Lessons learned from dealing with the challenge of canine brucellosis in practice.

With more and more dogs being imported to the UK, and no requirement for preimport screening for Brucella canis, veterinary teams are now encountering canine brucellosis on an increasingly regular basis. At BVA Live Mark Moreton and Elizabeth McLennan-Green will reflect on their experiences of developing guidance to help practices manage the risks associated with this zoonotic pathogen.

Trait variation in patchy landscapes: Morphology of spotted salamanders (Ambystoma maculatum) varies more within ponds than between ponds.

The influence of intraspecific trait variation on species interactions makes trait-based approaches critical to understanding eco-evolutionary processes. Because species occupy habitats that are patchily distributed in space, species interactions are influenced not just by the degree of intraspecific trait variation but also the relative proportion of trait variation that occurs within- versus between-patches. Advancement in trait-based ecology hinges on understanding how trait variation is distributed within and between habitat patches across the landscape. We sampled larval spotted salamanders (Ambystoma maculatum) across six spatially discrete ponds to quantify within- and between-pond variation in mass, length, and various metrics associated with their relationship (scaling, body condition, shape). Across all traits, within-pond variation contributed more to total observed morphological variation than between-pond variation. Between-pond variation was not negligible, however, and explained 20-41% of total observed variation in measured traits. Between-pond variation was more pronounced in salamander tail morphology compared to head or body morphology, suggesting that pond-level factors more strongly influence tails than other body parts. We also observed differences in mass-length relationships across ponds, both in terms of scaling slopes and intercepts, though differences in the intercepts were much stronger. Preliminary evidence hinted that newly constructed ponds were a driver of the observed differences in mass-length relationships and morphometrics. General pond-level difference in salamander trait covariation suggest that allometric scaling of morphological traits is context dependent in patchy landscapes. Effects of pond age offer the hypothesis that habitat restoration through pond construction is a driver of variation in trait scaling, which managers may leverage to bolster trait diversity.

Henle fiber layer thickening and deficits in objective retinal function in participants with a history of multiple traumatic brain injuries.

Introduction: This study tested whether multiple traumatic brain injuries (TBIs) alter the structure of the Henle fiber layer (HFL) and degrade cell-specific function in the retinas of human participants. Methods: A cohort of case participants with multiple TBIs and a cohort of pair-matched control participants were prospectively recruited. Directional optical coherence tomography and scanning laser polarimetry measured HFL thickness and phase retardation, respectively. Full-field flash electroretinography (fERG) assessed retinal function under light-adapted (LA) 3.0, LA 30 Hz, dark-adapted (DA) 0.01, DA 3.0, and DA 10 conditions. Retinal imaging and fERG outcomes were averaged between both eyes, and paired t-tests or Wilcoxon signed-rank tests analyzed inter-cohort differences. Results: Global HFL thickness was significantly (p = 0.02) greater in cases (8.4 ± 0.9 pixels) than in controls (7.7 ± 1.1 pixels). There was no statistically significant difference (p = 0.91) between the cohorts for global HFL phase retardation. For fERG, LA 3.0 a-wave amplitude was significantly reduced (p = 0.02) in cases (23.5 ± 4.2 µV) compared to controls (29.0 ± 8.0 µV). There were no other statistically significant fERG outcomes between the cohorts. Discussion: In summary, the HFL thickens after multiple TBIs, but phase retardation remains unaltered in the macula. Multiple TBIs may also impair retinal function, indicated by a reduction in a-wave amplitude. These results support the potential of the retina as a site to detect TBI-associated pathology.

The Effect of Trimethoprim on Thiamine Absorption: A Transporter-Mediated Drug-Nutrient Interaction.

Trimethoprim is predicted to inhibit several thiamine transporters, including the primary thiamine intestinal absorptive transporter, ThTR-2, and the hepatic and renal organic cation transporters, OCT1, OCT2, and MATEs. To investigate the effect of trimethoprim on thiamine absorption, studies were conducted in cells, mice, and healthy volunteers and supported by use of real-world data. In a randomized, crossover clinical study, seven healthy volunteers were given a single oral dose of thiamine or thiamine plus trimethoprim, followed by blood sampling. The thiamine area under the curve (AUC) increased with trimethoprim co-administration (P value = 0.031). Similar results were seen in mice. Trimethoprim appeared to act on thiamine absorption through inhibition of hepatic OCT1 as evidenced from its ability to modulate levels of isobutyrylcarnitine and propionylcarnitine, OCT1 biomarkers identified from metabolomic analyses. Real-world data further supported this finding, showing an association between trimethoprim use and higher levels of triglycerides, LDL cholesterol, and total cholesterol, consistent with OCT1 inhibition (P values: 2.2 × 10-16 , 5.75 × 10-7 , and 5.82 × 10-7 , respectively). These findings suggest that trimethoprim increases plasma levels of thiamine by inhibiting hepatic OCT1. Trimethoprim reduced urinary excretion and clearance of biomarkers for OCT2 and MATEs, consistent with inhibition of renal organic cation transporters. This inhibition did not appear to play a role in the observed increases in thiamine levels. This study highlights the potential for drug-nutrient interactions involving transporters, in addition to transporters' established role in drug-drug interactions.

Structure and function of retinal ganglion cells in subjects with a history of repeated traumatic brain injury.

This study tested whether repeated traumatic brain injuries (TBIs) alter the objective structure or the objective function of retinal ganglion cells (RGCs) in human subjects recruited from an optometry clinic. Case subjects (n = 25) with a history of repeated TBIs (4.12 ± 2.76 TBIs over 0-41 years) and healthy pair-matched control subjects (n = 30) were prospectively recruited. Retinal nerve fiber layer (RNFL) thickness was quantified with spectral-domain optical coherence tomography, and scanning laser polarimetry measured RNFL phase retardation. Measurements of the photopic negative response were made using full-field flash electroretinography. There was no statistically significant difference (p = 0.42) in global RNFL thickness between the case cohort (96.6 ± 9.4 microns) and the control cohort (94.9 ± 7.0 microns). There was no statistically significant difference (p = 0.80) in global RNFL phase retardation between the case cohort (57.9 ± 5.7 nm) and the control cohort (58.2 ± 4.6 nm). There were no statistically significant differences in the peak time (p = 0.95) of the PhNR or in the amplitude (p = 0.11) of the PhNR between the case cohort (69.9 ± 6.9 ms and 24.1 ± 5.1 µV, respectively) and the control cohort (70.1 ± 8.9 ms and 27.8 ± 9.1 µV, respectively). However, PhNR amplitude was more variable (p < 0.025) in the control cohort than in the case cohort. Within the case cohort, there was a strong positive (r = 0.53), but not statistically significant (p = 0.02), association between time since last TBI and PhNR amplitude. There was also a modest positive (r = 0.45), but not statistically significant (p = 0.04), association between time since first TBI and PhNR amplitude. Our results suggest that there were no statistically significant differences in the objective structure or in the objective function of RGCs between the case cohort and the control cohort. Future large, longitudinal studies will be necessary to confirm our negative results and to more fully investigate the potential interaction between PhNR amplitude and time since first or last TBI.

Interdisciplinary staff perceptions of advance care planning in long-term care homes: a qualitative study.

BACKGROUND: Residents living in long-term care homes (LTCH) have complex care needs, multiple chronic conditions, increasing frailty and cognitive impairment. A palliative approach that incorporates advance care planning (ACP) should be integrated with chronic disease management, yet it is not a norm in most LTCHs. Despite its growing need, there remains a lack of staff engagement in the ACP process. OBJECTIVES: The aim of this study was to explore the perceptions and experiences of interdisciplinary staff related to the practice of ACP in LTCHs. METHODS: This study is part of a larger Canadian project, iCAN ACP, that aims to increase uptake, and access to ACP for older Canadians living with frailty. An exploratory qualitative design using an interpretive descriptive approach was employed utilizing focus groups and semi-structured interviews with staff from four LTCHs in Ontario, Canada. FINDINGS: There were 98 participants, including nurses (n = 36), physicians (n = 4), personal support workers (n = 34), support staff (n = 23), and a public guardian (n = 1). Three common themes and nine subthemes were derived: a) ongoing nature of ACP; b) complexities around ACP conversations; and c) aspirations for ACP becoming a standard of care in LTCHs. DISCUSSION: The findings of this study provide important contributions to our understanding of the complexities surrounding ACP implementation as a standard of practice in LTCHs. One of the critical findings relates to a lack of ACP conversations prior to admission in the LTCHs, by which time many residents may have already lost cognitive abilities to engage in these discussions. The hierarchical nature of LTCH staffing also serves as a barrier to the interdisciplinary collaboration required for a successful implementation of ACP initiatives. Participants within our study expressed support for ACP communication and the need for open lines of formal and informal interdisciplinary communication. There is a need for revitalizing care in LTCHs through interdisciplinary care practices, clarification of role descriptions, optimized staffing, capacity building of each category of staff and commitment from the LTCH leadership for such care. CONCLUSION: The findings build on a growing body of research illustrating the need to improve staff engagement in ACP communication in LTCHs.

New Sex Chromosomes in Lake Victoria Cichlid Fishes (Cichlidae: Haplochromini).

African cichlid fishes harbor an extraordinary diversity of sex-chromosome systems. Within just one lineage, the tribe Haplochromini, at least 6 unique sex-chromosome systems have been identified. Here we focus on characterizing sex chromosomes in cichlids from the Lake Victoria basin. In Haplochromis chilotes, we identified a new ZW system associated with the white blotch color pattern, which shows substantial sequence differentiation over most of LG16, and is likely to be present in related species. In Haplochromis sauvagei, we found a coding polymorphism in amh that may be responsible for an XY system on LG23. In Pundamilia nyererei, we identified a feminizing effect of B chromosomes together with XY- and ZW-patterned differentiation on LG23. In Haplochromis latifasciatus, we identified a duplication of amh that may be present in other species of the Lake Victoria superflock. We further characterized the LG5-14 XY system in Astatotilapia burtoni and identified the oldest stratum on LG14. This species also showed ZW differentiation on LG2. Finally, we characterized an XY system on LG7 in Astatoreochromis alluaudi. This report brings the number of distinct sex-chromosome systems in haplochromine cichlids to at least 13, and highlights the dynamic evolution of sex determination and sex chromosomes in this young lineage.

Survival Outcomes Associated With Cytoreductive Nephrectomy in Patients With Metastatic Clear Cell Renal Cell Carcinoma.

Importance: Level I evidence has failed to demonstrate an overall survival (OS) advantage for cytoreductive nephrectomy in patients with metastatic clear cell renal cell carcinoma (ccRCC) in the modern era, which is at odds with observational studies reporting a marked OS benefit associated with these operations. These observational studies were not designed to adjust for unmeasured confounding. Objective: To assess whether cytoreductive nephrectomy is associated with improved OS in patients with metastatic ccRCC. Design, Setting, and Participants: This cohort study identified patients with metastatic ccRCC in the National Cancer Database from January 1, 2006, to December 31, 2016, who received systemic targeted therapy. The analysis was finalized on July 23, 2021. Exposures: Receipt of cytoreductive nephrectomy. Main Outcomes and Measures: The primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. Distance from the patients' zip code of residence to the treating facility was identified as a valid instrument and was used in a 2-stage residual inclusion instrumental variable analysis. Conventional adjustments for selection bias, multivariable Cox proportional hazards regression, and propensity score matching were performed for comparison. Measured covariates adjusted for in all analyses included age, sex, race, Charlson-Deyo score, facility type, year of diagnosis, clinical T stage, and clinical N stage. Results: The final study population included 12 766 patients (median age, 63 years; IQR, 56-70 years; 8744 [68%] male; 11 206 [88%] White). Cytoreductive nephrectomy was performed in 5005 patients (39%). Conventional adjustments for selection bias demonstrated a significant OS benefit associated with cytoreductive nephrectomy (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% CI, 0.47-0.51; propensity score matching: HR, 0.48; 95% CI, 0.46-0.50). Instrumental variable estimates did not demonstrate an association between cytoreductive nephrectomy and OS (HR, 0.92; 95% CI, 0.78-1.09). Conclusions and Relevance: Instrumental variable analysis did not demonstrate a survival advantage associated with cytoreductive nephrectomy for patients with metastatic ccRCC. This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets.

Foveal Phase Retardation Correlates With Optically Measured Henle Fiber Layer Thickness.

This study quantified and compared phase retardation distribution in the central macula with the thickness of the Henle fiber layer (HFL). A scanning laser polarimeter (SLP) was used to acquire 20° × 40° macular-centered images, either with fixed corneal compensation or with variable corneal compensation, in two cohorts of clinically normal subjects (N = 36). Phase retardation maps from SLP imaging were used to generate a macular cross pattern (fixed compensation) or an annulus pattern (variable compensation) centered on the macula. Intensity profiles in the phase retardation maps were produced using annular regions of interest at eccentricities from 0.25° to 3°. Pixel intensity was averaged at each eccentricity, acting as a surrogate for macular phase retardation. Directional OCT images were acquired in the horizontal and vertical meridians in all subjects, allowing visualization of the HFL thickness. HFL thickness was manually segmented in each meridian and averaged. In both cohorts, phase retardation and HFL thickness were highly correlated in the central 3° assessed, providing further evidence that the source of the phase retardation signal in the central macula is dominated by the HFL and that the center of the macula on cross sectional imaging corresponds closely with the center of the macular cross on SLP imaging.

Comparative effectiveness analysis of first-line immunotherapy versus chemotherapy in metastatic urothelial carcinoma of the bladder.

BACKGROUND: Clinical trials have not shown a significant overall survival (OS) difference between chemotherapy and immunotherapy as first-line agents in metastatic urothelial carcinoma (UC). However, the generalizability of these findings in a real-world setting has not yet been evaluated in comparative effectiveness studies. OBJECTIVE: To assess the effectiveness of first-line immunotherapy compared with chemotherapy regimens on OS in patients with metastatic UC of the bladder. DESIGN, SETTING, AND PARTICIPANTS: This retrospective propensity-matched study identified metastatic bladder UC patients in the National Cancer Database from 2014 to 2017 who received either first-line immunotherapy-monotherapy or multi-agent chemotherapy, and who were not treated on a clinical trial protocol. OUTCOME MEASURES AND ANALYSIS: The primary outcome was OS from the date of diagnosis to date of death or censoring at last follow-up. Patients were stratified into first-line immunotherapy and chemotherapy treatment groups. After 1:1 nearest-neighbor caliper-matching of propensity scores, the survival analysis was conducted using Cox regression modeling and Kaplan-Meier estimates. RESULTS AND LIMITATIONS: A total of 2,796 patients were included in the final study population, and 960 in the matched cohort (480 per treatment group). Utilization of immunotherapy increased over the time period studied as chemotherapy decreased (Immunotherapy: 3%-37%; Chemotherapy: 97%-63%; P < 0.001). In the overall cohort, patients who received first-line immunotherapy were older and more comorbid than those who received first-line chemotherapy (Age: 73 v. 67, respectively, P < 0.001; Charlson-Deyo score ≥2: 17% v. 11.5%, respectively, P < 0.001). In the matched cohort, patients who were treated with first-line immunotherapy had similar OS to those who were treated with first-line chemotherapy (HR: 0.91, 95CI 0.72-1.15). Due to the retrospective nature of the study, interpretation is limited by potential selection bias from unmeasured confounding. CONCLUSIONS AND RELEVANCE: Metastatic bladder UC patients who received first-line immunotherapy had similar OS to those who received first-line chemotherapy.

Methodological advances for hypothesis-driven ethnobiology.

Ethnobiology as a discipline has evolved increasingly to embrace theory-inspired and hypothesis-driven approaches to study why and how local people choose plants and animals they interact with and use for their livelihood. However, testing complex hypotheses or a network of ethnobiological hypotheses is challenging, particularly for data sets with non-independent observations due to species phylogenetic relatedness or socio-relational links between participants. Further, to account fully for the dynamics of local ecological knowledge, it is important to include the spatially explicit distribution of knowledge, changes in knowledge, and knowledge transmission and use. To promote the use of advanced statistical modelling approaches that address these limitations, we synthesize methodological advances for hypothesis-driven research in ethnobiology while highlighting the need for more figures than tables and more tables than text in ethnobiological literature. We present the ethnobiological motivations for conducting generalized linear mixed-effect modelling, structural equation modelling, phylogenetic generalized least squares, social network analysis, species distribution modelling, and predictive modelling. For each element of the proposed ethnobiologists quantitative toolbox, we present practical applications along with scripts for a widespread implementation. Because these statistical modelling approaches are rarely taught in most ethnobiological programs but are essential for careers in academia or industry, it is critical to promote workshops and short courses focused on these advanced methods. By embracing these quantitative modelling techniques without sacrificing qualitative approaches which provide essential context, ethnobiology will progress further towards an expansive interaction with other disciplines.

Pathological Downstaging and Survival Outcomes Associated with Neoadjuvant Chemotherapy for Variant Histology Muscle Invasive Bladder Cancer.

PURPOSE: Patients with muscle invasive bladder cancer (MIBC) of variant histology have a poor prognosis. It is unclear if neoadjuvant chemotherapy prior to radical cystectomy is associated with pathological downstaging or improved overall survival (OS) for patients with variant histology. Our objective was to assess for associations between receipt of neoadjuvant chemotherapy, pathological downstaging and OS for patients with variant histology MIBC. MATERIALS AND METHODS: Patients were identified in the National Cancer Database from 2004 to 2017 with MIBC, without metastases, who underwent radical cystectomy. Patients were stratified by histological subgroup, and receipt or nonreceipt of neoadjuvant chemotherapy. Pathological downstaging was defined as pT0N0 or pT ≤1N0, and OS from the time of diagnosis to date of death or censoring at last followup. Multivariable logistic regression analysis determined associations between neoadjuvant chemotherapy and pathological downstaging. Multivariable Cox regression analysis determined associations between neoadjuvant chemotherapy and OS. RESULTS: A total of 31,218 patients were included in the final study population (urothelial carcinoma [UC]: 27,779; sarcomatoid UC: 501; micropapillary UC: 418; squamous cell carcinoma: 1,141; neuroendocrine carcinoma: 629; adenocarcinoma: 750). Neoadjuvant chemotherapy was associated with pathological downstaging to pT0N0 in all histological subgroups (UC: OR 5.1 [4.6-5.6]; sarcomatoid UC: OR 13.8 [5.5-39.0]; micropapillary UC: OR 9.7 [2.8-46.8]; squamous cell carcinoma: OR 7.4 [2.1-24.5]; neuroendocrine: OR 4.7 [2.6-9.2]; adenocarcinoma: OR 23.3 [8.0-74.2]). Neoadjuvant chemotherapy was associated with improved OS for UC (HR 0.8 [0.77-0.84]), sarcomatoid UC (HR 0.64 [0.44-0.91]) and neuroendocrine carcinoma (HR 0.55 [0.43-0.70]). CONCLUSIONS: Neoadjuvant chemotherapy was associated with pathological downstaging for all MIBC histological variants, with improved OS for patients with UC, sarcomatoid variant UC and neuroendocrine carcinoma.

Real-World Survival Outcomes Associated With First-Line Immunotherapy, Targeted Therapy, and Combination Therapy for Metastatic Clear Cell Renal Cell Carcinoma.

Importance: Clinical trials have shown an overall survival (OS) benefit associated with first-line immunotherapy (IT) and combination targeted therapy (TT) and IT regimens compared with TT among patients with metastatic clear cell renal cell carcinoma (RCC). Generalizability of these findings in a real-world cohort outside of a clinical trial setting is unclear. Objective: To assess the association of first-line TT, IT, and combination TT and IT regimens with OS in a real-world cohort of patients with metastatic clear cell RCC. Design, Setting, and Participants: This retrospective propensity-matched cohort study identified 5872 patients with metastatic clear cell RCC in the National Cancer Database from January 1, 2015, to December 31, 2017, who received first-line TT, IT, or combination TT and IT and were not treated on a clinical trial protocol. Patients were stratified by first-line systemic treatment. Statistical analysis was conducted from October 1 to December 1, 2020. Main Outcomes and Measures: The primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. After 1:1:1 nearest-neighbor caliper matching of propensity scores, survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. Results: The final study population included 5872 patients (TT group: n = 4755 [81%]; 3332 men [70%]; median age, 64 years [interquartile range, 57-71 years]; IT group: n = 638 [11%]; 475 men [74%]; median age, 61 years [interquartile range, 54-69 years]; and combination TT and IT group: n = 479 [8%]; 321 men [67%]; median age, 62 years [interquartile range, 55-69 years]), and the matched cohort included 1437 patients (479 per treatment group). Patients in the IT and combination TT and IT groups were younger than those in the TT group, had fewer comorbid conditions (Charlson-Deyo score of 0, 480 of 638 [75%] in the TT group, 356 of 479 [74%] in the IT group, and 3273 of 4755 [69%] in the combination TT and IT group), and were more often treated at academic centers (315 of 638 [49%], 216 of 479 [45%], and 1935 of 4755 [41%], respectively). Both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC (IT group: hazard ratio [HR], 0.60 [95% CI, 0.48-0.75]; P < .001; combination TT and IT group: HR, 0.74 [95% CI, 0.60-0.91]; P = .005). No survival difference was seen between the IT and combination TT and IT groups (combination TT and IT: HR, 1.24 [95% CI, 0.98-1.56]; P = .08). Conclusions and Relevance: This study suggests that both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC. These findings are similar to those identified in recently reported clinical trials, lending confidence to the broader applicability of these findings outside of a clinical trial setting.

Clinical Utility of Cell-free and Circulating Tumor DNA in Kidney and Bladder Cancer: A Critical Review of Current Literature.

CONTEXT: Bladder and kidney cancers require invasive procedures for definitive diagnosis, and bladder cancer requires repeated procedures to monitor for disease recurrence. Given the recent work to identify molecular alterations in liquid biopsies to diagnose and monitor these diseases, a synthesis of the growing body of evidence is merited. OBJECTIVE: To review current data on cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) and to synthesize their roles in the diagnosis, monitoring, and prognostication of bladder and kidney cancer. EVIDENCE ACQUISITION: A literature review was conducted through August 15, 2020 including prospective and retrospective studies. Keywords included "cell-free DNA", "circulating tumor DNA", "kidney cancer", "renal cell carcinoma", "bladder cancer", "upper tract urothelial carcinoma", and "urothelial carcinoma". EVIDENCE SYNTHESIS: Urine tumor DNA (utDNA) has sensitivity of 91% and specificity of 96% for detecting bladder cancer, outperforming cystoscopy and cytology. Increased utDNA and ctDNA are associated with progression from non-muscle-invasive to muscle-invasive disease. In patients undergoing cystectomy, ctDNA detection is associated with worse overall survival and disease recurrence, and with persistent tumor on surgical pathology in those who received neoadjuvant chemotherapy. cfDNA is significantly higher in patients with kidney cancer than in healthy controls or in those with benign lesions, and detectable ctDNA and increased cfDNA are associated with decreased survival. CONCLUSIONS: Combined data from small studies provide evidence that cfDNA and ctDNA may have the ability to detect, monitor, and prognosticate in patients with bladder, upper tract urothelial, and kidney cancers. PATIENT SUMMARY: In this review, we looked at the work that has been published so far on cell-free and circulating tumor DNA in bladder and kidney cancers. We found that while many of the studies were small, there is evidence that cell-free tumor DNA can emerge as a tool for the diagnosis and monitoring of treatment response for patients with these cancers.

Child development assessment: Practitioner input in the revision for Griffiths III.

INTRODUCTION: The input from practitioners in developmental assessment test revision is a crucial and leading component of the project. This paper highlights six key phases of the Griffiths III revision process and the value of having a guiding plan that includes test practitioner input. METHODS: The revision of the Griffiths III consisted of six separate phases that were supported by practitioner and user input and feedback. These six phases and practitioner views ensured that the necessary core constructs and new areas for item development were included in the revised version. These processes also underscored the construct development and task review, item design, piloting and standardization of the revised version, as well as its production, release and subsequent training methods. RESULTS: The six guiding phases provided a methodologically robust frame to the revision process. Practitioners valued an overall developmental measure with discrete data about and within the 'avenues of learning' allowing them to analyse a child's strengths and weaknesses. Communication with practitioners across the world demonstrated the wide disparity of culture and environments that the Griffiths Scales are deployed in. It is not possible to design a revised scale that is appropriate for all areas of use, so in this revision process, it was decided to design the scales as culturally fair as possible and support practitioners in other countries to translate and validate the scales for use. CONCLUSIONS: The revision of the Griffiths III found test users to be valuable sources of information on the basis of their experiences with the test and professional knowledge. Creating a continuous feedback mechanism within a phased process provided opportunities for the revision team to engage meaningfully with the data being obtained as well as test users to advance the scope and quality of the test. Revision teams are encouraged to consider the process and engagement methods explored in this study during their projects.

Scientific considerations for global drug development.

Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.

Below the canopy: global trends in forest vertebrate populations and their drivers.

Global forest assessments use forest area as an indicator of biodiversity status, which may mask below-canopy pressures driving forest biodiversity loss and 'empty forest' syndrome. The status of forest biodiversity is important not only for species conservation but also because species loss can have consequences for forest health and carbon storage. We aimed to develop a global indicator of forest specialist vertebrate populations to improve assessments of forest biodiversity status. Using the Living Planet Index methodology, we developed a weighted composite Forest Specialist Index for the period 1970-2014. We then investigated potential correlates of forest vertebrate population change. We analysed the relationship between the average rate of change of forest vertebrate populations and satellite-derived tree cover trends, as well as other pressures. On average, forest vertebrate populations declined by 53% between 1970 and 2014. We found little evidence of a consistent global effect of tree cover change on forest vertebrate populations, but a significant negative effect of exploitation threat on forest specialists. In conclusion, we found that the forest area is a poor indicator of forest biodiversity status. For forest biodiversity to recover, conservation management needs to be informed by monitoring all threats to vertebrates, including those below the canopy.

Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3).

BACKGROUND: Transporter-mediated drug-nutrient interactions have the potential to cause serious adverse events. However, unlike drug-drug interactions, these drug-nutrient interactions receive little attention during drug development. The clinical importance of drug-nutrient interactions was highlighted when a phase III clinical trial was terminated due to severe adverse events resulting from potent inhibition of thiamine transporter 2 (ThTR-2; SLC19A3). OBJECTIVE: In this study, we tested the hypothesis that therapeutic drugs inhibit the intestinal thiamine transporter ThTR-2, which may lead to thiamine deficiency. METHODS: For this exploration, we took a multifaceted approach, starting with a high-throughput in vitro primary screen to identify inhibitors, building in silico models to characterize inhibitors, and leveraging real-world data from electronic health records to begin to understand the clinical relevance of these inhibitors. RESULTS: Our high-throughput screen of 1360 compounds, including many clinically used drugs, identified 146 potential inhibitors at 200 µM. Inhibition kinetics were determined for 28 drugs with half-maximal inhibitory concentration (IC50) values ranging from 1.03 µM to >1 mM. Several oral drugs, including metformin, were predicted to have intestinal concentrations that may result in ThTR-2-mediated drug-nutrient interactions. Complementary analysis using electronic health records suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs found to significantly inhibit ThTR-2, particularly in vulnerable populations (e.g., individuals with alcoholism). CONCLUSIONS: Our comprehensive analysis of prescription drugs suggests that several marketed drugs inhibit ThTR-2, which may contribute to thiamine deficiency, especially in at-risk populations.

Relating characteristics of global biodiversity targets to reported progress.

To inform governmental discussions on the nature of a revised Strategic Plan for Biodiversity of the Convention on Biological Diversity (CBD), we reviewed the relevant literature and assessed the framing of the 20 Aichi Biodiversity Targets in the current strategic plan. We asked international experts from nongovernmental organizations, academia, government agencies, international organizations, research institutes, and the CBD to score the Aichi Targets and their constituent elements against a set of specific, measurable, ambitious, realistic, unambiguous, scalable, and comprehensive criteria (SMART based, excluding time bound because all targets are bound to 2015 or 2020). We then investigated the relationship between these expert scores and reported progress toward the target elements by using the findings from 2 global progress assessments (Global Biodiversity Outlook and the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services). We analyzed the data with ordinal logistic regressions. We found significant positive relationships (p < 0.05) between progress and the extent to which the target elements were perceived to be measurable, realistic, unambiguous, and scalable. There was some evidence of a relationship between progress and specificity of the target elements, but no relationship between progress and ambition. We are the first to show associations between progress and the extent to which the Aichi Targets meet certain SMART criteria. As negotiations around the post-2020 biodiversity framework proceed, decision makers should strive to ensure that new or revised targets are effectively structured and clearly worded to allow the translation of targets into actionable policies that can be successfully implemented nationally, regionally, and globally.

Relación de las Características de los Objetivos Mundiales de Biodiversidad con el Progreso Reportado Resumen Para informar las discusiones gubernamentales sobre la naturaleza de una revisión del Plan Estratégico para la Biodiversidad del Convenio sobre la Diversidad Biológica (CBD, en inglés), revisamos la literatura relevante y evaluamos el marco de 20 Objetivos de Biodiversidad de Aichi en el plan estratégico actual. Le pedimos a expertos internacionales de organizaciones no gubernamentales, de la academia, de agencias gubernamentales, organizaciones internacionales, de institutos de investigación y de la CBD que puntuaran los Objetivos de Aichi y sus elementos constituyentes frente a un conjunto de criterios específicos, medibles, ambiciosos, realistas (basados en SMART [las iniciales en inglés] y excluyendo aquellos limitados por el tiempo, pues todos los objetivos están limitados al 2015 o al 2020), inequívocos, expansibles y completos (excluyendo aquellos limitados por el tiempo). Después investigamos la relación entre los puntajes de estos expertos y el progreso reportado hacia los elementos objetivo usando los resultados de dos valoraciones mundiales del progreso (el Pronóstico Mundial de la Biodiversidad y la Plataforma Intergubernamental de Ciencia y Política sobre la Biodiversidad y los Servicios Ambientales). Analizamos los datos con regresiones logísticas ordinales. Encontramos relaciones positivas significativas (p < 0.05) entre el progreso y el alcance al que fueron percibidos como medibles, realistas, inequívocos y expansibles los elementos objetivo. Hubo algo de evidencia de la relación entre el progreso y la ambición. Somos los primeros en mostrar las asociaciones entre el progreso y la extensión hasta la que los Objetivos de Aichi cumplen con ciertos criterios SMART. Conforme proceden las negociaciones en torno al marco de trabajo de biodiversidad post-2020, quienes toman las decisiones deberían esforzarse por asegurar que los objetivos nuevos o revisados estén estructurados efectivamente y redactados claramente para permitir la traducción de los objetivos hacia políticas factibles que puedan implementarse exitosamente a nivel nacional, regional y mundial.