Suppression of host humoral immunity by Borrelia burgdorferi varies over the course of infection.

Borrelia burgdorferi, the spirochetal agent of Lyme disease, utilizes a variety of strategies to evade and suppress the host immune response, which enables it to chronically persist in the host. The resulting immune response is characterized by unusually strong IgM production and a lack of long-term protective immunity. Previous studies in mice have shown that infection with B. burgdorferi also broadly suppresses host antibody responses against unrelated antigens. Here, we show that mice infected with B. burgdorferi and concomitantly immunized with recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein had an abrogated antibody response to the immunization. To further define how long this humoral immune suppression lasts, mice were immunized at 2, 4, and 6 weeks post-infection. Suppression of host antibody production against the SARS-CoV-2 spike protein peaked at 2 weeks post-infection but continued for all timepoints measured. Antibody responses against the SARS-CoV-2 spike protein were also assessed following antibiotic treatment to determine whether this immune suppression persists or resolves following clearance of B. burgdorferi. Host antibody production against the SARS-CoV-2 spike protein returned to baseline following antibiotic treatment; however, anti-SARS-CoV-2 IgM remained high, comparable to levels found in B. burgdorferi-infected but untreated mice. Thus, our data demonstrate restored IgG responses following antibiotic treatment but persistently elevated IgM levels, indicating lingering effects of B. burgdorferi infection on the immune system following treatment.

Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data.

Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings. We tested RENEW in an unselected cohort of 1066 undiagnosed cases with a broad spectrum of phenotypes from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. 5741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 s per variant (32 h total time). Reviewed cases were classified as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) definitively diagnosed. New strategies are needed to enable efficient review of genomic findings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process.

Opportunities for intervention for alcohol and other drug use problems for men before prison: A qualitative study.

Research into opportunities for prevention including health promotion information about alcohol and other drugs (AoD) harms for people who go to prison is sparce. This is despite there being ample research reporting how much and how frequently AoD have been used by people who go to prison. This article describes results from a qualitative thematic analysis of interviews with 31 men in a Sydney prison, about where they first received health promotion information about AoD-related harms and their first-ever treatment episode. No participant reported receiving education on AoD harms or treatment support services in primary school or high school. Only one participant received their first treatment episode through a health service (in his case from a doctor) and none reported being screened for AoD use at a health service. Almost all (n = 27) participants had their first session with a trained AoD professional through the criminal justice system. Pro-active screening in health services for AoD use disorders and referral to appropriate health services is needed.

Enhanced Adsorption of Epoxy-Functional Nanoparticles onto Stainless Steel Significantly Reduces Friction in Tribological Studies.

Epoxy-functional sterically-stabilized diblock copolymer nanoparticles (ca. 27 nm) are prepared via RAFT dispersion polymerization in mineral oil. Nanoparticle adsorption onto stainless steel is examined using a quartz crystal microbalance. Incorporating epoxy groups within the steric stabilizer chains results in a two-fold increase in the adsorbed amount, Γ, at 20 °C (7.6 mg m-2 ) compared to epoxy-core functional nanoparticles (3.7 mg m-2 ) or non-functional nanoparticles (3.8 mg m-2 ). A larger difference in Γ is observed at 40 °C; this suggests chemical adsorption of the nanoparticles rather than merely physical adsorption. A remarkable near five-fold increase in Γ is observed for ca. 50 nm epoxy-functional nanoparticles compared to non-functional nanoparticles (31.3 vs. 6.4 mg m-2 , respectively). Tribological studies confirm that chemical adsorption of the latter epoxy-functional nanoparticles leads to a significant reduction in friction between 60 °C and 120 °C.

Neurexin 1 variants as risk factors for suicide death.

Suicide is a significant public health concern with complex etiology. Although the genetic component of suicide is well established, the scope of gene networks and biological mechanisms underlying suicide has yet to be defined. Previously, we reported genome-wide evidence that neurexin 1 (NRXN1), a key synapse organizing molecule, is associated with familial suicide risk. Here we present new evidence for two non-synonymous variants (rs78540316; P469S and rs199784139; H885Y) associated with increased familial risk of suicide death. We tested the impact of these variants on binding interactions with known partners and assessed functionality in a hemi-synapse formation assay. Although the formation of hemi-synapses was not altered with the P469S variant relative to wild-type, both variants increased binding to the postsynaptic binding partner, leucine-rich repeat transmembrane neuronal 2 (LRRTM2) in vitro. Our findings indicate that variants in NRXN1 and related synaptic genes warrant further study as risk factors for suicide death.

Effect of perfusate volume on amikacin concentrations after saphenous intravenous regional limb perfusion in standing, sedated horses.

OBJECTIVE: To determine the influence of perfusate volume on synovial fluid amikacin concentrations in the joints of the hind limb after standing saphenous intravenous regional limb perfusion (IVRLP). STUDY DESIGN: Randomized crossover design. ANIMALS: Six adult horses. METHODS: Saphenous IVRLP was performed in 6 standing horses with 1 g of amikacin diluted with 0.9% NaCl to volumes of 10 ml, 60 ml, and 120 ml. Samples of synovial fluid from the tarsocrural, metatarsophalangeal, and hind limb distal interphalangeal joints were collected at 15 and 30 min after perfusate administration. Concentrations of 40 µg/ml and 160 µg/ml were considered therapeutic for susceptible and resistant pathogens, respectively. RESULTS: No difference in synovial fluid amikacin concentrations was detected between volumes in any joint (P = .4). All synovial fluid amikacin concentrations were higher at 30 min compared to 15 min (P = .003). All median synovial fluid amikacin concentrations at 30 min were > 40 µg/ml using the 60 ml and 120 ml volumes. Synovial fluid amikacin concentrations >40 µg/ml were only reached in the hind limb distal interphalangeal joint when the 10 ml volume was used. All median synovial fluid amikacin concentrations observed were < 160 µg/ml. CONCLUSIONS: Target concentrations for pathogens that were considered susceptible were consistently reached with perfusate volumes of 60 ml and 120 ml. However, median synovial fluid amikacin concentrations did not reach target levels for resistant pathogens. CLINICAL SIGNIFICANCE: Perfusate volumes of 60 ml or 120 ml are recommended to treat infections due to susceptible pathogens in the joints of the distal hind limb. These results justify investigation of saphenous IVRLP with different perfusate volumes using higher doses of amikacin.

Kirrel3-Mediated Synapse Formation Is Attenuated by Disease-Associated Missense Variants.

Missense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability, but it has not been reported if or how these variants disrupt Kirrel3 function. Previously, we studied Kirrel3 loss of function using KO mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse in vivo Here, we developed an in vitro, gain-of-function assay for Kirrel3 using neuron cultures prepared from male and female mice and rats. We find that WT Kirrel3 induces synapse formation selectively between Kirrel3-expressing neurons via homophilic, transcellular binding. We tested six disease-associated Kirrel3 missense variants and found that five attenuate this synaptogenic function. All variants tested traffic to the cell surface and localize to synapses similar to WT Kirrel3. Two tested variants lack homophilic transcellular binding, which likely accounts for their reduced synaptogenic function. Interestingly, we also identified variants that bind in trans but cannot induce synapses, indicating that Kirrel3 transcellular binding is necessary but not sufficient for its synaptogenic function. Collectively, these results suggest Kirrel3 functions as a synaptogenic, cell-recognition molecule, and this function is attenuated by missense variants associated with autism spectrum disorder and intellectual disability. Thus, we provide critical insight to the mechanism of Kirrel3 function and the consequences of missense variants associated with autism and intellectual disability.SIGNIFICANCE STATEMENT Here, we advance our understanding of mechanisms mediating target-specific synapse formation by providing evidence that Kirrel3 transcellular interactions mediate target recognition and signaling to promote synapse development. Moreover, this study tests the effects of disease-associated Kirrel3 missense variants on synapse formation, and thereby, increases understanding of the complex etiology of neurodevelopmental disorders arising from rare missense variants in synaptic genes.

Genome-wide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide.

Suicide is the 10th leading cause of death in the United States. Although environment has undeniable impact, evidence suggests that genetic factors play a significant role in completed suicide. We linked a resource of ~ 4500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over eight million individuals. This linking has resulted in the identification of high-risk extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07-1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. Although PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~ 1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.

Standardised neonatal parenteral nutrition formulations - Australasian neonatal parenteral nutrition consensus update 2017.

BACKGROUND: The first consensus standardised neonatal parenteral nutrition formulations were implemented in many neonatal units in Australia in 2012. The current update involving 49 units from Australia, New Zealand, Singapore, Malaysia and India was conducted between September 2015 and December 2017 with the aim to review and update the 2012 formulations and guidelines. METHODS: A systematic review of available evidence for each parenteral nutrient was undertaken and new standardised formulations and guidelines were developed. RESULTS: Five existing preterm Amino acid-Dextrose formulations have been modified and two new concentrated Amino acid-Dextrose formulations added to optimise amino acid and nutrient intake according to gestation. Organic phosphate has replaced inorganic phosphate allowing for an increase in calcium and phosphate content, and acetate reduced. Lipid emulsions are unchanged, with both SMOFlipid (Fresenius Kabi, Australia) and ClinOleic (Baxter Healthcare, Australia) preparations included. The physicochemical compatibility and stability of all formulations have been tested and confirmed. Guidelines to standardise the parenteral nutrition clinical practice across facilities have also been developed. CONCLUSIONS: The 2017 PN formulations and guidelines developed by the 2017 Neonatal Parenteral Nutrition Consensus Group offer concise and practical instructions to clinicians on how to implement current and up-to-date evidence based PN to the NICU population.

Mapping the prison mental health service workforce in Australia.

OBJECTIVE: The rapidly growing number of people in prison in Australia, combined with the high prevalence of mental disorder in this population, results in high demand for mental health services in prison settings. Despite their critical role as part of a national mental health response, prison mental health services (PMHS) in Australia have been poorly characterised. In this paper, we describe findings of the first national survey of PMHS in Australia. METHODS: We distributed a survey to key representatives of PMHS in all Australian states and territories in 2016. RESULTS: Our method constitutes a replicable process for quantifying and comparing PMHS in Australia. We describe the structure, governance and staffing models in seven jurisdictions. When compared against international recommendations, only one Australian jurisdiction (the ACT) is funded to provide services at a level equivalent to mental health services provided in the community. CONCLUSION: Prison mental health services in Australia are delivered by a complex mix of government, private sector and non-government services. Services appear to be severely under-resourced when compared with the available benchmarks.

Oral Methods of Urinary Alkalinization for High-dose Methotrexate Administration: Alternatives to Intravenous Sodium Bicarbonate During a Critical Drug Shortage.

A nationwide shortage of intravenous (IV) sodium bicarbonate required institutions to explore alternative options for urinary alkalinization for high-dose methotrexate (HDMTX). Children's Hospital Colorado implemented a protocol utilizing oral alkalinizing agents as alternatives to intravenous sodium bicarbonate during the shortage. The purpose of this study was to determine the safety and efficacy of oral alkalinization strategies for HDMTX administration. This retrospective study was conducted at a pediatric institution and evaluated cycles of HDMTX administered with at least one dose of oral sodium bicarbonate tablets or sodium citrate-citric acid oral solution. The time to achieve urine pH of ≥7 was 3.48 hours from the start of alkalinization. A median dose of 66.4 mEq/m/day of oral sodium bicarbonate was administered to maintain a urine pH of ≥7 until methotrexate was cleared. Gastrointestinal side effects occurred with 43% of HDMTX cycles and patients switched to IV sodium acetate in 25.5% of HDMTX cycles, primarily due to inadequate alkalinization or intolerance. During a shortage of IV sodium bicarbonate, oral alkalinization is an effective strategy for most patients to allow for administration of HDMTX.

North Carolina Nurse Leader Project: A Replication Study to Assess Nurse Leadership Capacity.

OBJECTIVES: The study examined nurse leader roles, barriers, and the need for nurse leader succession planning in North Carolina (NC). BACKGROUND: This study was conducted to assess leadership capacity in NC and further the efforts of the Future of Nursing report, which calls for nurses to lead change and advance health. METHODS: This study employed an exploratory research design using the Florida Action Coalition 56-item survey of active RNs and advanced practice RNs in NC. RESULTS: Key findings include nurse leader demographics, roles, barriers, retirement and succession plans, and development needs of current leaders in NC. NC nurse leaders are predominately female, white, non-Hispanic, and older than 50 years; plan to retire within the next 10 years; and report that their organizations do not have succession plans for nursing leadership. CONCLUSIONS: Attention toward assessing nurse leadership capacity should be a priority to meet workforce needs.

Learning about Aboriginal health and wellbeing at the postgraduate level: novel application of the Growth and Empowerment Measure.

INTRODUCTION: Public health education strives to transform and empower students to engage in policy and practice improvement. However, little is known of the nature of such change among students, especially when studying Aboriginal health and wellbeing, which may involve disrupting long held assumptions and prejudices. This article reports findings regarding the feasibility, specificity and sensitivity of the Growth and Empowerment Measure (GEM) in the evaluation of two innovative Australian 13-week postgraduate public health electives focused on Aboriginal health and wellbeing. The GEM's 14-item Emotional Empowerment Scale (EES14) and its subscales Inner Peace and Self-Capacity, and 12 Scenarios (S12) and its subscales Healing and Growth and Connection and Purpose were used to examine transformative experiences. A new short form of the S12, the Core6, was also trialled as a briefer measure of functional empowerment. METHODS: Pre-course GEM responses and demographic information were collected from consenting students during the mandatory, face-to-face workshops of the Aboriginal public health Perspectives course and the Aboriginal empowerment and wellbeing Lifespan course. The two-day Perspectives course workshop introduced a group scenario-building activity towards ending health inequality. Lifespan students experienced a 3-day immersion based on Stage 1 of the Aboriginal Family Well Being empowerment program. Insights from both workshops were further integrated through structured online discussions and written assessments. At the end of semester, a post-course GEM was mailed to students for completion and return. Students could also provide feedback through evaluation surveys and semi-structured focus groups. Effect sizes were assessed using paired t-tests, Wilcoxon signed-rank tests and multiple ANOVA. Cronbach's alpha confirmed internal consistency. RESULTS: Baseline GEM data was provided for 147 out of a total of 194 workshop experiences from participating students. Twenty students attended workshops for both Perspectives and Lifespan. Fifty-five matched pairs (representing 52 individual participants) were obtained from 170 students who completed one or both courses. Statistically significant positive change of small to medium effect size was detected in all GEM scales, subscales and some individual items. Lifespan yielded larger effects than Perspectives, most markedly on two subscales: Inner Peace, and Connection and Purpose. Participating students reported significant growth in the Scenario item 'knowing and being who I am' following Perspectives and Lifespan. Those completing Perspectives also reported a significant increase in 'gaining voice and being heard', consistent with its action-oriented scenario-building assessment. In contrast, the psychosocial development approach embedded in Lifespan stimulated strong development in spirituality, responding constructively to judgement, appreciating empowerment in their communities and skills to make changes in their lives. Feedback indicated that students valued these personal and professional growth experiences. CONCLUSION: The GEM was sensitive and specific in measuring components of empowering change among participants. Challenges included low post-course response rates that limited extrapolation to overall course impact, and attention needed to starting point when comparing the increment of change. The GEM is a promising tool for studying postgraduate courses designed to stimulate transformative learning, wellbeing and cultural competence through empowerment, and relevant in the education of health professionals in the fields of Aboriginal and rural health.

High-performance probes for light and electron microscopy.

We describe an engineered family of highly antigenic molecules based on GFP-like fluorescent proteins. These molecules contain numerous copies of peptide epitopes and simultaneously bind IgG antibodies at each location. These 'spaghetti monster' fluorescent proteins (smFPs) distributed well in neurons, notably into small dendrites, spines and axons. smFP immunolabeling localized weakly expressed proteins not well resolved with traditional epitope tags. By varying epitope and scaffold, we generated a diverse family of mutually orthogonal antigens. In cultured neurons and mouse and fly brains, smFP probes allowed robust, orthogonal multicolor visualization of proteins, cell populations and neuropil. smFP variants complement existing tracers and greatly increase the number of simultaneous imaging channels, and they performed well in advanced preparations such as array tomography, super-resolution fluorescence imaging and electron microscopy. In living cells, the probes improved single-molecule image tracking and increased yield for RNA-seq. These probes facilitate new experiments in connectomics, transcriptomics and protein localization.

Are Men With a History of Head Injury Less Responsive to Cognitive Behavioral Therapy for Intimate Partner Violence?

Head injury is highly prevalent among intimate partner violence (IPV) offenders. This study investigates responsiveness to cognitive behavioral therapy (CBT) for partnerviolent men with and without a history of head injury using archival data on 310 males seeking IPV counseling at a community domestic violence agency. Participants reported on their history of head injury, age at injury, and length of time unconscious in a structured interview at program intake. Criminal justice outcomes were assessed for the 2-year period after scheduled completion of treatment using a publicly available state database. A significantly greater percentage of men with a history of head injury (N = 84) than those without (N = 226) had criminal involvement for incidents of partner abuse during the follow-up period. In addition, men with a history of moderate-to-severe head injury (n = 25) had more criminal involvement for general violence than those with no history of head injury. The findings highlight the need to screen partner-violent men for head injury and to develop and investigate intervention enhancements for those individuals.

Intimate Partner Violence Victimization and Cognitive Function in a Mixed-Sex Epidemiological Sample of Urban Adults.

Intimate partner violence (IPV) victimization is associated with a wide range of mental and physical health problems, but little is known about the effect of IPV on cognitive decline. Previous research suggests an association between IPV victimization and cognitive dysfunction, but the few studies that have examined this phenomenon were cross-sectional in design and focused only on female victims of IPV. This study examined cognitive function over time among a diverse population of both male and female victims of IPV. Regression analyses indicated increased completion time on Trail Making Test (TMT) A for both male and female victims of IPV living below poverty as well as for female victims of IPV without previously depressive symptomatology. Results also indicated increased completion time on TMT B for male victims of IPV. Our findings support an association between IPV victimization and increased cognitive decline that is moderated by poverty status and previous depressive symptomatology.

Juvenile social status predicts primary sex allocation in a sex changing fish.

Both individual sex and population sex ratio can affect lifetime reproductive success. As a result, multiple mechanisms have evolved to regulate sexual phenotype, including adult sex change in fishes. While adult sex change is typically socially regulated, few studies focus on the non-chromosomal mechanisms regulating primary sex allocation. We investigated primary sex determination in the bluebanded goby (Lythrypnus dalli), a bidirectionally sex-changing fish. Of the studies investigating primary sex determination in species with adult sex change, this is the first to incorporate the roles of social status and size, key factors for determining adult sex allocation. For L. dalli, adult sex is regulated by social status: dominants are male; subordinates are female. In social groups of laboratory-reared juveniles, we demonstrate that status also predicts primary sex. Dominant juveniles developed male-typical genitalia, and their gonads contained significantly less ovarian tissue than subordinates, which developed female-typical genitalia. To better understand natural development, we quantified the distribution of juveniles and adults on the reef and analyzed genital papilla and gonad morphology in a sample of wild-caught juveniles. Juveniles were observed in various social environments, and most grouped with other juveniles and/or adults. The majority of field-caught juveniles had female-typical genitalia and bisexual, female-biased gonads. These data are consistent with a single mechanism that regulates sexual phenotype throughout life. Social status could first cause and then maintain through adulthood a female-biased population, allowing individuals to regulate sex based on local conditions, which is important for optimizing lifetime reproductive success.