Integrating long-acting reversible contraceptives into primary care internal medicine practices: A clinical innovation to reduce wait time.

BACKGROUND: Long-acting reversible contraception (LARC) has long been regarded as highly effective and safe. However, access is limited and lengthy when specialty referrals are required. OBJECTIVES: To integrate LARC services into an urban internal medicine primary care practice to decrease wait time for LARC procedures. DESIGN/METHODS: This pre-post with control group study took place at two large urban academic primary care practices (Practices A and B) and included patients ages 18 to 45 years assigned female sex at birth. Pre-implementation baseline data were collected retrospectively from 2019 to 2020 by identifying subjects who requested LARC insertion or removal via their primary care practice and were referred to Obstetrics and Gynecology (Ob/Gyn) for the procedure. Wait time was noted from time of initial request in the medical record to time of procedure. Practice A developed an integrated primary care LARC program in which one of their LARC-trained providers began offering these procedures within their own practice. All other providers within the practice were educated on how to counsel patients about the devices and procedures. Practice B did not have an in-house LARC provider and continued referring patients to Ob/Gyn. Post-implementation data were collected prospectively 2021-2022. RESULTS: Ninety-one patients in Practice A experienced a significant decrease in wait time (87 vs 21 days, p < 0.001) over the observation period, with a majority undergoing procedures on their first visit with the in-house LARC provider. Wait time for the 54 patients in Practice B remained unchanged (57 vs 47 days, p = .59), often requiring multiple specialty visits. CONCLUSION: Integrating LARC services into a primary care internal medicine practice can significantly reduce wait times for these procedures with the potential to contribute to increased reproductive and menstrual autonomy.

Computed tomographic arthrography, gross anatomy and histology demonstrate a communication between synovial invaginations in the proximal aspect of the third interosseous muscle and the carpometacarpal joint in horses.

This descriptive anatomical study investigates the relationship between the third interosseous muscle, also known as the suspensory ligament, and the carpometacarpal joint in forelimbs of horses, with the hypothesis that there was a direct synovial communication between these structures as shown by computed tomographic arthrography, histology, and gross anatomy sections. Computed tomography of the carpus and metacarpal region was performed on two groups. Group 1 consisted of eight cadaver limbs undergoing computed tomographic arthrography following injection of a mixture of positive contrast medium, saline, and color-pigmented fluid solution into the middle carpal joint. Group 2 consisted of eight forelimbs assessed using plain computed tomography. The images were interpreted subjectively for contrast medium distribution and objectively by comparing Hounsfield values of the proximal suspensory ligament at 0.5 cm intervals starting at the origin and extending 3 cm distal to the proximal subchondral bone plate of the third metacarpal bone. Of the 16 limbs, two were sectioned for gross anatomy and one was documented histologically. The proximal suspensory ligament was visualized with clear margins on computed tomography images. The positive contrast medium was found within the lateral and medial lobes of the suspensory ligament in all eight (100%) limbs. Hounsfield units within the suspensory ligament following contrast injection were significantly higher than in those in the plain CT group between 0.5 and 2.5 cm distal to the proximal subchondral bone plate of the third metacarpal bone (p < 0.05). The gross anatomy sections showed color pigmentation within the suspensory ligament correlating to the contrast medium distribution evident on computed tomography images. Histology confirmed a synovial lined cavity within the suspensory ligament. The demonstration of a direct synovial communication between the internal structure of the proximal suspensory ligament and the carpometacarpal joint in horses offers further explanation for commonly encountered interactions of diagnostic local anesthesia of the carpal and subcarpal regions. When performing diagnostic or therapeutic injections into the middle carpal joint, the likely effect on the proximal suspensory ligament should be considered. Furthermore, as the proximal suspensory ligament was identified clearly on CT images, further studies are needed to elucidate the utility of CT in clinical cases with suspected soft tissue pathology in the subcarpal region.

Impaired Arithmetic Fact Retrieval in an Adult with Developmental Dyscalculia: Evidence from Behavioral and Functional Brain Imaging Data.

Developmental dyscalculia (DD) is a developmental disorder characterized by arithmetic difficulties. Recently, it has been suggested that the neural networks supporting procedure-based calculation (e.g., in subtraction) and left-hemispheric verbal arithmetic fact retrieval (e.g., in multiplication) are partially distinct. Here we compared the neurofunctional correlates of subtraction and multiplication in a 19-year-old student (RM) with DD to 18 age-matched controls. Behaviorally, RM performed significantly worse than controls in multiplication, while subtraction was unaffected. Neurofunctional differences were most pronounced regarding multiplication: RM showed significantly stronger activation than controls not only in left angular gyrus but also in a fronto-parietal network (including left intraparietal sulcus and inferior frontal gyrus) typically activated during procedure-based calculation. Region-of-interest analyses indicated group differences in multiplication only, which, however, did not survive correction for multiple comparisons. Our results are consistent with dissociable and processing-specific, but not operation-specific neurofunctional networks. Procedure-based calculation is not only associated with subtraction but also with (untrained) multiplication facts. Only after rote learning, facts can be retrieved quasi automatically from memory. We suggest that this learning process and the associated shift in activation patterns has not fully occurred in RM, as reflected in her need to resort to procedure-based strategies to solve multiplication facts.

Mass spectrometry detection of inhaled drug in distal fibrotic lung.

BACKGROUND: Currently the only available therapies for fibrotic Interstitial Lung Disease are administered systemically, often causing significant side effects. Inhaled therapy could avoid these but to date there is no evidence that drug can be effectively delivered to distal, fibrosed lung. We set out to combine mass spectrometry and histopathology with rapid sample acquisition using transbronchial cryobiopsy to determine whether an inhaled drug can be delivered to fibrotic, distal lung parenchyma in participants with Interstitial Lung Disease. METHODS: Patients with radiologically and multidisciplinary team confirmed fibrotic Interstitial Lung Disease were eligible for this study. Transbronchial cryobiopsies and endobronchial biopsies were taken from five participants, with Interstitial Lung Disease, within 70 min of administration of a single dose of nebulised ipratropium bromide. Thin tissue cryosections were analysed by Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging and correlated with histopathology. The remainder of the cryobiopsies were homogenised and analysed by Liquid Chromatography-tandem Mass Spectrometry. RESULTS: Drug was detected in proximal and distal lung samples from all participants. Fibrotic regions were identified in research samples of four of the five participants. Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging showed co-location of ipratropium with fibrotic regions in samples from three participants. CONCLUSIONS: In this proof of concept study, using mass spectrometry, we demonstrate for the first-time that an inhaled drug can deposit in distal fibrotic lung parenchyma in patients with Interstitial Lung Disease. This suggests that drugs to treat pulmonary fibrosis could potentially be administered by the inhaled route. Trial registration A prospective clinical study approved by London Camden and Kings Cross Research Ethics Committee and registered on clinicaltrials.gov (NCT03136120).

A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models.

RNA vaccines have demonstrated efficacy against SARS-CoV-2 in humans, and the technology is being leveraged for rapid emergency response. In this report, we assessed immunogenicity and, for the first time, toxicity, biodistribution, and protective efficacy in preclinical models of a two-dose self-amplifying messenger RNA (SAM) vaccine, encoding a prefusion-stabilized spike antigen of SARS-CoV-2 Wuhan-Hu-1 strain and delivered by lipid nanoparticles (LNPs). In mice, one immunization with the SAM vaccine elicited a robust spike-specific antibody response, which was further boosted by a second immunization, and effectively neutralized the matched SARS-CoV-2 Wuhan strain as well as B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta) variants. High frequencies of spike-specific germinal center B, Th0/Th1 CD4, and CD8 T cell responses were observed in mice. Local tolerance, potential systemic toxicity, and biodistribution of the vaccine were characterized in rats. In hamsters, the vaccine candidate was well-tolerated, markedly reduced viral load in the upper and lower airways, and protected animals against disease in a dose-dependent manner, with no evidence of disease enhancement following SARS-CoV-2 challenge. Therefore, the SARS-CoV-2 SAM (LNP) vaccine candidate has a favorable safety profile, elicits robust protective immune responses against multiple SARS-CoV-2 variants, and has been advanced to phase 1 clinical evaluation (NCT04758962).

Do mechanisms matter? Comparing cancer treatment strategies across mathematical models and outcome objectives.

When eradication is impossible, cancer treatment aims to delay the emergence of resistance while minimizing cancer burden and treatment. Adaptive therapies may achieve these aims, with success based on three assumptions: resistance is costly, sensitive cells compete with resistant cells, and therapy reduces the population of sensitive cells. We use a range of mathematical models and treatment strategies to investigate the tradeoff between controlling cell populations and delaying the emergence of resistance. These models extend game theoretic and competition models with four additional components: 1) an Allee effect where cell populations grow more slowly at low population sizes, 2) healthy cells that compete with cancer cells, 3) immune cells that suppress cancer cells, and 4) resource competition for a growth factor like androgen. In comparing maximum tolerable dose, intermittent treatment, and adaptive therapy strategies, no therapeutic choice robustly breaks the three-way tradeoff among the three therapeutic aims. Almost all models show a tight tradeoff between time to emergence of resistant cells and cancer cell burden, with intermittent and adaptive therapies following identical curves. For most models, some adaptive therapies delay overall tumor growth more than intermittent therapies, but at the cost of higher cell populations. The Allee effect breaks these relationships, with some adaptive therapies performing poorly due to their failure to treat sufficiently to drive populations below the threshold. When eradication is impossible, no treatment can simultaneously delay emergence of resistance, limit total cancer cell numbers, and minimize treatment. Simple mathematical models can play a role in designing the next generation of therapies that balance these competing objectives.

Standardized and reproducible measurement of decision-making in mice.

Progress in science requires standardized assays whose results can be readily shared, compared, and reproduced across laboratories. Reproducibility, however, has been a concern in neuroscience, particularly for measurements of mouse behavior. Here, we show that a standardized task to probe decision-making in mice produces reproducible results across multiple laboratories. We adopted a task for head-fixed mice that assays perceptual and value-based decision making, and we standardized training protocol and experimental hardware, software, and procedures. We trained 140 mice across seven laboratories in three countries, and we collected 5 million mouse choices into a publicly available database. Learning speed was variable across mice and laboratories, but once training was complete there were no significant differences in behavior across laboratories. Mice in different laboratories adopted similar reliance on visual stimuli, on past successes and failures, and on estimates of stimulus prior probability to guide their choices. These results reveal that a complex mouse behavior can be reproduced across multiple laboratories. They establish a standard for reproducible rodent behavior, and provide an unprecedented dataset and open-access tools to study decision-making in mice. More generally, they indicate a path toward achieving reproducibility in neuroscience through collaborative open-science approaches.

In science, it is of vital importance that multiple studies corroborate the same result. Researchers therefore need to know all the details of previous experiments in order to implement the procedures as exactly as possible. However, this is becoming a major problem in neuroscience, as animal studies of behavior have proven to be hard to reproduce, and most experiments are never replicated by other laboratories. Mice are increasingly being used to study the neural mechanisms of decision making, taking advantage of the genetic, imaging and physiological tools that are available for mouse brains. Yet, the lack of standardized behavioral assays is leading to inconsistent results between laboratories. This makes it challenging to carry out large-scale collaborations which have led to massive breakthroughs in other fields such as physics and genetics. To help make these studies more reproducible, the International Brain Laboratory (a collaborative research group) et al. developed a standardized approach for investigating decision making in mice that incorporates every step of the process; from the training protocol to the software used to analyze the data. In the experiment, mice were shown images with different contrast and had to indicate, using a steering wheel, whether it appeared on their right or left. The mice then received a drop of sugar water for every correction decision. When the image contrast was high, mice could rely on their vision. However, when the image contrast was very low or zero, they needed to consider the information of previous trials and choose the side that had recently appeared more frequently. This method was used to train 140 mice in seven laboratories from three different countries. The results showed that learning speed was different across mice and laboratories, but once training was complete the mice behaved consistently, relying on visual stimuli or experiences to guide their choices in a similar way. These results show that complex behaviors in mice can be reproduced across multiple laboratories, providing an unprecedented dataset and open-access tools for studying decision making. This work could serve as a foundation for other groups, paving the way to a more collaborative approach in the field of neuroscience that could help to tackle complex research challenges.

Multimodal imaging of drug and excipients in rat lungs following an inhaled administration of controlled-release drug laden PLGA microparticles.

Controlled-release formulations, in the form of micro- or nanoparticles, are increasingly attractive to the pharmaceutical industry for drug delivery. For respiratory illnesses, controlled-release microparticle formulations provide an opportunity to deliver a higher percentage of an inhaled medicament dose to the lung, thus potentially reducing the therapeutic dose, frequency of dosing, and minimising side-effects. We describe the use of a multimodal approach consisting of MALDI MS imaging, 3D depth profiling TOF-SIMS analysis, and histopathology to monitor the distribution of drug and excipients in sections taken from excised rat lungs following an inhaled administration of drug-laden microparticles. Following a single dose, the administered drug was detected in the lung via both MALDI MS and TOF-SIMS over a range of time points. Both imaging techniques enabled the characterisation of the distribution and retention of drug particles and identified differences in the capabilities of both imaging modalities. Histochemical staining of consecutive sections was used to provide biological context to the findings and will also be discussed in this presentation. We demonstrate how this multimodal approach could be used to help increase our understanding of the use of controlled release microparticles.

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency.

Recommended Guidelines for Developing, Qualifying, and Implementing Complex In Vitro Models (CIVMs) for Drug Discovery.

The pharmaceutical industry is continuing to face high research and development (R&D) costs and low overall success rates of clinical compounds during drug development. There is an increasing demand for development and validation of healthy or disease-relevant and physiological human cellular models that can be implemented in early-stage discovery, thereby shifting attrition of future therapeutics to a point in discovery at which the costs are significantly lower. There needs to be a paradigm shift in the early drug discovery phase (which is lengthy and costly), away from simplistic cellular models that show an inability to effectively and efficiently reproduce healthy or human disease-relevant states to steer target and compound selection for safety, pharmacology, and efficacy questions. This perspective article covers the various stages of early drug discovery from target identification (ID) and validation to the hit/lead discovery phase, lead optimization, and preclinical safety. We outline key aspects that should be considered when developing, qualifying, and implementing complex in vitro models (CIVMs) during these phases, because criteria such as cell types (e.g., cell lines, primary cells, stem cells, and tissue), platform (e.g., spheroids, scaffolds or hydrogels, organoids, microphysiological systems, and bioprinting), throughput, automation, and single and multiplexing endpoints will vary. The article emphasizes the need to adequately qualify these CIVMs such that they are suitable for various applications (e.g., context of use) of drug discovery and translational research. The article ends looking to the future, in which there is an increase in combining computational modeling, artificial intelligence and machine learning (AI/ML), and CIVMs.

Relationships Between Pre-Clinical Summative Assessment Scores and the Clinical Performance of Physiotherapy Students.

AIM: Education providers need to ensure that students allocated to a clinical placement are optimised for success. The aim of this study was to determine the relationships between physiotherapy students' summative assessment scores in pre-clinical coursework and their future performance in clinical practice. METHODS: Selected as potential subjects were 123 students from four consecutive intakes (2010-2013) of an Australian entry-level Doctor of Physiotherapy program. Retrospective cohort summative assessment data for pre-clinical (Objective Structured Clinical Examinations [OSCEs], written examinations, and seminar presentations) and clinical practice (clinical practice scores) subjects in core areas of physiotherapy were retrieved. Clinical practice performance was assessed using the reliable and validated Assessment of Physiotherapy Practice instrument. A descriptive analysis, Pearson's correlations and multiple regressions were performed between mean pre-clinical and clinical performance scores. RESULTS: Assessment data from 118 students were analysed. Pre-clinical assessment scores were positively related to clinical performance: OSCE r=0.57, p<0.001; written examination r=0.39, p<0.001; seminar presentations r=0.29, p=0.012. A multiple regression model identified OSCE as an independent contributor to clinical performance scores (adjusted R2=0.33, p<0.001). CONCLUSION: OSCE scores were strongly related to clinical performance and explained 32% of physiotherapy students' future clinical performance. Pre-clinical OSCE scores could provide opportunity to implement proactive support and enhancement strategies to increase stakeholder satisfaction and maintain quality placement experiences.

Isotopic niche variation from the Holocene to today reveals minimal partitioning and individualistic dynamics among four sympatric desert mice.

Species interact with each other and their environment over a range of temporal scales, yet our understanding of resource partitioning and the mechanisms of species coexistence is largely restricted to modern time-scales of years to decades. Furthermore, the relative magnitudes of inter- vs. intraspecific variation in resource use are rarely considered, despite the potential for the latter to influence a species' ability to cope with changing environmental conditions. Modern desert rodent communities are thought to be strongly structured by competitive interactions, with niche partitioning of food resources hypothesized to explain the coexistence of multiple sympatric granivores. Yet the stability of niche dynamics over extended temporal scales within desert rodent communities is unknown. I examined the isotopic niche dynamics of four common sympatric desert mice (three granivores: Chaetodipus formosus, Perognathus longimembris and Reithrodontomys megalotis, and one omnivore: Peromyscus maniculatus) in the Smoke Creek Desert of northwestern Nevada using 13 C and 15 N isotopes obtained from "Modern" (2008-2013 CE), "Historical" (1989-2005 CE) and Holocene fossil specimens spanning the last c. 7,500 years. I found significant variation in niche position, niche breadth and interspecific niche overlap of these species through time. The niche breadth dynamics of the cricetids (P. maniculatus and R. megalotis) were positively correlated with one another, while the niche breadth dynamics of the heteromyid C. formosus were negatively correlated with those of all other species. Body size, dietary functional group, palaeoenvironmental trends and time-averaging provided little explanatory power. Importantly, Modern and Historical patterns of resource use and partitioning differed from Holocene baselines in terms of decreased niche overlap and in the absolute and relative position of each species' niche in at least one isotopic axis. These observations suggest that each species' resource use changed individualistically over the Holocene, hence niche dynamics are poorly explained by the hypothesis of temporally stable species interactions at millennial time-scales. Furthermore, changes to the resource base over the last century (likely due to the spread of invasive cheatgrass) may be increasing resource partitioning in the Modern, pushing species past their baseline ranges of resource use variation.

Biodiversity and Topographic Complexity: Modern and Geohistorical Perspectives.

Topographically complex regions on land and in the oceans feature hotspots of biodiversity that reflect geological influences on ecological and evolutionary processes. Over geologic time, topographic diversity gradients wax and wane over millions of years, tracking tectonic or climatic history. Topographic diversity gradients from the present day and the past can result from the generation of species by vicariance or from the accumulation of species from dispersal into a region with strong environmental gradients. Biological and geological approaches must be integrated to test alternative models of diversification along topographic gradients. Reciprocal illumination among phylogenetic, phylogeographic, ecological, paleontological, tectonic, and climatic perspectives is an emerging frontier of biogeographic research.

Do coursework summative assessments predict clinical performance? A systematic review.

BACKGROUND: Two goals of summative assessment in health profession education programs are to ensure the robustness of high stakes decisions such as progression and licensing, and predict future performance. This systematic and critical review aims to investigate the ability of specific modes of summative assessment to predict the clinical performance of health profession education students. METHODS: PubMed, CINAHL, SPORTDiscus, ERIC and EMBASE databases were searched using key terms with articles collected subjected to dedicated inclusion criteria. Rigorous exclusion criteria were applied to ensure a consistent interpretation of 'summative assessment' and 'clinical performance'. Data were extracted using a pre-determined format and papers were critically appraised by two independent reviewers using a modified Downs and Black checklist with level of agreement between reviewers determined through a Kappa analysis. RESULTS: Of the 4783 studies retrieved from the search strategy, 18 studies were included in the final review. Twelve were from the medical profession and there was one from each of physiotherapy, pharmacy, dietetics, speech pathology, dentistry and dental hygiene. Objective Structured Clinical Examinations featured in 15 papers, written assessments in four and problem based learning evaluations, case based learning evaluations and student portfolios each featured in one paper. Sixteen different measures of clinical performance were used. Two papers were identified as 'poor' quality and the remainder categorised as 'fair' with an almost perfect (k = 0.852) level of agreement between raters. Objective Structured Clinical Examination scores accounted for 1.4-39.7% of the variance in student performance; multiple choice/extended matching questions and short answer written examinations accounted for 3.2-29.2%; problem based or case based learning evaluations accounted for 4.4-16.6%; and student portfolios accounted for 12.1%. CONCLUSIONS: Objective structured clinical examinations and written examinations consisting of multiple choice/extended matching questions and short answer questions do have significant relationships with the clinical performance of health professional students. However, caution should be applied if using these assessments as predictive measures for clinical performance due to a small body of evidence and large variations in the predictive strength of the relationships identified. Based on the current evidence, the Objective Structured Clinical Examination may be the most appropriate summative assessment for educators to use to identify students that may be at risk of poor performance in a clinical workplace environment. Further research on this topic is needed to improve the strength of the predictive relationship.

Histopathological Evaluation of Skeletal Muscle with Specific Reference to Mouse Models of Muscular Dystrophy.

The muscular dystrophies are a diverse group of degenerative diseases for which many mouse models are available. These models are frequently used to assess potential therapeutic interventions and histological evaluation of multiple muscles is an important part of this assessment. Histological evaluation is especially useful when combined with tests of muscle function. This unit describes a protocol for necropsy, processing, cryosectioning, and histopathological evaluation of murine skeletal muscles, which is applicable to both models of muscular dystrophy and other neuromuscular conditions. Key histopathological features of dystrophic muscle are discussed using the mdx mouse (a model of Duchenne muscular dystrophy) as an example. Optimal handling during dissection, processing and sectioning is vital to avoid artifacts that can confound or prevent future analyses. Muscles carefully processed using this protocol are suitable for further evaluation using immunohistochemistry, immunofluorescence, special histochemical stains, and immuoblotting. © 2016 by John Wiley & Sons, Inc.