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OBJECTIVE: Patients with brachial plexus birth injuries (BPBIs) are at risk for limitations in shoulder external rotation. The role of lower trapezius tendon transfer to restore shoulder external rotation in this population has not been well-characterized. This study aimed to evaluate the utility of lower trapezius tendon transfer for restoration of external rotation in a subset of pediatric patients. METHODS: Seventeen pediatric patients with BPBI were treated with lower trapezius tendon transfer to restore external rotation of the shoulder. Mean age at surgery was eight years, and 11 were female. Six patients had prior shoulder surgery to restore external rotation, while one had prior nerve surgery to restore shoulder function. Range of motion before lower trapezius transfer and at latest follow-up were obtained. Mean follow-up was 36 months. RESULTS: Active forward flexion did not significantly change from preoperative to final follow-up (mean, 147° and 141°; p=0.46). External rotation in adduction significantly changed from preoperative to final follow-up, (mean, 4° and 26°; p<0.001). External rotation in abduction significantly changed from preoperative to final follow-up (mean, 75° and 84°; p=0.048). Six patients (35%) had subsequent surgeries at average 17 months from this procedure. Significant univariate associations with subsequent surgery included certain intraoperative concomitant procedures-coracoid osteotomy/excision (p=0.02) and biceps tenodesis (p=0.04)-while bony glenoid augmentation/reconstruction trended toward significant association (p=0.05). CONCLUSION: Lower trapezius tendon transfer for BPBI showed a statistically significant but unlikely clinically meaningful improvement in external rotation with a high rate of reoperation.

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TOPIC: The timing of primary repair of open-globe injury is variable in major trauma centres around the world and there is a lack of consensus on optimal timing. CLINICAL RELEVANCE: Surgery is the mainstay of open-globe injury management, and appropriate timing of surgical repair may minimise the risk of potentially blinding complications such as endophthalmitis, thereby optimising visual outcomes. METHODS: A systematic literature review was performed following PRISMA guidelines (PROSPERO registration number: CRD42023442972). CENTRAL, MEDLINE, Embase, ISRCTN registry and ClinicalTrials.gov were searched from inception to 29 October 2023. Prospective and retrospective non-randomised studies of patients with open-globe injury with a minimum of one month follow up after primary repair were included. Primary outcomes included visual acuity at last follow-up, and the proportion of patients who developed endophthalmitis. Certainty of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach. RESULTS: A total of 16 studies met inclusion criteria, reporting a total of 8497 eyes. The most common injury types were penetrating and intraocular foreign body (IOFB). Meta-analysis found that primary repair less than 24 hours after open-globe injury was associated with an odds of endophthalmitis of 0.30 compared to primary repair conducted more than 24 hours after trauma (OR 0.39; 95% CI 0.19-0.79; I2 95%; p = 0.01). There was no significant difference in reported visual outcomes between patients whose open-globe injuries were repaired more than, compared to less than, 24 hours after trauma (OR 0.89; 95% CI 0.61-1.29; I2 70%; p = 0.52). All included studies were retrospective and non-randomised, demonstrating an overall low certainty of evidence on GRADE assessment. CONCLUSION: Only retrospective data exist around the effect of timing of open-globe repair, causing low certainty of the available evidence. However, this review of the current body of evidence, predominantly including penetrating and IOFB injuries, suggests that primary repair performed less than 24 hours after open-globe injury was associated with a reduced endophthalmitis rate, compared to longer delays, consistent with delay to primary repair increasing endophthalmitis risk.

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During the COVID-19 pandemic, unexpected activity patterns emerged among Yucatan mini-swine models for heart failure and atrial fibrillation. As part of our laboratory research, we tracked activity data by FitBark™ collars that the Yucatan mini-swine wore. Previously, staff engaged with the swine daily, such as applying lotion and conducting 6-min treadmill runs. However, pandemic restrictions reduced interaction to 1 or 2 times a week, often for less than 10 min each session. Contrary to expectations, there was a significant increase in the swine's activity levels during these minimal interaction periods. After cleaning, moisturizing, weighing, and FitBark data collection, staff engaged with the swine through feeding and play. Three time frames were analyzed: prepandemic, pandemic, and reentry. Prepandemic and reentry periods involved daily 15-min interactions with 2 staff members per swine to maintain cleanliness and health. During the pandemic, interaction was reduced to 1 or 2 times weekly. The hours between 1000 and 1400 were designated as 'passive activity', representing the swines' isolated behavior, unaffected by staff interaction. The chronic heart failure swine (n = 3) had an average passive activity area under the curve prepandemic value of 47.23 ± 2.52 compared with pandemic 57.09 ± 2.90, pandemic 57.09 ± 2.90 compared with reentry 50.44 ± 1.61, and prepandemic compared with reentry. The atrial fibrillation swine (n = 3) had an average passive activity area under the curve minimal interaction (mimicking pandemic) value of 59.27 ± 6.67 compared with interaction (mimicking prepandemic or reentry) 37.63 ± 1.74. The heightened activity levels during minimal interaction suggest physiologic and psychologic changes in the animals due to reduced socialization. This highlights the importance of enrichment and interaction in research animals and underscores the broader impact of the COVID-19 pandemic on research outcomes. These findings could also shed light on the effects of the pandemic on human behavior.

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Collagen fiber architecture within the skeletal muscle extracellular matrix (ECM) is significant to passive muscle mechanics. While it is thought that collagen fibers re-orient themselves in response to changes in muscle length, this has not been dynamically visualized and quantified within a muscle. The goal of this study was to measure changes in collagen alignment across a range of muscle lengths and compare the corresponding alignment to muscle mechanics. We hypothesized that collagen fibers dynamically increase alignment in response to muscle stretching, and this change in alignment is related to passive muscle stiffness. Further, we hypothesized that digesting collagen fibers with collagenase would reduce the re-alignment response to muscle stretching. Using DBA/2J and D2.mdx mice, we isolated extensor digitorum longus (EDL), soleus, and diaphragm muscles for collagenase or sham treatment and decellularization to isolate intact or collagenase-digested decellularized muscles (DCMs). These DCMs were mechanically tested and imaged using second harmonic generation microscopy to measure collagen alignment across a range of strains. We found that collagen alignment increased in a strain-dependent fashion, but collagenase did not significantly affect the strain-dependent change in alignment. We also saw that the collagen fibers in the diaphragm epimysium (surface ECM) and perimysium (deep ECM) started at different angles, but still re-oriented in the same direction in response to stretching. These robust changes in collagen alignment were weakly related to passive DCM stiffness. Overall, we demonstrated that the architecture of muscle ECM is dynamic in response to strain and is related to passive muscle mechanics. STATEMENT OF SIGNIFICANCE: Our study presents a unique visualization and quantification of strain-induced changes in muscle collagen fiber alignment as they relate to passive mechanics. Using dynamic imaging of collagen in skeletal muscle we demonstrate that as skeletal muscle is stretched, collagen fibers re-orient themselves along the axis of stretch and increase their alignment. The degree of alignment and the increase in alignment are each weakly related to passive muscle stiffness. Collagenase treatments further demonstrate that the basis for muscle Extracellular matrix stiffness is dependent on factors beyond collagen crosslinking and alignment. Together the study contributes to the knowledge of the structure-function relationships of muscle extracellular matrix to tissue stiffness relevant to conditions of fibrosis and aberrant stiffness.

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BACKGROUND: Enhanced Recovery After Surgery (ERAS) programs have spread after initial success in colorectal surgery decreasing length of stay (LOS) and decreasing opioid consumption. Adoption of ERAS specifically for ventral hernia patients remains in evolution. This study presents the development and implementation of an ERAS pathway for ventral hernia. METHODS: A multidisciplinary team met weekly over 6 months to develop an ERAS pathway specific to ventral hernia patients. 75 process components and outcome measures were included, spanning multiple phases of care: Preoperative-Clinic, Preoperative Day of Surgery (DOS), Intraoperative, and Postoperative. Preoperative components included education and physiologic optimization. Pain control across phases of care focuses on nonopioid, multimodal analgesia. Postoperatively, the pathway emphasizes early diet advancement, early mobilization, and minimization of IV fluids. We compared compliance and outcome measures between a Pre Go-Live (PGL) period (9/1/2020-8/30/2021) and After Go-live (AGL) period (5/12/2022-5/19/2023). RESULTS: There were 125 patients in the PGL group and 169 patients in the AGL group. Overall, ERAS compliance increased from 73.9% to 82.9% after implementation. Length of stay decreased from an average of 2.27 days PGL to 1.92 days AGL. Finally, the average daily postoperative opioid usage decreased from 25.4 to 13.5 MME after the implementation. DISCUSSION: Enhanced Recovery After Surgery can be successfully applied to the care of hernia patients with improvements in LOS and decreased opioid consumption. Institutional support and multidisciplinary cooperation were key for the development of such a program.

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Though surface water quality has been monitored in southern Peru over the past and current century, it has been implemented by multiple organizations. The data lacks a centralized repository and access requires logistical and temporal hurdles associated with official requests. A substantial portion of the data has not been quality assured and is in difficult-to-access formats such as scanned PDF documents. These obstacles collectively make it challenging to maximize the impact of these monitoring efforts such as efficiently evaluating long-term water quality trends. To address this opportunity, we gathered available surface water quality information from five watersheds in the Arequipa Region of southern Peru: Camaná, Chili, Ocoña, Tambo, and Yauca. The effort required entry of more than 130,000 records of water quality properties across 274 monitoring stations with data including the concentration of select nutrients, metals, organic compounds, and biological taxa. The water quality records in the Chili watershed go back as far as 1905, while data for the other watersheds was largely confined to the years 2012-2021. This document describes how the surface water quality information was assimilated with quality control and provides a centralized Excel database so that the data can be efficiently used for research and decision making purposes.

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BACKGROUND AND AIMS: Home treatment is considered safe in acute pulmonary embolism (PE) patients selected by a validated triage tool (e.g. simplified PE severity index score or Hestia rule), but there is uncertainty regarding the applicability in underrepresented subgroups. The aim was to evaluate the safety of home treatment by performing an individual patient-level data meta-analysis. METHODS: Ten prospective cohort studies or randomized controlled trials were identified in a systematic search, totalling 2694 PE patients treated at home (discharged within 24 h) and identified by a predefined triage tool. The 14- and 30-day incidences of all-cause mortality and adverse events (combined endpoint of recurrent venous thromboembolism, major bleeding, and/or all-cause mortality) were evaluated. The relative risk (RR) for 14- and 30-day mortalities and adverse events is calculated in subgroups using a random effects model. RESULTS: The 14- and 30-day mortalities were 0.11% [95% confidence interval (CI) 0.0-0.24, I2 = 0) and 0.30% (95% CI 0.09-0.51, I2 = 0). The 14- and 30-day incidences of adverse events were 0.56% (95% CI 0.28-0.84, I2 = 0) and 1.2% (95% CI 0.79-1.6, I2 = 0). Cancer was associated with increased 30-day mortality [RR 4.9; 95% prediction interval (PI) 2.7-9.1; I2 = 0]. Pre-existing cardiopulmonary disease, abnormal troponin, and abnormal (N-terminal pro-)B-type natriuretic peptide [(NT-pro)BNP] at presentation were associated with an increased incidence of 14-day adverse events [RR 3.5 (95% PI 1.5-7.9, I2 = 0), 2.5 (95% PI 1.3-4.9, I2 = 0), and 3.9 (95% PI 1.6-9.8, I2 = 0), respectively], but not mortality. At 30 days, cancer, abnormal troponin, and abnormal (NT-pro)BNP were associated with an increased incidence of adverse events [RR 2.7 (95% PI 1.4-5.2, I2 = 0), 2.9 (95% PI 1.5-5.7, I2 = 0), and 3.3 (95% PI 1.6-7.1, I2 = 0), respectively]. CONCLUSIONS: The incidence of adverse events in home-treated PE patients, selected by a validated triage tool, was very low. Patients with cancer had a three- to five-fold higher incidence of adverse events and death. Patients with increased troponin or (NT-pro)BNP had a three-fold higher risk of adverse events, driven by recurrent venous thromboembolism and bleeding.

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KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

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Climate-induced changes in hypoxia are among the most serious threats facing estuaries, which are among the most productive ecosystems on Earth. Future projections of estuarine hypoxia typically involve long-term multi-decadal continuous simulations or more computationally efficient time slice and delta methods that are restricted to short historical and future periods. We make a first comparison of these three methods by applying a linked terrestrial-estuarine model to the Chesapeake Bay, a large coastal-plain estuary in the eastern United States. Results show that the time slice approach accurately captures the behavior of the continuous approach, indicating a minimal impact of model memory. However, increases in mean annual hypoxic volume by the mid-twenty-first century simulated by the delta approach (+ 19%) are approximately twice as large as the time slice and continuous experiments (+ 9% and + 11%, respectively), indicating an important impact of changes in climate variability. Our findings suggest that system memory and projected changes in climate variability, as well as simulation length and natural variability of system hypoxia, should be considered when deciding to apply the more computationally efficient delta and time slice methods.

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RATIONALE: Cystic Fibrosis (CF) progresses through recurrent infection and inflammation, causing permanent lung function loss and airway remodeling. CT scans reveal abnormally low-density lung parenchyma in CF, but its microstructural nature remains insufficiently explored due to clinical CT limitations. To this end, diffusion-weighted 129Xe MRI is a non-invasive and validated measure of lung microstructure. In this work, we investigate microstructural changes in people with CF (pwCF) relative to age-matched, healthy subjects using comprehensive imaging and analysis involving pulmonary-function tests (PFTs), and 129Xe MRI. METHODS: 38 healthy subjects (age 6-40; 17.2 ± 9.5 years) and 39 pwCF (age 6-40; 15.6 ± 8.0 years) underwent 129Xe-diffusion MRI and PFTs. The distribution of diffusion measurements (i.e., apparent diffusion coefficients (ADC) and morphometric parameters) was assessed via linear binning (LB). The resulting volume percentages of bins were compared between controls and pwCF. Mean ADC and morphometric parameters were also correlated with PFTs. RESULTS: Mean whole-lung ADC correlated significantly with age (P < 0.001) for both controls and CF, and with PFTs (P < 0.05) specifically for pwCF. Although there was no significant difference in mean ADC between controls and pwCF (P = 0.334), age-adjusted LB indicated significant voxel-level diffusion (i.e., ADC and morphometric parameters) differences in pwCF compared to controls (P < 0.05). CONCLUSIONS: 129Xe diffusion MRI revealed microstructural abnormalities in CF lung disease. Smaller microstructural size may reflect compression from overall higher lung density due to interstitial inflammation, fibrosis, or other pathological changes. While elevated microstructural size may indicate emphysema-like remodeling due to chronic inflammation and infection.

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BACKGROUND: We hypothesized that deeper sedation in the postanesthesia care unit (PACU) increases the risk of subsequent sedation in general care wards (ward sedation) and that patients with ward sedation have more postoperative adverse events than those without ward sedation. METHODS: We reviewed the health records of adult patients who underwent procedures with general anesthesia at Mayo Clinic from May 5, 2018, through December 31, 2020, and were discharged from the PACU to the general care ward. Patient groups were dichotomized as with ward sedation (Richmond Agitation-Sedation Scale [RASS], ≤-2) and without ward sedation (RASS, ≥-1) within the first 24 hours after PACU discharge. Multivariable logistic regression was used to assess the association between clinical variables and ward sedation. RESULTS: A total of 23,766 patients were included in our analysis, of whom 1131 had ward sedation (incidence, 4.8 [Poisson 95% confidence interval, CI, 4.5-5.0]) per 100 patients after general anesthesia. Half of the ward sedation episodes occurred within 32 minutes after PACU discharge. The risk of ward sedation increased with the depth of PACU sedation. The odds ratios (95% CI) of ward sedation for patients with a PACU RASS score of -1 was 0.98 (0.75-1.27); -2, 1.87 (1.44-2.43); -3, 2.98 (2.26-3.93); and ≤-4, 3.97 (2.91-5.42). Adverse events requiring an emergency intervention occurred more often for patients with ward sedation (n = 92, 8.1%) than for those without ward sedation (n = 326, 1.4%; P < .001). CONCLUSIONS: Among patients who met our criteria for PACU discharge, deeper sedation during anesthesia recovery was associated with an increased risk of ward sedation. Patients who had ward sedation had worse outcomes than those without ward sedation.

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The bidirectional long-distance transport of organelles is crucial for cell body-synapse communication. However, the mechanisms by which this transport is modulated for synapse formation, maintenance, and plasticity are not fully understood. Here, we demonstrate through quantitative analyses that maintaining sensory neuron-motor neuron synapses in the Aplysia gill-siphon withdrawal reflex is linked to a sustained reduction in the retrograde transport of lysosomal vesicles in sensory neurons. Interestingly, while mitochondrial transport in the anterograde direction increases within 12 hours of synapse formation, the reduction in lysosomal vesicle retrograde transport appears three days after synapse formation. Moreover, we find that formation of new synapses during learning induced by neuromodulatory neurotransmitter serotonin further reduces lysosomal vesicle transport within 24 hours, whereas mitochondrial transport increases in the anterograde direction within one hour of exposure. Pharmacological inhibition of several signaling pathways pinpoints PKA as a key regulator of retrograde transport of lysosomal vesicles during synapse maintenance. These results demonstrate that synapse formation leads to organelle-specific and direction specific enduring changes in long-distance transport, offering insights into the mechanisms underlying synapse maintenance and plasticity.

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With the rapid and significant cost reduction of next-generation sequencing, low-coverage whole-genome sequencing (lcWGS), followed by genotype imputation, is becoming a cost-effective alternative to single-nucleotide polymorphism (SNP)-array genotyping. The objectives of this study were 2-fold: (1) construct a haplotype reference panel for genotype imputation from lcWGS data in rainbow trout (Oncorhynchus mykiss); and (2) evaluate the concordance between imputed genotypes and SNP-array genotypes in 2 breeding populations. Medium-coverage (12×) whole-genome sequences were obtained from a total of 410 fish representing 5 breeding populations with various spawning dates. The short-read sequences were mapped to the rainbow trout reference genome, and genetic variants were identified using GATK. After data filtering, 20,434,612 biallelic SNPs were retained. The reference panel was phased with SHAPEIT5 and was used as a reference to impute genotypes from lcWGS data employing GLIMPSE2. A total of 90 fish from the Troutlodge November breeding population were sequenced with an average coverage of 1.3×, and these fish were also genotyped with the Axiom 57K rainbow trout SNP array. The concordance between array-based genotypes and imputed genotypes was 99.1%. After downsampling the coverage to 0.5×, 0.2×, and 0.1×, the concordance between array-based genotypes and imputed genotypes was 98.7, 97.8, and 96.7%, respectively. In the USDA odd-year breeding population, the concordance between array-based genotypes and imputed genotypes was 97.8% for 109 fish downsampled to 0.5× coverage. Therefore, the reference haplotype panel reported in this study can be used to accurately impute genotypes from lcWGS data in rainbow trout breeding populations.

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BACKGROUND: Benefits of thoracic enhanced recovery after surgery programs have been described. However, there is ongoing discussion on the importance of full protocol compliance. The objective of this study was to determine whether strict adherence to an enhanced recovery after surgery protocol leads to further improvement in outcomes compared with less strict compliance. METHODS: This was a multihospital prospective cohort study of all consecutive anatomic lung resection patients on the thoracic enhanced recovery after surgery pathway from May 2021 to March 2023, with comparison with a historical control from January 2019 to April 2021. Compliance to 5 key protocol elements was tracked. Patients were grouped into high- and low-compliance cohorts, defined as adherence to 4-5/5 or 0-3/5 elements, respectively. The primary outcome was overall morbidity; secondary outcomes included cardiac, respiratory, and infectious morbidity and length of stay. RESULTS: Of the 960 patients, 429 (44.7%) were enhanced recovery after surgery patients and 531 (55.3%) were in the historical control group. Across all patients, 250 (26.0%) were considered high compliance and 710 (74.0%) were considered low compliance. After adjustment for enhanced recovery after surgery status and confounders, the association between high compliance and improved outcomes persisted for all but infectious morbidity. Compared with low compliance, high compliance was associated with decreased odds of any morbidity (0.41 [95% CI, 0.22-0.77]), cardiac morbidity (0.31 [0.11-0.91]), respiratory morbidity (0.46 [0.23-0.90]) and decreased length of stay (0.38 [0.18-0.87]). CONCLUSION: Enhanced recovery after surgery protocols improve outcomes after anatomic lung resection. Increasing compliance to individual elements (>80%) further improves patient outcomes. Continued efforts should be directed at increasing compliance to individual protocol elements.

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Axonal outgrowth, cell crawling, and cytokinesis utilize actomyosin, microtubule-based motors, cytoskeletal dynamics, and substrate adhesions to produce traction forces and bulk cellular motion. While it has long been appreciated that growth cones resemble crawling cells and that the mechanisms that drive cytokinesis help power cell crawling, they are typically viewed as unique processes. To better understand the relationship between these modes of motility, here, we developed a unified active fluid model of cytokinesis, amoeboid migration, mesenchymal migration, neuronal migration, and axonal outgrowth in terms of cytoskeletal flow, adhesions, viscosity, and force generation. Using numerical modeling, we fit subcellular velocity profiles of the motions of cytoskeletal structures and docked organelles from previously published studies to infer underlying patterns of force generation and adhesion. Our results indicate that, during cytokinesis, there is a primary converge zone at the cleavage furrow that drives flow towards it; adhesions are symmetric across the cell, and as a result, cells are stationary. In mesenchymal, amoeboid, and neuronal migration, the site of the converge zone shifts, and differences in adhesion between the front and back of the cell drive crawling. During neuronal migration and axonal outgrowth, the primary convergence zone lies within the growth cone, which drives actin retrograde flow in the P-domain and bulk anterograde flow of the axonal shaft. They differ in that during neuronal migration, the cell body is weakly attached to the substrate and thus moves forward at the same velocity as the axon. In contrast, during axonal outgrowth, the cell body strongly adheres to the substrate and remains stationary, resulting in a decrease in flow velocity away from the growth cone. The simplicity with which cytokinesis, cell crawling, and axonal outgrowth can be modeled by varying coefficients in a simple model suggests a deep connection between them.

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Understanding and predicting population responses to climate change is a crucial challenge. A key component of population responses to climate change are cases in which focal biological rates (e.g., population growth rates) change in response to climate change due to non-compensatory effects of changes in the underlying components (e.g., birth and death rates) determining the focal rates. We refer to these responses as non-compensatory climate change effects. As differential responses of biological rates to climate change have been documented in a variety of systems and arise at multiple levels of organization within and across species, non-compensatory effects may be nearly ubiquitous. Yet, how non-compensatory climate change responses combine and scale to influence the demographics of populations is often unclear and requires mapping them to the birth and death rates underlying population change. We provide a flexible framework for incorporating non-compensatory changes in upstream rates within and among species and mapping their consequences for additional downstream rates across scales to their eventual effects on population growth rates. Throughout, we provide specific examples and potential applications of the framework. We hope this framework helps to enhance our understanding of and unify research on population responses to climate change.

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The purpose of this review was to summarize the evidence with regard to behavioral and psychosocial assessment of the periodontitis patient, the candidate for implant therapy, and the peri-implantitis patient. Periodontitis has an adverse effect on quality of life and its treatment can lead to significant improvements experienced by the patient. The latter is true for rehabilitation with dental implants, although patients harbor diverse expectations and perceptions of implant therapy, which can often interfere with satisfaction and/or influence long-term success. A thorough behavioral assessment of the candidate for implant therapy is essential, which should include, perceptions, expectations, as well as risk for behavioral disorders. Remedial action is essential to correct misperceptions and any identified risks. Finally, patients have limited awareness of limited ability to identify signs of peri-implantitis. The diagnosis of peri-implantitis can be a cause of significant distress, resentment, and loss of trust to the treatment and the caregivers. Despite documented value in clinical research, currently available instruments assessing patient-reported outcomes have little application in day-to-day clinical practice. Face-to-face patient to doctor open-ended communication remains the most effective way to comprehensively establish the long-term "therapeutic alliance" essential for the long journey for the periodontitis patient.

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Infectious hematopoietic necrosis (IHN) is a disease of salmonid fish that is caused by the IHN virus (IHNV), which can cause substantial mortality and economic losses in rainbow trout aquaculture and fisheries enhancement hatchery programs. In a previous study on a commercial rainbow trout breeding line that has undergone selection, we found that genetic resistance to IHNV is controlled by the oligogenic inheritance of several moderate and many small effect quantitative trait loci (QTL). Here we used genome wide association analyses in two different commercial aquaculture lines that were naïve to previous exposure to IHNV to determine whether QTL were shared across lines, and to investigate whether there were major effect loci that were still segregating in the naïve lines. A total of 1,859 and 1,768 offspring from two commercial aquaculture strains were phenotyped for resistance to IHNV and genotyped with the rainbow trout Axiom 57K SNP array. Moderate heritability values (0.15-0.25) were estimated. Two statistical methods were used for genome wide association analyses in the two populations. No major QTL were detected despite the naïve status of the two lines. Further, our analyses confirmed an oligogenic architecture for genetic resistance to IHNV in rainbow trout. Overall, 17 QTL with notable effect (≥1.9% of the additive genetic variance) were detected in at least one of the two rainbow trout lines with at least one of the two statistical methods. Five of those QTL were mapped to overlapping or adjacent chromosomal regions in both lines, suggesting that some loci may be shared across commercial lines. Although some of the loci detected in this GWAS merit further investigation to better understand the biological basis of IHNV disease resistance across populations, the overall genetic architecture of IHNV resistance in the two rainbow trout lines suggests that genomic selection may be a more effective strategy for genetic improvement in this trait.

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Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.