence that the intervention led to perceived positive changes, including sleeping better, dealing more effectively with assessments and managing interpersonal challenges. Future steps in the evaluation of the REP-S are discussed.

This paper argues that the dominant framework for conceptualizing validation evidence and analysis--the "five sources" framework from the 1999 "Standards"--is seriously limited. Its limitation raises a significant barrier to understanding the nature of comprehensive validation, and this presents a significant threat to effective validation practice. Motivated by a belief that "validity by design" ought to be substantiated through "validation of design" this paper demonstrates the importance of adopting a broader conceptual framework. It introduces a new framework, based upon the metaphor of different validation lenses through which to scrutinize assessment procedures at differing levels of detail, with micro-validation lenses at one end of a continuum and macro-validation lenses at the other. The evolution of validation theory can be seen as a very gradual, if somewhat reluctant, acknowledgement of the importance of micro-validation. This paper recommends micro-validation as the natural foundation for any comprehensive validation program.

Educational assessment involves eliciting, transmitting, and receiving information concerning the level of proficiency of a learner in a specified domain. With that in mind, it is perhaps surprising that the literature seems to make very little use of the signal processing metaphor. The present article begins by making a general case for greater use of this metaphor, as a simple and intuitive thinking tool for helping to explain how educational assessment works. The main body of the article extends this argument by demonstrating the utility of the metaphor in helping to explain how educational assessment can go wrong. During the 1980s and 1990s, Samuel Messick extensively discussed two major ways in which educational assessment can go wrong via construct-irrelevant variance and construct underrepresentation, respectively. Despite their importance, these concepts have had only a limited impact on the literature. Part of the reason for this may be a lack of clarity and comprehensiveness in their articulation. The present article aims to articulate these concepts more clearly and comprehensively, within a framework provided by the signal processing metaphor, reconfiguring them as signal contamination and signal deficiency, respectively.