General practice pharmacist-led antipsychotic physical health monitoring: a prospective intervention scoping study.

BACKGROUND: People with severe mental health illness die prematurely, often due to preventable cardiometabolic disease, which can be exacerbated by antipsychotic medicines that are effective for treating mental illness. Literature demonstrates that physical health monitoring, as recommended in guidelines, for people receiving antipsychotics is substandard. Therefore, we aimed to scope the potential of a general practice clinical pharmacist (GPCP)-led multidisciplinary intervention optimising adherence to cardiometabolic monitoring guidelines and delivering polypharmacy reviews. METHOD: Prospective intervention scoping study in three urban general practices; one usual care, two intervention. Patients 18-65 years old prescribed oral antipsychotics were identified from records, and invited for cardiometabolic monitoring and GPCP medication review, from January to December 2022. Interventions and onward referrals were recorded and collated. Anonymised pre- and post-review data were analysed, and actions were graded for clinical importance. RESULTS: In total 1.5% (210/14,159) of patients aged 18-65 years met inclusion criteria; usual care practice (n = 58); and intervention practices (n = 152). From baseline, the usual care practice achieved an absolute 7% increase in the cardiometabolic monitoring care bundle (glucose/glycosylated haemoglobin, lipids, blood pressure plus body mass index) versus 19-58% in the intervention practices. Two-thirds (92/152) of patients participated in medication reviews, requiring pharmacological and/or non-pharmacological clinical actions. The majority of actions were graded as moderate importance. Seven percentage of patients were identified as new pre-diabetic/diabetic and 6% were at high risk of cardiovascular disease requiring statin initiation. CONCLUSION: A pharmacist-led multidisciplinary general practice-based approach may be effective at optimising cardiometabolic monitoring; identifying and treating diabetic and cardiovascular risk factors.

People with severe mental illness die 15­20 years earlier than the general population, many due to preventable and/or treatable heart disease. While antipsychotic medicines are effective for treating mental illness they are associated with potential adverse effects; weight gain, increased blood pressure, blood sugar, and cholesterol. Therefore, guidelines advise regular physical health checks for people with severe mental illness, and those receiving antipsychotics, to reduce avoidable harms and optimise preventative treatments. However, routine monitoring is substandard. This study aimed to explore the potential of a general practice pharmacist-led intervention to optimise physical health monitoring and medication reviews, from January to December 2022. Three practices participated; one providing usual care, and two the pharmacist intervention. The usual care practice achieved a 7% increase in all monitoring parameters (weight, blood pressure, blood sugars plus cholesterol), whereas the pharmacist-led practices achieved a 19­58% increase in monitoring. Two in three patients (92/152) participated in a medication review with the pharmacists that addressed a range of mental and physical health issues. Of the 152 patients in the intervention practices 6% were identified as being at high risk of heart disease requiring preventative medicines, and 7% were identified as having new diabetes and/or pre-diabetes.

Predicting Visual Field Worsening with Longitudinal OCT Data Using a Gated Transformer Network.

PURPOSE: To identify visual field (VF) worsening from longitudinal OCT data using a gated transformer network (GTN) and to examine how GTN performance varies for different definitions of VF worsening and different stages of glaucoma severity at baseline. DESIGN: Retrospective longitudinal cohort study. PARTICIPANTS: A total of 4211 eyes (2666 patients) followed up at the Johns Hopkins Wilmer Eye Institute with at least 5 reliable VF results and 1 reliable OCT scan within 1 year of each reliable VF test. METHODS: For each eye, we used 3 trend-based methods (mean deviation [MD] slope, VF index slope, and pointwise linear regression) and 3 event-based methods (Guided Progression Analysis, Collaborative Initial Glaucoma Treatment Study scoring system, and Advanced Glaucoma Intervention Study [AGIS] scoring system) to define VF worsening. Additionally, we developed a "majority of 6" algorithm (M6) that classifies an eye as worsening if 4 or more of the 6 aforementioned methods classified the eye as worsening. Using these 7 reference standards for VF worsening, we trained 7 GTNs that accept a series of at least 5 as input OCT scans and provide as output a probability of VF worsening. Gated transformer network performance was compared with non-deep learning models with the same serial OCT input from previous studies-linear mixed-effects models (MEMs) and naive Bayes classifiers (NBCs)-using the same training sets and reference standards as for the GTN. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC). RESULTS: The M6 labeled 63 eyes (1.50%) as worsening. The GTN achieved an AUC of 0.97 (95% confidence interval, 0.88-1.00) when trained with M6. Gated transformer networks trained and optimized with the other 6 reference standards showed an AUC ranging from 0.78 (MD slope) to 0.89 (AGIS). The 7 GTNs outperformed all 7 MEMs and all 7 NBCs accordingly. Gated transformer network performance was worse for eyes with more severe glaucoma at baseline. CONCLUSIONS: Gated transformer network models trained with OCT data may be used to identify VF worsening. After further validation, implementing such models in clinical practice may allow us to track functional worsening of glaucoma with less onerous structural testing. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A surplus no more? Variation in krill availability impacts reproductive rates of Antarctic baleen whales.

The krill surplus hypothesis of unlimited prey resources available for Antarctic predators due to commercial whaling in the 20th century has remained largely untested since the 1970s. Rapid warming of the Western Antarctic Peninsula (WAP) over the past 50 years has resulted in decreased seasonal ice cover and a reduction of krill. The latter is being exacerbated by a commercial krill fishery in the region. Despite this, humpback whale populations have increased but may be at a threshold for growth based on these human-induced changes. Understanding how climate-mediated variation in prey availability influences humpback whale population dynamics is critical for focused management and conservation actions. Using an 8-year dataset (2013-2020), we show that inter-annual humpback whale pregnancy rates, as determined from skin-blubber biopsy samples (n = 616), are positively correlated with krill availability and fluctuations in ice cover in the previous year. Pregnancy rates showed significant inter-annual variability, between 29% and 86%. Our results indicate that krill availability is in fact limiting and affecting reproductive rates, in contrast to the krill surplus hypothesis. This suggests that this population of humpback whales may be at a threshold for population growth due to prey limitations. As a result, continued warming and increased fishing along the WAP, which continue to reduce krill stocks, will likely impact this humpback whale population and other krill predators in the region. Humpback whales are sentinel species of ecosystem health, and changes in pregnancy rates can provide quantifiable signals of the impact of environmental change at the population level. Our findings must be considered paramount in developing new and more restrictive conservation and management plans for the Antarctic marine ecosystem and minimizing the negative impacts of human activities in the region.

Machine-Identified Patterns of Visual Field Loss and an Association with Rapid Progression in the Ocular Hypertension Treatment Study.

PURPOSE: To identify patterns of visual field (VF) loss based on unsupervised machine learning and to identify patterns that are associated with rapid progression. DESIGN: Cross-sectional and longitudinal study. PARTICIPANTS: A total of 2231 abnormal VFs from 205 eyes of 176 Ocular Hypertension Treatment Study (OHTS) participants followed over approximately 16 years. METHODS: Visual fields were assessed by an unsupervised deep archetypal analysis algorithm and an OHTS-certified VF reader to identify prevalent patterns of VF loss. Machine-identified patterns of glaucoma damage were compared against those patterns previously identified (expert-identified) in the OHTS in 2003. Based on the longitudinal VFs of each eye, VF loss patterns that were strongly associated with rapid glaucoma progression were identified. MAIN OUTCOME MEASURES: Machine-expert correspondence and type of patterns of VF loss associated with rapid progression. RESULTS: The average VF mean deviation (MD) at conversion to glaucoma was -2.7 decibels (dB) (standard deviation [SD] = 2.4 dB), whereas the average MD of the eyes at the last visit was -5.2 dB (SD = 5.5 dB). Fifty out of 205 eyes had MD rate of -1 dB/year or worse and were considered rapid progressors. Eighteen machine-identified patterns of VF loss were compared with expert-identified patterns, in which 13 patterns of VF loss were similar. The most prevalent expert-identified patterns included partial arcuate, paracentral, and nasal step defects, and the most prevalent machine-identified patterns included temporal wedge, partial arcuate, nasal step, and paracentral VF defects. One of the machine-identified patterns of VF loss predicted future rapid VF progression after adjustment for age, sex, and initial MD. CONCLUSIONS: An automated machine learning system can identify patterns of VF loss and could provide objective and reproducible nomenclature for characterizing early signs of visual defects and rapid progression in patients with glaucoma.

Does the morphology of cutaneous melanoma help to explain the international differences in survival? Results from 1 578 482 adults diagnosed during 2000-2014 in 59 countries (CONCORD-3).

BACKGROUND: CONCORD-3 highlighted wide disparities in population-based 5-year net survival for cutaneous melanoma during 2000-2014. Clinical evidence suggests marked international differences in the proportion of lethal acral and nodular subtypes of cutaneous melanoma. OBJECTIVES: We aimed to assess whether the differences in morphology may explain global variation in survival. METHODS: Patients with melanoma were grouped into the following seven morphological categories: malignant melanoma, not otherwise specified (International Classification of Diseases for Oncology, third revision morphology code 8720), superficial spreading melanoma (8743), lentigo maligna melanoma (8742), nodular melanoma (8721), acral lentiginous melanoma (8744), desmoplastic melanoma (8745) and other morphologies (8722-8723, 8726-8727, 8730, 8740-8741, 8746, 8761, 8770-8774, 8780). We estimated net survival using the nonparametric Pohar Perme estimator, correcting for background mortality by single year of age, sex and calendar year in each country or region. All-ages survival estimates were standardized using the International Cancer Survival Standard weights. We fitted a flexible parametric model to estimate the effect of morphology on the hazard of death. RESULTS: Worldwide, the proportion of nodular melanoma ranged between 7% and 13%. Acral lentiginous melanoma accounted for less than 2% of all registrations but was more common in Asia (6%) and Central and South America (7%). Overall, 36% of tumours were classified as superficial spreading melanoma. During 2010-2014, age-standardized 5-year net survival for superficial spreading melanoma was 95% or higher in Oceania, North America and most European countries, but was only 71% in Taiwan. Survival for acral lentiginous melanoma ranged between 66% and 95%. Nodular melanoma had the poorest prognosis in all countries. The multivariable analysis of data from registries with complete information on stage and morphology found that sex, age and stage at diagnosis only partially explain the higher risk of death for nodular and acral lentiginous subtypes. CONCLUSIONS: This study provides the broadest picture of distribution and population-based survival trends for the main morphological subtypes of cutaneous melanoma in 59 countries. The poorer prognosis for nodular and acral lentiginous melanomas, more frequent in Asia and Latin America, suggests the need for health policies aimed at specific populations to improve awareness, early diagnosis and access to treatment. What is already known about this topic? The histopathological features of cutaneous melanoma vary markedly worldwide. The proportion of melanomas with the more aggressive acral lentiginous or nodular histological subtypes is higher in populations with predominantly dark skin than in populations with predominantly fair skin. What does this study add? We aimed to assess the extent to which these differences in morphology may explain international variation in survival when all histological subtypes are combined. This study provides, for the first time, international comparisons of population-based survival at 5 years for the main histological subtypes of melanoma for over 1.5 million adults diagnosed during 2000-2014. This study highlights the less favourable distribution of histological subtypes in Asia and Central and South America, and the poorer prognosis for nodular and acral lentiginous melanomas. We found that later stage at diagnosis does not fully explain the higher excess risk of death for nodular and acral lentiginous melanoma compared with superficial spreading melanoma.

New ways of working releasing general practitioner capacity with pharmacy prescribing support: a cost-consequence analysis.

BACKGROUND: General practice in the United Kingdom is experiencing a workforce crisis. Greater multidisciplinary working, including more general practice pharmacists, is seen as part of the solution. However, it is unknown what impact and cost-consequences that pharmacists may have in freeing general practitioner (GP) capacity. OBJECTIVE: To evaluate the cost-consequences of additional pharmacists in releasing GP capacity. METHODS: This cost-consequences evaluation of a prospective observational cohort study in 15 urban practices involving 69 GPs in 1 locality serving a population of 82,000 people. GPs recorded the time they spent addressing key targeted prescribing activities during 5 distinct 2-week audit periods. Pharmacists performed these key prescribing activities to release GP capacity. An additional 225 h of pharmacists' time per week was committed to the locality. Standardized staff costings were used to estimate the financial impact. Prescribing indicator performance was assessed against the other 7 localities within the health board. RESULTS: When compared with employing extra nonsalaried GPs this required an estimated additional investment of £16.73 (range £5.97-20.87) per h to free GP capacity. This achieved a sustainable 47% (73 h per week, F(4,56) = 16.05, P < 0.001) reduction in GP time spent on key prescribing activities; equating to 4.9 h (95% confidence interval 3.1-6.7) per practice per week. No significant step changes in locality safety and quality prescribing measures, and no negative effects on locality-level prescribing cost-efficiency work were observed. CONCLUSION: Appropriately resourced general practice pharmacy teams delivered prescribing cost-efficiencies as well as sustainably freeing GP capacity by performing key prescribing activities.

General practice in the United Kingdom is experiencing a workforce crisis, and is struggling to deliver services. Pharmacists have been shown to be effective in freeing general practitioner (GP) capacity. However, it is unknown how much it costs to do this. Therefore, we aimed to assess the cost-consequences of releasing GP capacity. All practices in 1 region took part. GPs recorded the time it routinely took them to address key prescribing activities, Spring 2016. Pharmacists then delivered the key prescribing activities. The region got an extra 225 h of pharmacists' time to do these activities. Then in Spring 2018, the GPs and pharmacists recorded the time took to do the key prescribing activities. Standard salary costs were used to estimate how much money was needed to free GP capacity with pharmacists. The impact on routine cost-effective work was also assessed. Pharmacists delivering key prescribing activities freed 73 h per week of GP time. This equalled an average of 5 h per week per practice. Freeing GP capacity was estimated to cost an extra £16.73 (range £5.97­20.87) per h. There were no negative effects on cost-efficiency work. Appropriately resourcing general practice with pharmacists delivers sustainable prescribing cost-efficiencies and frees GP capacity.

Evaluation of the Melbourne Rapid Fields Test Procedure.

SIGNIFICANCE: Both the Melbourne Rapid Fields (MRF) tablet and home versions are easy-to-use, portable, and low-cost and accurate methods of evaluating visual fields. PURPOSE: This study aimed to investigate the clinical capabilities of the MRF perimetry test by comparing it with the Humphrey Field Analyzer (HFA), determine MRF consistency, assess the influence of refractive error, ascertain ambient illumination effects, and evaluate the consistency between the tablet and Internet Web site versions of the MRF. METHODS: Forty healthy young participants with normal visual function (33 female, 7 male; average age, 24 years) underwent two MRF office-based tablet, two HFA tests, and two MRF Web site-based tests, one in our laboratory and one at home on their own computer using the 24-2 test pattern each time. An additional six healthy participants with normal visual function performed the 24-2 test with varying amounts of blur. RESULTS: The average individual sensitivity values of MRF and HFA were within 4.02 dB (right eye) and 4.15 dB (left eye). The dynamic range of the MRF was smaller (30 dB) than that of the HFA. When sensitivity values greater than 30 dB were excluded, the sensitivity differences were within 2.2 dB (right eye) and 2.46 dB (left eye) of each other. Only a small number of cases produced reliability values (false positives, false negatives, fixation losses) that were outside of normal limits. There was a high correlation between test results obtained with the tablet version of the MRF test when compared with the Internet-based Web site version. CONCLUSIONS: Quantitative visual field testing and perimetric screening procedures can be performed effectively and can provide results that are comparable with bowl perimeter test results.

A Consensus Statement on the Terminology for Automated Visual Field Abnormalities.

BACKGROUND: A multitude of terms have been used to describe automated visual field abnormalities. To date, there is no universally accepted system of definitions or guidelines. Variability among clinicians creates the risk of miscommunication and the compromise of patient care. The purposes of this study were to 1) assess the degree of consistency among a group of neuro-ophthalmologists in the description of visual field abnormalities and 2) to create a consensus statement with standardized terminology and definitions. METHODS: In phase one of the study, all neuro-ophthalmologists in Israel were asked to complete a survey in which they described the abnormalities in 10 selected automated visual field tests. In phase 2 of the study, the authors created a national consensus statement on the terminology and definitions for visual field abnormalities using a modified Delphi method. In phase 3, the neuro-ophthalmologists were asked to repeat the initial survey of the 10 visual fields using the consensus statement to formulate their answers. RESULTS: Twenty-six neuro-ophthalmologists participated in the initial survey. On average, there were 7.5 unique descriptions for each of the visual fields (SD 3.17), a description of only the location in 24.6% (SD 0.19), and an undecided response in 6.15% (SD 4.13). Twenty-two neuro-ophthalmologists participated in the creation of a consensus statement which included 24 types of abnormalities with specific definitions. Twenty-three neuro-ophthalmologists repeated the survey using the consensus statement. On average, in the repeated survey, there were 5.9 unique descriptions for each of the visual fields (SD 1.79), a description of only the location in 0.004% (SD 0.01), and an undecided response in 3.07% (SD 2.11%). Relative to the first survey, there was a significant improvement in the use of specific and decisive terminology. CONCLUSIONS: The study confirmed a great degree of variability in the use of terminology to describe automated visual field abnormalities. The creation of a consensus statement was associated with improved use of specific terminology. Future efforts may be warranted to further standardize terminology and definitions.

Do Additional Testing Locations Improve the Detection of Macular Perimetric Defects in Glaucoma?

PURPOSE: To evaluate the ability of additional central testing locations to improve detection of macular visual field (VF) defects in glaucoma. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Four hundred forty healthy people and 499 patients with glaucomatous optic neuropathy (GON) were tested with a fundus tracked perimeter (CMP; CenterVue) using a 24-2 grid with 12 additional macular locations (24-2+). METHODS: Glaucomatous optic neuropathy was identified based on expert evaluation of optic nerve head photographs and OCT scans, independently of the VF. We defined macular defects as locations with measurements outside the 5% and 2% normative limits on total deviation (TD) and pattern deviation (PD) maps within the VF central 10°. Classification was based on the total number of affected macular locations (overall detection) or the largest number of affected macular locations connected in a contiguous cluster (cluster detection). Criteria based on the number of locations and cluster size were used to obtain equivalent specificity between the 24-2 grid and the 24-2+ grids, calculated using false detections in the healthy cohort. Partial areas under the receiver operating characteristic curve (pAUCs) were also compared at specificities of 95% or more. MAIN OUTCOME MEASURES: Matched specificity comparison of the ability to detect glaucomatous macular defects between the 24-2 and 24-2+ grids. RESULTS: At matched specificity, cluster detection identified more macular defects with the 24-2+ grid compared with the 24-2 grid. For example, the mean increase in percentage of detection was 8% (95% confidence interval [CI], 5%-11%) and 10% (95% CI, 7%-13%) for 5% TD and PD maps, respectively, and 5% (95% CI, 2%-7%) and 6% (95% CI, 4%-8%) for the 2% TD and PD maps, respectively. Good agreement was found between the 2 grids. The improvement measured by pAUCs was also significant but generally small. The percentage of eyes with macular defects ranged from about 30% to 50%. Test time for the 24-2+ grid was longer (21% increase) for both cohorts. Between 74% and 98% of defects missed by the 24-2 grid had at least 1 location with sensitivity of < 20 dB. CONCLUSIONS: Visual field examinations with additional macular locations can improve the detection of macular defects in GON modestly without loss of specificity when appropriate criteria are selected.

Reproducibility and accuracy of microscale thermophoresis in the NanoTemper Monolith: a multi laboratory benchmark study.

Microscale thermophoresis (MST), and the closely related Temperature Related Intensity Change (TRIC), are synonyms for a recently developed measurement technique in the field of biophysics to quantify biomolecular interactions, using the (capillary-based) NanoTemper Monolith and (multiwell plate-based) Dianthus instruments. Although this technique has been extensively used within the scientific community due to its low sample consumption, ease of use, and ubiquitous applicability, MST/TRIC has not enjoyed the unambiguous acceptance from biophysicists afforded to other biophysical techniques like isothermal titration calorimetry (ITC) or surface plasmon resonance (SPR). This might be attributed to several facts, e.g., that various (not fully understood) effects are contributing to the signal, that the technique is licensed to only a single instrument developer, NanoTemper Technology, and that its reliability and reproducibility have never been tested independently and systematically. Thus, a working group of ARBRE-MOBIEU has set up a benchmark study on MST/TRIC to assess this technique as a method to characterize biomolecular interactions. Here we present the results of this study involving 32 scientific groups within Europe and two groups from the US, carrying out experiments on 40 Monolith instruments, employing a standard operation procedure and centrally prepared samples. A protein-small molecule interaction, a newly developed protein-protein interaction system and a pure dye were used as test systems. We characterized the instrument properties and evaluated instrument performance, reproducibility, the effect of different analysis tools, the influence of the experimenter during data analysis, and thus the overall reliability of this method.

Implementation of the Canadian Cardiovascular Society guidelines for perioperative risk assessment and management: an interrupted time series study.

PURPOSE: The Canadian Cardiovascular Society (CCS) guidelines for patients undergoing non-cardiac surgery address the lack of standardized management for patients at risk of perioperative cardiovascular complications. Our interdisciplinary group evaluated the implementation of these guidelines. METHODS: We used an interrupted time series design to evaluate the effect of implementation of the CCS guidelines, using routinely collected hospital data. The study population consisted of elective, non-cardiac surgery patients who were: i) inpatients following surgery and ii) age ≥ 65 or age 45-64 yr with a Revised Cardiac Risk Index ≥ 1. Outcomes included adherence to troponin I (TnI) monitoring (primary) and adherence to appropriate consultant care for patients with elevated TnI (secondary). Exploratory outcomes included cost measures and clinical outcomes such as length of stay. RESULTS: We included 1,421 patients (706 pre- and 715 post-implementation). We observed a 67% absolute increase (95% confidence interval, 55 to 80; P < 0.001) in adherence to TnI testing following the implementation of the guidelines. In patients who had elevated TnI following guideline implementation (n = 64), the majority (85%) received appropriate follow-up care in the form of a general medicine or cardiology consult, all received at least one electrocardiogram, and half received at least one advanced cardiac test (e.g., cardiac perfusion scan, or percutaneous intervention). CONCLUSIONS: Our study showed the ability to implement and adhere to the CCS guidelines. Large-scale multicentre evaluations of CCS guideline implementation are needed to gain a better understanding of potential effects on clinically relevant outcomes.

RéSUMé: OBJECTIF: Les lignes directrices de la Société canadienne de cardiologie (SCC) concernant les patients subissant une chirurgie non cardiaque ont été conçues pour pallier l'absence de standardisation dans la prise en charge des patients à risque de complications cardiovasculaires périopératoires. Notre groupe interdisciplinaire a évalué la mise en œuvre de ces lignes directrices. MéTHODE: Nous avons utilisé une méthodologie de série chronologique interrompue pour évaluer l'effet de la mise en œuvre des lignes directrices de la SCC, à l'aide des données hospitalières habituellement recueillies. La population à l'étude se composait de patients de chirurgies non cardiaques non urgentes qui étaient : i) hospitalisés après leur chirurgie et ii) âgés de ≥ 65 ans ou de 45 à 64 ans avec un Indice de risque cardiaque révisé ≥ 1. Les critères d'évaluation comprenaient l'observance du monitorage de la troponine I (TnI) (critère d'évaluation primaire) et l'observance des soins spécialisés appropriés aux patients présentant un taux élevé de TnI (critère secondaire). Les critères exploratoires comprenaient des mesures de coûts et des résultats cliniques tels que la durée de séjour. RéSULTATS: Nous avons inclus 1421 patients (706 avant et 715 après la mise en œuvre). Nous avons observé une augmentation absolue de 67 % (intervalle de confiance de 95 %, 55 à 80; P < 0,001) de l'observance des tests de la TnI suite à la mise en œuvre des lignes directrices. Parmi les patients présentant un taux élevé de TnI suite à la mise en œuvre des lignes directrices (n = 64), la majorité (85%) a reçu des soins de suivi appropriés sous la forme d'une consultation en médecine générale ou en cardiologie; tous ont subi au moins un électrocardiogramme, et la moitié ont passé au moins un examen cardiaque subséquent (p. ex., évaluation de la perfusion myocardique par scintigraphie ou cathétérisme percutané). CONCLUSION: Notre étude a montré qu'il est possible de mettre en œuvre et d'adhérer aux nouvelles lignes directrices de la SCC. Des évaluations multicentriques à grande échelle portant sur la mise en œuvre des lignes directrices de la SCC sont nécessaires pour mieux comprendre ses effets potentiels sur les devenirs cliniquement pertinents.

A Digital Intervention for Primary Care Practitioners to Support Antidepressant Discontinuation (Advisor for Health Professionals): Development Study.

BACKGROUND: The number of people receiving antidepressants has increased in the past 3 decades, mainly because of people staying on them longer. However, in many cases long-term treatment is not evidence based and risks increasing side effects. Additionally, prompting general practitioners (GPs) to review medication does not improve the rate of appropriate discontinuation. Therefore, GPs and other health professionals may need help to support patients discontinuing antidepressants in primary care. OBJECTIVE: This study aims to develop a digital intervention to support practitioners in helping patients discontinue inappropriate long-term antidepressants (as part of a wider intervention package including a patient digital intervention and patient telephone support). METHODS: A prototype digital intervention called Advisor for Health Professionals (ADvisor HP) was planned and developed using theory, evidence, and a person-based approach. The following elements informed development: a literature review and qualitative synthesis, an in-depth qualitative study, the development of guiding principles for design elements, and theoretical behavioral analyses. The intervention was then optimized through think-aloud qualitative interviews with health professionals while they were using the prototype intervention. RESULTS: Think-aloud qualitative interviews with 19 health professionals suggested that the digital intervention contained useful information and was readily accessible to practitioners. The development work highlighted a need for further guidance on drug tapering schedules for practitioners and clarity about who is responsible for broaching the subject of discontinuation. Practitioners highlighted the need to have information in easily and quickly accessible formats because of time constraints in day-to-day practice. Some GPs felt that some information was already known to them but understood why this was included. Practitioners differed in their ideas about how they would use ADvisor HP in practice, with some preferring to read the resource in its entirety and others wanting to dip in and out as needed. Changes were made to the wording and structure of the intervention in response to the feedback provided. CONCLUSIONS: ADvisor HP is a digital intervention that has been developed using theory, evidence, and a person-based approach. The optimization work suggests that practitioners may find this tool to be useful in supporting the reduction of long-term antidepressant use. Further quantitative and qualitative evaluation through a randomized controlled trial is needed to examine the feasibility, effectiveness, and cost-effectiveness of the intervention.

A Comparison between the Compass Fundus Perimeter and the Humphrey Field Analyzer.

PURPOSE: To evaluate relative diagnostic precision and test-retest variability of 2 devices, the Compass (CMP, CenterVue, Padova, Italy) fundus perimeter and the Humphrey Field Analyzer (HFA, Zeiss, Dublin, CA), in detecting glaucomatous optic neuropathy (GON). DESIGN: Multicenter, cross-sectional, case-control study. PARTICIPANTS: We sequentially enrolled 499 patients with glaucoma and 444 normal subjects to analyze relative precision. A separate group of 44 patients with glaucoma and 54 normal subjects was analyzed to assess test-retest variability. METHODS: One eye of recruited subjects was tested with the index tests: HFA (Swedish interactive thresholding algorithm [SITA] standard strategy) and CMP (Zippy Estimation by Sequential Testing [ZEST] strategy), 24-2 grid. The reference test for GON was specialist evaluation of fundus photographs or OCT, independent of the visual field (VF). For both devices, linear regression was used to calculate the sensitivity decrease with age in the normal group to compute pointwise total deviation (TD) values and mean deviation (MD). We derived 5% and 1% pointwise normative limits. The MD and the total number of TD values below 5% (TD 5%) or 1% (TD 1%) limits per field were used as classifiers. MAIN OUTCOME MEASURES: We used partial receiver operating characteristic (pROC) curves and partial area under the curve (pAUC) to compare the diagnostic precision of the devices. Pointwise mean absolute deviation and Bland-Altman plots for the mean sensitivity (MS) were computed to assess test-retest variability. RESULTS: Retinal sensitivity was generally lower with CMP, with an average mean difference of 1.85±0.06 decibels (dB) (mean ± standard error, P < 0.001) in healthy subjects and 1.46±0.05 dB (mean ± standard error, P < 0.001) in patients with glaucoma. Both devices showed similar discriminative power. The MD metric had marginally better discrimination with CMP (pAUC difference ± standard error, 0.019±0.009, P = 0.035). The 95% limits of agreement for the MS were reduced by 13% in CMP compared with HFA in participants with glaucoma and by 49% in normal participants. Mean absolute deviation was similar, with no significant differences. CONCLUSIONS: Relative diagnostic precision of the 2 devices is equivalent. Test-retest variability of MS for CMP was better than for HFA.

Micro Methods for Megafauna: Novel Approaches to Late Quaternary Extinctions and Their Contributions to Faunal Conservation in the Anthropocene.

Drivers of Late Quaternary megafaunal extinctions are relevant to modern conservation policy in a world of growing human population density, climate change, and faunal decline. Traditional debates tend toward global solutions, blaming either dramatic climate change or dispersals of Homo sapiens to new regions. Inherent limitations to archaeological and paleontological data sets often require reliance on scant, poorly resolved lines of evidence. However, recent developments in scientific technologies allow for more local, context-specific approaches. In the present article, we highlight how developments in five such methodologies (radiocarbon approaches, stable isotope analysis, ancient DNA, ancient proteomics, microscopy) have helped drive detailed analysis of specific megafaunal species, their particular ecological settings, and responses to new competitors or predators, climate change, and other external phenomena. The detailed case studies of faunal community composition, extinction chronologies, and demographic trends enabled by these methods examine megafaunal extinctions at scales appropriate for practical understanding of threats against particular species in their habitats today.

Natural and anthropogenic drivers of calcium depletion in a northern forest during the last millennium.

The pace and degree of nutrient limitation are among the most critical uncertainties in predicting terrestrial ecosystem responses to global change. In the northeastern United States, forest growth has recently declined along with decreased soil calcium (Ca) availability, suggesting that acid rain has depleted soil Ca to the point where it may be a limiting nutrient. However, it is unknown whether the past 60 y of changes in Ca availability are strictly anthropogenic or partly a natural consequence of long-term ecosystem development. Here, we report a high-resolution millennial-scale record of Ca and 16 other elements from the sediments of Mirror Lake, a 15-ha lake in the White Mountains of New Hampshire surrounded by northern hardwood forest. We found that sedimentary Ca concentrations had been declining steadily for 900 y before regional Euro-American settlement. This Ca decline was not a result of serial episodic disturbances but instead the gradual weathering of soils and soil Ca availability. As Ca availability was declining, nitrogen availability concurrently was increasing. These data indicate that nutrient availability on base-poor, parent materials is sensitive to acidifying processes on millennial timescales. Forest harvesting and acid rain in the postsettlement period mobilized significant amounts of Ca from watershed soils, but these effects were exacerbated by the long-term pattern. Shifting nutrient limitation can potentially occur within 10,000 y of ecosystem development, which alters our assessments of the speed and trajectory of nutrient limitation in forests, and could require reformulation of global models of forest productivity.

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 1011 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics.

Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo-Controlled, Phase 3 Studies.

PURPOSE: To evaluate the effectiveness and safety of oral memantine as a potential neuroprotective agent in open-angle glaucoma (OAG) at risk for progression. DESIGN: Two randomized, double-masked, placebo-controlled, parallel-group, multicenter, 48-month studies identically designed, initiated 1 year apart, and completed in 2006. Protocol amendments included a 1-year extension (first study) and change in primary endpoint and analysis (second study). PARTICIPANTS: Patients (2298 total) with bilateral OAG; glaucomatous optic disc damage and visual field loss in 1 eye; glaucomatous optic disc damage and/or visual field loss in the contralateral eye (at screening), topically treated or untreated intraocular pressure (IOP) of 21 mmHg or less (at baseline); and at risk of glaucomatous progression (per prespecified criteria). METHODS: Patients were randomized 3:2:2 to receive memantine 20 mg, memantine 10 mg, or placebo tablets daily. Glaucomatous progression was assessed in the intent-to-treat population by full-threshold standard automated perimetry (SAP), frequency doubling technology (FDT), and stereoscopic optic disc photographs, standardized by quality control assessment at centralized reading centers. Safety evaluations included adverse events (AEs), best-corrected visual acuity, biomicroscopy, IOP, and ophthalmoscopy. Efficacy data from each study were analyzed per protocol. Pooled analyses of efficacy and safety data were also performed. MAIN OUTCOME MEASURES: The predefined primary efficacy measure was glaucomatous visual field progression, as measured by SAP. Additional efficacy measures included glaucomatous progression of visual field (FDT) and optic nerve damage (stereoscopic optic disc photographs). RESULTS: The proportion of patients who completed the studies was similar among groups (80%-83%). Compared with placebo, daily treatment with memantine 10 mg or 20 mg for 48 months did not delay glaucomatous progression significantly in the individual studies and pooled analyses. The pooled risk reduction ratio (95% confidence interval) assessed by SAP was -0.13 (-0.40, 0.09) and -0.17 (-0.46, 0.07) for memantine 10 mg and 20 mg, respectively. Results were similar per FDT and stereoscopic optic disc photographs. The most common AEs leading to treatment discontinuations were dizziness, headache, fatigue, and nausea. CONCLUSIONS: With technologies available when the studies were conducted, daily treatment with memantine over 48 months was not shown to prevent glaucomatous progression in this patient population.

Interactive visual exploration and refinement of cluster assignments.

BACKGROUND: With ever-increasing amounts of data produced in biology research, scientists are in need of efficient data analysis methods. Cluster analysis, combined with visualization of the results, is one such method that can be used to make sense of large data volumes. At the same time, cluster analysis is known to be imperfect and depends on the choice of algorithms, parameters, and distance measures. Most clustering algorithms don't properly account for ambiguity in the source data, as records are often assigned to discrete clusters, even if an assignment is unclear. While there are metrics and visualization techniques that allow analysts to compare clusterings or to judge cluster quality, there is no comprehensive method that allows analysts to evaluate, compare, and refine cluster assignments based on the source data, derived scores, and contextual data. RESULTS: In this paper, we introduce a method that explicitly visualizes the quality of cluster assignments, allows comparisons of clustering results and enables analysts to manually curate and refine cluster assignments. Our methods are applicable to matrix data clustered with partitional, hierarchical, and fuzzy clustering algorithms. Furthermore, we enable analysts to explore clustering results in context of other data, for example, to observe whether a clustering of genomic data results in a meaningful differentiation in phenotypes. CONCLUSIONS: Our methods are integrated into Caleydo StratomeX, a popular, web-based, disease subtype analysis tool. We show in a usage scenario that our approach can reveal ambiguities in cluster assignments and produce improved clusterings that better differentiate genotypes and phenotypes.

Rectal cancer survival in the United States by race and stage, 2001 to 2009: Findings from the CONCORD-2 study.

BACKGROUND: In the first CONCORD study, 5-year survival for patients with diagnosed with rectal cancer between 1990 and 1994 was <60%, with large racial disparities noted in the majority of participating states. We have updated these findings to 2009 by examining population-based survival by stage of disease at the time of diagnosis, race, and calendar period. METHODS: Data from the CONCORD-2 study were used to compare survival among individuals aged 15 to 99 years who were diagnosed in 37 states encompassing up to 80% of the US population. We estimated net survival up to 5 years after diagnosis correcting for background mortality with state-specific and race-specific life table. Survival estimates were age-standardized with the International Cancer Survival Standard weights. We present survival estimates by race (all, black, and white) for 2001 through 2003 and 2004 through 2009 to account for changes in collecting the data for Surveillance, Epidemiology, and End Results Summary Stage 2000. RESULTS: There was a small increase in 1-year, 3-year, and 5-year net survival between 2001-2003 (84.6%, 70.7%, and 63.2%, respectively), and 2004-2009 (85.1%, 71.5%, and 64.1%, respectively). Black individuals were found to have lower 1-year, 3-year, and 5-year survival than white individuals in both periods; the absolute difference in survival between black and white individuals declined only for 5-year survival. Black patients had lower 5-year survival than whites at each stage at the time of diagnosis in both time periods. CONCLUSIONS: There was little improvement noted in net survival for patients with rectal cancer, with persistent disparities noted between black and white individuals. Additional investigation is needed to identify and implement effective interventions to ensure the consistent and equitable use of high-quality screening, diagnosis, and treatment to improve survival for patients with rectal cancer. Cancer 2017;123:5037-58. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Predicting conversion to glaucoma using standard automated perimetry and frequency doubling technology.

PURPOSE: To test the hypothesis that development of glaucomatous visual fields can be predicted several years earlier from prior visual field information. METHODS: One-hundred and seven eyes with glaucomatous optic neuropathy (n = 47 eyes) or which were suspicious for glaucoma (n = 60) were prospectively enrolled in a longitudinal study. Visual fields were evaluated on an annual basis using standard automated perimetry (SAP), the original version of frequency doubling technology (FDT) perimetry, and a custom version of FDT that used the 24-2 stimulus pattern. All SAP fields were within normal limits at the initial visit. When the SAP glaucoma hemifield test was 'outside normal limits' or the pattern standard deviation probability was worse than the lower 5th percentile or more than two clustered locations at the p < 0.05 level were present on the pattern deviation probability plot, an eye was defined as being abnormal. We used a classification tree analysis to predict which eyes would convert, using only baseline test results. RESULTS: Classification trees that were constructed using only baseline data had excellent specificity (near 100%) but worse sensitivity (25-50%) for predicting which eyes would convert during follow-up. CONCLUSIONS: Predictive information is present in visual field results, even when they are still within normal limits.