Olecranon Osteotomy Exposure for Distal Humeral Fracture Treatment.

Background: Olecranon osteotomy (OO) is commonly utilized to improve exposure when treating intra-articular distal humeral fractures. A chevron-shaped osteotomy facilitates reduction and increases surface area for healing1. Following distal humeral fracture reduction and fixation, the OO fragment is fixed with a precontoured plate. The OO technique yields comparable outcomes to alternative techniques1,2. Description: The technique is performed as follows. (1) Imaging is reviewed and preoperative planning is performed. (2) The patient is positioned in the lateral decubitus position with the operative extremity placed over a bolster. (3) A longitudinal posterior skin incision is centered just medial or lateral to the tip of the olecranon. Full-thickness skin flaps are raised medially and laterally. (4) The ulnar nerve is identified and mobilized for later anterior subcutaneous transposition. (5) An OO is performed at the non-articular "bare area" of the trochlear notch with an oscillating saw and completed with an osteotome. (6) Open reduction and internal fixation of the distal humerus is performed. (7) The osteotomy fragment is reduced, and a precontoured plate is applied. (8) A small longitudinal slit in the distal triceps over the proximal edge of the plate decreases plate prominence and is repaired with suture. (9) The subcutaneous tissues and skin are closed in the usual manner. Alternatives: Alterative techniques include extra-articular OO, triceps splitting, triceps reflecting, and lateral para-olecranon combined with a medial approach. Multiple drill holes and a thin osteotome can help mitigate the kerf created by the oscillating saw. Alternative fixation methods include a predrilled 6.5-mm intramedullary screw, a tension band construct, suture fixation, or a one-third tubular plate. Rationale: The OO technique provides improved exposure when compared with alternative techniques, enabling accurate reduction and fixation of distal humeral fractures1-3. Wilkinson and Stanley found that OO exposed the distal humeral articular surface to a greater degree than the triceps-splitting and triceps-reflecting approaches3. OO has not been associated with triceps weakness, unlike some of the alternative techniques2. Expected Outcomes: The incidence of good-to-excellent outcomes is similar when comparing the techniques for exposure of intra-articular distal humeral fractures4. Osteotomies united in all patients in 2 reported series, totaling 84 cases1,2. Removal of symptomatic hardware used in OO fragment fixation can occur in a small subset of patients1,2. Important Tips: Provisionally size a precontoured plate and fix it on the olecranon to aid in later reduction and fracture fixation.The bare area is the desired position for the OO because of its natural lack of cartilage5,6. This non-articular bare area is located just distal to the deepest portion of the trochlear notch, approximately 2 to 2.5 cm distal to the olecranon tip5,6.An (apex-distal) chevron osteotomy angle of ∼130° will help to keep the osteotomy within the non-articular bare area6.Beginning on the dorsal surface of the ulna, directly posterior to the bare area, an oscillating saw is utilized to create a chevron osteotomy to subchondral bone, perpendicular to the long axis of the ulna5,6.The OO is completed by fracturing through the osteochondral surface, which leaves an irregular chondral cancellous surface that can accurately interdigitate. This facilitates later reduction and stability of the osteotomy.Anatomic articular reduction of the OO is not solely judged on the dorsal cortical bone because of the kerf removed by the saw blade. Instead, examination of the articular surface of the trochlear notch is the primary assessment of reduction.Placement of suture through the proximal portion of the plate aids in the repair of the longitudinal split of the distal triceps.Successful treatment of distal humeral fractures requires accurate reduction and rigid fixation aided by adequate exposure achieved through OO. Acronyms and Abbreviations: ORIF = open reduction and internal fixationOT = occupational therapyHWR = hardware removalK-wire = Kirschner wireROM = range of motion.

On-Site More Frequent Dialysis May Hasten Return Home for Nursing Home End-Stage Renal Disease Patients.

BACKGROUND: A direct outcome comparison between Skilled nursing facility (SNF) patients receiving on-site more frequent dialysis (MFD) targeting 14 hours of treatment over five sessions weekly compared to on-site conventional dialysis for death, hospitalization and speed of return home has not been reported. METHODS: From Jan 1, 2022, to July 1, 2023, in a retrospective prospective observational design, using an intent to treat and competing risk strategy, all new admissions to an on-site in SNF dialysis service admitted to nursing homes with on-site MFD dialysis were compared to admissions to nursing homes providing on-site conventional dialysis for the outcome goal of 90 day cumulative incidence of discharge to home, while monitoring safety issues represented by the competing risks of hospitalization and death. RESULTS: 10,246 MFD dialytic episodes and 3,451 conventional dialytic episodes were studied in 195 nursing homes in 12 states. At baseline the MFD population was consistently sicker than CONVENTIONAL dialysis population with a first systolic blood pressure in 23% vs 7.6% (p<.001), lower mean hemoglobin (9.3g/dl vs 10.4g/dl; p<.001), lower iron saturation (25.7% vs 26.6%; p=0.02), higher Charlson score (3.5 vs 3.0; p<.001), higher mean age (67.6 vs 66.7; p<.001). ), more complicated diabetes (31% vs 24%; P<.001), cerebrovascular disease ( 12.6% vs 6.8%:p<.001), and congestive heart failure (24% vs 18%). At 42 days, discharge to home was 25% greater in the MFD than conventional group (17.5% vs 14%) without worsened hospitalization or death. CONCLUSION: Despite a handicap of sicker patients at baseline, real-world application of MFD appears to hasten return home from SNFs compared to conventional dialysis. The findings suggests that MFD allows for SNF acceptance of sicker patients, presumably permitting earlier hospital discharge, without safety compromise as measured by death or rehospitalization benefitting hospitals, patients, and payers.

Effect of Surgery Setting for Outpatient Shoulder Procedures on Early Postoperative Complications in a Military Population.

BACKGROUND: There has been a recent push to transition procedures previously performed at hospital-based outpatient surgical departments (HOPDs) to ambulatory surgery centers (ASCs). However, limited data regarding differences in early postoperative complications and care utilization (e.g., emergency department visits and unplanned admissions) may drive increased overall costs or worse outcomes. PURPOSE: /Hypothesis: The purpose of this study was to examine differences in early 90-day adverse outcomes and postoperative emergency department visits associated with shoulder surgeries excluding arthroplasties that were performed in HOPDs and ASCs in a closed military health care system. We hypothesized that there would be no difference in outcomes between treatment settings. METHODS: We retrospectively evaluated the records for 1,748 elective shoulder surgeries from 2015 to 2020. Patients were considered as one of two cohorts depending on whether they underwent surgery in an ASC or HOPD setting. We evaluated groups for differences incomplexity, surgical time, and medical risk. Outcome measures were emergency department visits, unplanned hospital admissions, and complications within the first 90 days after surgery. RESULTS: There was no difference in 90-day postoperative emergency department visits between procedures performed at HOPDs (n = 606) and ASCs (n = 1142). There was a slight increase in rate of unplanned hospital admission within 90 days after surgery in the HOPD cohort, most commonly for pain or overnight observation. The surgical time was significantly shorter (105 vs 119 minutes, p <0.01) at the ASC, but there was no difference in case complexity between the cohorts (p = 0.28). DISCUSSION/CONCLUSION: Our results suggest that in appropriate patients, surgery in ASCs can be safely leveraged for its costs savings, efficiency, patient satisfaction, decreases in operative time, and potentially decreased resource utilization both during surgery and in the early postoperative period.

Clinical impact of rapid molecular diagnostic tests in patients presenting with viral respiratory symptoms: A systematic literature review.

BACKGROUND: Molecular tests can detect lower concentrations of viral genetic material over a longer period of respiratory infection than antigen tests. Delays associated with central laboratory testing can result in hospital-acquired transmission, avoidable patient admission, and unnecessary use of antimicrobials, all which may lead to increased cost of patient management. The aim of this study was to summarize comparisons of clinical outcomes associated with rapid molecular diagnostic tests (RMDTs) versus other diagnostic tests for viral respiratory infections. METHODS: A systematic literature review (SLR) conducted in April 2023 identified studies evaluating clinical outcomes of molecular and antigen diagnostic tests for patients suspected of having respiratory viral infections. RESULTS: The SLR included 21 studies, of which seven and 14 compared RMDTs (conducted at points of care or at laboratories) to standard (non-rapid) molecular tests or antigen tests to detect SARS-CoV-2 and influenza, respectively. In studies testing for SARS-CoV-2, RMDTs led to reductions in time to test results versus standard molecular tests (range of the reported medians: 0.2-3.8 hours versus 4.3-35.9 hours), with similar length of emergency department stay (3.2-8 hours versus 3.7-28.8 hours). Similarly, in studies testing for influenza, RMDTs led to reductions in time to test results versus standard molecular tests (1-3.5 hours versus 18.2-29.2 hours), with similar length of emergency department stay (3.7-11 hours versus 3.8-11.9 hours). RMDTs were found to decrease exposure time of uninfected patients, rate of hospitalization, length of stay at the hospitals, and frequency of unnecessary antiviral and antibacterial therapy, while improving patient flow, compared to other tests. CONCLUSIONS: Compared to other diagnostic tests, RMDTs improve clinical outcomes, test turnaround time, and stewardship by decreasing unnecessary use of antibiotics and antivirals. They also reduce hospital admission and length of stay, which may, in turn, reduce unnecessary exposure of patients to hospital-acquired infections and their associated costs.

Neural circuit-selective, multiplexed pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception.

Selective manipulation of neural circuits using optogenetics and chemogenetics holds great translational potential but requires genetic access to neurons. Here, we demonstrate a general framework for identifying genetic tool-independent, pharmacological strategies for neural circuit-selective modulation. We developed an economically accessible calcium imaging-based approach for large-scale pharmacological scans of endogenous receptor-mediated neural activity. As a testbed for this approach, we used the mouse locus coeruleus due to the combination of its widespread, modular efferent neural circuitry and its wide variety of endogenously expressed GPCRs. Using machine learning-based action potential deconvolution and retrograde tracing, we identified an agonist cocktail that selectively inhibits medial prefrontal cortex-projecting locus coeruleus neurons. In vivo, this cocktail produces synergistic antinociception, consistent with selective pharmacological blunting of this neural circuit. This framework has broad utility for selective targeting of other neural circuits under different physiological and pathological states, facilitating non-genetic translational applications arising from cell type-selective discoveries.

CUREs for high-level Galectin-3 expression.

Galectins are a large and diverse protein family defined by the presence of a carbohydrate recognition domain (CRD) that binds ß-galactosides. They play important roles in early development, tissue regeneration, immune homeostasis, pathogen recognition, and cancer. In many cases, studies that examine galectin biology and the effect of manipulating galectins are aided by, or require the ability to express and purify, specific members of the galectin family. In many cases, E. coli is employed as a heterologous expression system, and galectin expression is induced with isopropyl ß-galactoside (IPTG). Here, we show that galectin-3 recognizes IPTG with micromolar affinity and that as IPTG induces expression, newly synthesized galectin can bind and sequester cytosolic IPTG, potentially repressing further expression. To circumvent this putative inhibitory feedback loop, we utilized an autoinduction protocol that lacks IPTG, leading to significantly increased yields of galectin-3. Much of this work was done within the context of a course-based undergraduate research experience, indicating the ease and reproducibility of the resulting expression and purification protocols.

PAM-free diagnostics with diverse type V CRISPR-Cas systems.

Type V CRISPR-Cas effectors have revolutionized molecular diagnostics by facilitating the detection of nucleic acid biomarkers. However, their dependence on the presence of protospacer adjacent motif (PAM) sites on the target double-stranded DNA (dsDNA) greatly limits their flexibility as diagnostic tools. Here we present a novel method named PICNIC that solves the PAM problem for CRISPR-based diagnostics with just a simple ∼10-min modification to contemporary CRISPR-detection protocols. Our method involves the separation of dsDNA into individual single-stranded DNA (ssDNA) strands through a high- temperature and high-pH treatment. We then detect the released ssDNA strands with diverse Cas12 enzymes in a PAM-free manner. We show the utility of PICNIC by successfully applying it for PAM-free detection with three different subtypes of the Cas12 family- Cas12a, Cas12b, and Cas12i. Notably, by combining PICNIC with a truncated 15-nucleotide spacer containing crRNA, we demonstrate PAM-independent detection of clinically important single- nucleotide polymorphisms with CRISPR. We apply this approach to detect the presence of a drug-resistant variant of HIV-1, specifically the K103N mutant, that lacks a PAM site in the vicinity of the mutation. Additionally, we successfully translate our approach to clinical samples by detecting and genotyping HCV-1a and HCV-1b variants with 100% specificity at a PAM-less site within the HCV genome. In summary, PICNIC is a simple yet groundbreaking method that enhances the flexibility and precision of CRISPR-Cas12-based diagnostics by eliminating the restriction of the PAM sequence.

Converting OMOP CDM to phenopackets: A model alignment and patient data representation evaluation.

OBJECTIVE: This study aims to promote interoperability in precision medicine and translational research by aligning the Observational Medical Outcomes Partnership (OMOP) and Phenopackets data models. Phenopackets is an expert knowledge-driven schema designed to facilitate the storage and exchange of multimodal patient data, and support downstream analysis. The first goal of this paper is to explore model alignment by characterizing the common data models using a newly developed data transformation process and evaluation method. Second, using OMOP normalized clinical data, we evaluate the mapping of real-world patient data to Phenopackets. We evaluate the suitability of Phenopackets as a patient data representation for real-world clinical cases. METHODS: We identified mappings between OMOP and Phenopackets and applied them to a real patient dataset to assess the transformation's success. We analyzed gaps between the models and identified key considerations for transforming data between them. Further, to improve ambiguous alignment, we incorporated Unified Medical Language System (UMLS) semantic type-based filtering to direct individual concepts to their most appropriate domain and conducted a domain-expert evaluation of the mapping's clinical utility. RESULTS: The OMOP to Phenopacket transformation pipeline was executed for 1,000 Alzheimer's disease patients and successfully mapped all required entities. However, due to missing values in OMOP for required Phenopacket attributes, 10.2 % of records were lost. The use of UMLS-semantic type filtering for ambiguous alignment of individual concepts resulted in 96 % agreement with clinical thinking, increased from 68 % when mapping exclusively by domain correspondence. CONCLUSION: This study presents a pipeline to transform data from OMOP to Phenopackets. We identified considerations for the transformation to ensure data quality, handling restrictions for successful Phenopacket validation and discrepant data formats. We identified unmappable Phenopacket attributes that focus on specialty use cases, such as genomics or oncology, which OMOP does not currently support. We introduce UMLS semantic type filtering to resolve ambiguous alignment to Phenopacket entities to be most appropriate for real-world interpretation. We provide a systematic approach to align OMOP and Phenopackets schemas. Our work facilitates future use of Phenopackets in clinical applications by addressing key barriers to interoperability when deriving a Phenopacket from real-world patient data.

A preliminary analysis of the effect of individual differences on cognitive performance in young companion dogs.

Many factors influence cognitive performance in dogs, including breed, temperament, rearing history, and training. Studies in working dog populations have demonstrated age-related improvements in cognitive task performance across the first years of development. However, the effect of certain factors, such as age, sex, and temperament, on cognitive performance in puppies has yet to be evaluated in a more diverse population of companion dogs. In this study, companion dogs under 12 months of age were tested once on two tasks purported to measure aspects of executive function: the delayed-search task (DST) and the detour reversal task (DRT). Owners also filled out the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) to evaluate how temperament influenced task performance. Contrary to prior research, performance did not improve with age on either task. However, the lack of age effects was likely the result of small sample sizes and individual differences across other factors influencing performance. Specifically, temperament differences as measured by the C-BARQ subscales for nonsocial fear and excitability predicted task performance on the DST, but the effect of temperament on task performance differed between males and females. Excitability also predicted performance on the DRT, but the effect depended on the age of the dog. In addition, no correlations were observed between task measures, indicating a lack of construct validity. Overall, these findings provide a preliminary analysis of factors that appear to influence cognitive task performance in young companion dogs and highlight suggestions for future research evaluating the impact of individual differences on cognitive performance.

Associations between memory performance and Bifidobacterium pseudolongum abundance in the canine gut microbiome.

Memory has been identified as the least heritable cognitive trait in canines, suggesting a significant influence of non-genetic factors. We observed a trend that overall memory scores (OMS) improve with age in a cohort of 27 young dogs, but considerable plasticity exists. Employing linear discriminant analysis of gut microbiome data from dogs exhibiting low and high OMS, a single bacterial species, Bifidobacterium pseudolongum, was identified and confirmed to be correlated with elevated OMS. Subsequent analysis using a random forest regression model revealed that sex, litter, and breed identity had minimal predictive importance. Age had some predictive value but failed to achieve statistical significance in this dataset. In sharp contrast, the abundance of 17 bacterial taxa in the microbiome showed a stronger predictive capacity for memory performance. Our findings provide insights into microbiome underpinnings of mammalian cognitive functions and suggest avenues for developing psychobiotics to enhance canine memory and learning.

Electrically Controlled All-Antiferromagnetic Tunnel Junctions on Silicon with Large Room-Temperature Magnetoresistance.

Antiferromagnetic (AFM) materials are a pathway to spintronic memory and computing devices with unprecedented speed, energy efficiency, and bit density. Realizing this potential requires AFM devices with simultaneous electrical writing and reading of information, which are also compatible with established silicon-based manufacturing. Recent experiments have shown tunneling magnetoresistance (TMR) readout in epitaxial AFM tunnel junctions. However, these TMR structures are not grown using a silicon-compatible deposition process, and controlling their AFM order required external magnetic fields. Here are shown three-terminal AFM tunnel junctions based on the noncollinear antiferromagnet PtMn3, sputter-deposited on silicon. The devices simultaneously exhibit electrical switching using electric currents, and electrical readout by a large room-temperature TMR effect. First-principles calculations explain the TMR in terms of the momentum-resolved spin-dependent tunneling conduction in tunnel junctions with noncollinear AFM electrodes.

Retrieval augmented scientific claim verification.

Objective: To automate scientific claim verification using PubMed abstracts. Materials and Methods: We developed CliVER, an end-to-end scientific Claim VERification system that leverages retrieval-augmented techniques to automatically retrieve relevant clinical trial abstracts, extract pertinent sentences, and use the PICO framework to support or refute a scientific claim. We also created an ensemble of three state-of-the-art deep learning models to classify rationale of support, refute, and neutral. We then constructed CoVERt, a new COVID VERification dataset comprising 15 PICO-encoded drug claims accompanied by 96 manually selected and labeled clinical trial abstracts that either support or refute each claim. We used CoVERt and SciFact (a public scientific claim verification dataset) to assess CliVER's performance in predicting labels. Finally, we compared CliVER to clinicians in the verification of 19 claims from 6 disease domains, using 189 648 PubMed abstracts extracted from January 2010 to October 2021. Results: In the evaluation of label prediction accuracy on CoVERt, CliVER achieved a notable F1 score of 0.92, highlighting the efficacy of the retrieval-augmented models. The ensemble model outperforms each individual state-of-the-art model by an absolute increase from 3% to 11% in the F1 score. Moreover, when compared with four clinicians, CliVER achieved a precision of 79.0% for abstract retrieval, 67.4% for sentence selection, and 63.2% for label prediction, respectively. Conclusion: CliVER demonstrates its early potential to automate scientific claim verification using retrieval-augmented strategies to harness the wealth of clinical trial abstracts in PubMed. Future studies are warranted to further test its clinical utility.

A locus coeruleus to dorsal hippocampus pathway mediates cue-induced reinstatement of opioid self-administration in male and female rats.

Opioid use disorder is a chronic relapsing disorder encompassing misuse, dependence, and addiction to opioid drugs. Long term maintenance of associations between the reinforcing effects of the drug and the cues associated with its intake are a leading cause of relapse. Indeed, exposure to the salient drug-associated cues can lead to drug cravings and drug seeking behavior. The dorsal hippocampus (dHPC) and locus coeruleus (LC) have emerged as important structures for linking the subjective rewarding effects of opioids with environmental cues. However, their role in cue-induced reinstatement of opioid use remains to be further elucidated. In this study, we showed that chemogenetic inhibition of excitatory dHPC neurons during re-exposure to drug-associated cues significantly attenuates cue-induced reinstatement of morphine-seeking behavior. In addition, the same manipulation reduced reinstatement of sucrose-seeking behavior but failed to alter memory recall in the object location task. Finally, intact activity of tyrosine hydroxylase (TH) LC-dHPCTh afferents is necessary to drive cue induced reinstatement of morphine-seeking as inhibition of this pathway blunts cue-induced drug-seeking behavior. Altogether, these studies show an important role of the dHPC and LC-dHPCTh pathway in mediating cue-induced reinstatement of opioid seeking.

Overcoming Patient Pain Together: Breast Cancer Patients and Caregivers' Pretreatment Psychosocial Distress Linked to Patients' Pain Interference During the First Year of Treatment.

Breast cancer patients experience treatment-related pain from surgery, radiation, chemotherapy, and long-term hormonal treatment, which can lead to poorer outcomes. Patient and family caregivers' psychosocial distress exacerbates patient pain interference, but this has not been directly examined among breast cancer patients in dyadic models longitudinally. Guided by a biopsychosocial framework, the Biobehavioral Family Model, we explore how multiple reports of patient pain interference across the first year of treatment are linked to the patient (N = 55) and caregiver (N = 55) pretreatment psychosocial distress (eg, depression, anxiety, marital satisfaction, family relationship quality). Specifically, we find that breast cancer patients' pain interference increases and then decreases over the first year of treatment. Additionally, caregivers' pretreatment anxiety was associated with increased patient pain interference over time (B = .19, SE = .07, P = .008), while patients' pretreatment psychosocial distress was not associated with a change in their pain interference. Yet, looking at clinically specific times during the first year of treatment, we find that caregiver-reported higher marital satisfaction is associated with lower patient-reported pain interference later in treatment (6 months: B = -.58, SE = .24, P = .017; 12 months: B = -.82, SE = .23, P < .001). We conclude that, per the Biobehavioral Family Model, pretreatment patient and caregiver psychosocial distress is linked to patient pain interference during the first year of breast cancer treatment. Thus, caregivers' psychosocial distress (ie, anxiety and marital satisfaction) may be a particularly important target in future dyadic behavioral intervention strategies to reduce breast cancer patient pain. PERSPECTIVE: This article presents the link between breast cancer patients and family caregiver pretreatment psychosocial distress (anxiety, depression, marital satisfaction, and family quality) on patient pain interference during 1 year of breast cancer treatment. Findings suggest that caregiver anxiety and marital satisfaction may be important targets for future dyadic behavioral pain interventions.

Surgical Treatment of Focal Chondral Lesions of the Knee in the Military Population: Current and Future Therapies.

INTRODUCTION: Chondral and osteochondral defects of the knee are common injuries in the military population that have a significant impact on readiness. Definitive treatment of these injuries is challenging since cartilage has a limited capacity for self-repair and regeneration. Management is particularly challenging in military patients who maintain a higher level of activity similar to athletes. Existing surgical techniques have variable results and often long recovery times, sparking the development of several new innovative technologies to return service members back to duty more quickly and effectively after cartilage injury. The purpose of this article is to review the current and future surgical treatments for chondral and osteochondral knee lesions and their relevance in managing these injuries in the military. METHODS: In this review article, we describe the current treatments for chondral and osteochondral defects of the knee, reporting on outcomes in military populations. We explore emerging treatment modalities for cartilage defects, reporting innovations, stage of research, and current data. Published results of each treatment option in military populations are reviewed throughout the article. RESULTS: This review includes 12 treatments for chondral lesions. Of these therapies, four are considered synthetic and the remaining are considered regenerative solutions. Regenerative therapies tend to perform better in younger, healthier populations with robust healing capacity. Success of treatment depends on lesions and patient characteristics. Nearly all modalities currently available in the USA were successful in improving patients from presurgical function in the short (<6 months) term, but the long-term efficacy is still challenged. Upcoming technologies show promising results in clinical and animal studies that may provide alternative options desirable for the military population. CONCLUSIONS: The current treatment options for cartilage lesions are not entirely satisfactory, usually with long recovery times and mixed results. An ideal therapy would be a single procedure that possesses the ability to enable a quick return to activity and duty, alleviate pain, provide long-term durability, and disrupt the progression of osteoarthritis. Evolving technologies for cartilage lesions are expanding beyond currently available techniques that may revolutionize the future of cartilage repair.

Microbes, the 'silent third partners' of bee-angiosperm mutualisms.

While bee-angiosperm mutualisms are widely recognized as foundational partnerships that have shaped the diversity and structure of terrestrial ecosystems, these ancient mutualisms have been underpinned by 'silent third partners': microbes. Here, we propose reframing the canonical bee-angiosperm partnership as a three-way mutualism between bees, microbes, and angiosperms. This new conceptualization casts microbes as active symbionts, processing and protecting pollen-nectar provisions, consolidating nutrients for bee larvae, enhancing floral attractancy, facilitating plant fertilization, and defending bees and plants from pathogens. In exchange, bees and angiosperms provide their microbial associates with food, shelter, and transportation. Such microbial communities represent co-equal partners in tripartite mutualisms with bees and angiosperms, facilitating one of the most important ecological partnerships on land.

Polygenic risk alters the penetrance of monogenic kidney disease.

Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.

Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice.

ABSTRACT: Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain-induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here, we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance conflict, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Furthermore, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury state and significantly correlates with mechanical thresholds. Together, these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays-even when individual inferential statistics do not demonstrate significant mean differences.

Endogenous opioids gate the locus coeruleus pain generator.

The locus coeruleus (LC) plays a paradoxical role in chronic pain. Although largely known as a potent source of endogenous analgesia, increasing evidence suggests injury can transform the LC into a chronic pain generator. We sought to clarify the role of this system in pain. Here, we show optogenetic inhibition of LC activity is acutely antinociceptive. Following long-term spared nerve injury, the same LC inhibition is analgesic - further supporting its pain generator function. To identify inhibitory substrates that may naturally serve this function, we turned to endogenous LC mu opioid receptors (LC-MOR). These receptors provide powerful LC inhibition and exogenous activation of LC-MOR is antinociceptive. We therefore hypothesized that endogenous LC-MOR-mediated inhibition is critical to how the LC modulates pain. Using cell type-selective conditional knockout and rescue of LC-MOR receptor signaling, we show these receptors bidirectionally regulate thermal and mechanical hyperalgesia - providing a functional gate on the LC pain generator.