Transdiagnostic and transtherapeutic strategies for optimising autobiographical memory.

Our memories for past personally experienced autobiographical events play an important role in therapy, irrespective of presenting issue, diagnoses or therapeutic modality. Here, we summarise evidence for how autobiographical memory abilities can influence our mental health and the relevance of this for the treatment of mental health problems. We then guide the reader through principles and strategies for optimising autobiographical memory within treatment. We ground these recommendations within research for stand-alone interventions for improving autobiographical memory and from studies of how to support the formation and retrieval of therapeutic memories. Options are given for clinicians to guide clients in improving retrieval of autobiographical memories within treatment, for improving autobiographical memory for the therapeutic experience itself, and for creating improvements in autobiographical memory that endure post-treatment. We also provide worksheets for clinicians to use within treatment.

Meeting the Challenge of Controlling Viral Immunopathology.

The mission of this review is to identify immune-damaging participants involved in antiviral immunoinflammatory lesions. We argue these could be targeted and their activity changed selectively by maneuvers that, at the same time, may not diminish the impact of components that help resolve lesions. Ideally, we need to identify therapeutic approaches that can reverse ongoing lesions that lack unwanted side effects and are affordable to use. By understanding the delicate balance between immune responses that cause tissue damage and those that aid in resolution, novel strategies can be developed to target detrimental immune components while preserving the beneficial ones. Some strategies involve rebalancing the participation of immune components using various approaches, such as removing or blocking proinflammatory T cell products, expanding regulatory cells, restoring lost protective cell function, using monoclonal antibodies (moAb) to counteract inhibitory molecules, and exploiting metabolic differences between inflammatory and immuno-protective responses. These strategies can help reverse ongoing viral infections. We explain various approaches, from model studies and some clinical evidence, that achieve innate and adaptive immune rebalancing, offering insights into potential applications for controlling chronic viral-induced lesions.

Hurricanes pose a substantial risk to New England forest carbon stocks.

Nature-based climate solutions (NCS) are championed as a primary tool to mitigate climate change, especially in forested regions capable of storing and sequestering vast amounts of carbon. New England is one of the most heavily forested regions in the United States (>75% forested by land area), and forest carbon is a significant component of climate mitigation policies. Large infrequent disturbances, such as hurricanes, are a major source of uncertainty and risk for policies relying on forest carbon for climate mitigation, especially as climate change is projected to alter the intensity and extent of hurricanes. To date, most research into disturbance impacts on forest carbon stocks has focused on fire. Here, we show that a single hurricane in the region can down between 121 and 250 MMTCO2e or 4.6%-9.4% of the total aboveground forest carbon, much greater than the carbon sequestered annually by New England's forests (16 MMTCO2e year-1). However, emissions from hurricanes are not instantaneous; it takes approximately 19 years for downed carbon to become a net emission and 100 years for 90% of the downed carbon to be emitted. Reconstructing hurricanes with the HURRECON and EXPOS models across a range of historical and projected wind speeds, we find that an 8% and 16% increase in hurricane wind speeds leads to a 10.7- and 24.8-fold increase in the extent of high-severity damaged areas (widespread tree mortality). Increased wind speed also leads to unprecedented geographical shifts in damage, both inland and northward, into heavily forested regions traditionally less affected by hurricanes. Given that a single hurricane can emit the equivalent of 10+ years of carbon sequestered by forests in New England, the status of these forests as a durable carbon sink is uncertain. Understanding the risks to forest carbon stocks from disturbances is necessary for decision-makers relying on forests as a NCS.

The role, relevance and management of immune exhaustion in bovine infectious diseases.

Immune exhaustion is a state of immune cell dysfunction that occurs most commonly following chronic exposure to an antigen which persists after the immune response fails to remove it. Exhaustion has been studied most thoroughly with several cancers, but has also been observed in several chronic infectious diseases. The topic has mainly been studied with CD8+ T cells, but it can also occur with CD4+ T cells and other immune cell types too. Exhaustion is characterized by a hierarchical loss of effector cell functions, up-regulation of immuno-inhibitory receptors, disruption of metabolic activities, and altered chromatin landscapes. Exhaustion has received minimal attention so far in diseases of veterinary significance and this review's purpose is to describe examples where immune exhaustion is occurring in several bovine disease situations. We also describe methodology to evaluate immune exhaustion as well as the prospects of controlling exhaustion and achieving a more suitable outcome of therapy in some chronic disease scenarios.

The necessity of removal of third molars involved in mandibular fractures: A retrospective study.

This retrospective analysis aimed to investigate the necessity of removing the wisdom tooth in cases of angle fractures of the mandible. The study retrieved 595 mandible fractures from January 2006 to December 2021 through the Hospital Inpatient Enquiry System, of which 303 involved a fracture through the angle of the mandible, including the wisdom tooth socket. Of these, 203 (66.9%) underwent open reduction and internal fixation with retention of the third molar. The authors found that only four (2%) patients returned for the removal of plates and the retained third molar during the follow-up period. Therefore, the authors concluded that wisdom teeth removal should remain an exception during open reduction and internal fixation of mandibular angle fractures unless they hinder fracture reduction, pose a potential infection risk, or interfere with occlusal stability.

The AO Spine Thoracolumbar Injury Classification System and Treatment Algorithm in Decision Making for Thoracolumbar Burst Fractures Without Neurologic Deficit.

STUDY DESIGN: Prospective Observational Study. OBJECTIVE: To determine the alignment of the AO Spine Thoracolumbar Injury Classification system and treatment algorithm with contemporary surgical decision making. METHODS: 183 cases of thoracolumbar burst fractures were reviewed by 22 AO Spine Knowledge Forum Trauma experts. These experienced clinicians classified the fracture morphology, integrity of the posterior ligamentous complex and degree of comminution. Management recommendations were collected. RESULTS: There was a statistically significant stepwise increase in rates of operative management with escalating category of injury (P < .001). An excellent correlation existed between recommended expert management and the actual treatment of each injury category: A0/A1/A2 (OR 1.09, 95% CI 0.70-1.69, P = .71), A3/4 (OR 1.62, 95% CI 0.98-2.66, P = .58) and B1/B2/C (1.00, 95% CI 0.87-1.14, P = .99). Thoracolumbar A4 fractures were more likely to be surgically stabilized than A3 fractures (68.2% vs 30.9%, P < .001). A modifier indicating indeterminate ligamentous injury increased the rate of operative management when comparing type B and C injuries to type A3/A4 injuries (OR 39.19, 95% CI 20.84-73.69, P < .01 vs OR 27.72, 95% CI 14.68-52.33, P < .01). CONCLUSIONS: The AO Spine Thoracolumbar Injury Classification system introduces fracture morphology in a rational and hierarchical manner of escalating severity. Thoracolumbar A4 complete burst fractures were more likely to be operatively managed than A3 fractures. Flexion-distraction type B injuries and translational type C injuries were much more likely to have surgery recommended than type A fractures regardless of the M1 modifier. A suspected posterior ligamentous injury increased the likelihood of surgeons favoring surgical stabilization.

"They just looked at me like I was human": The experiences of parenting women and providers with substance use disorder treatment.

BACKGROUND: The current US addiction treatment system does not effectively meet the needs of pregnant and parenting women with substance use disorder (SUD). The aim of this research was to identify barriers and facilitators to engagement and retention in SUD residential treatment for pregnant and parenting women. This research was part of a co-design process to collaboratively create a more patient-centered long-term residential program. DESIGN AND METHODS: The study conducted semi-structured individual interviews with both parenting women with lived experience (WWLE) in residential SUD treatment and SUD treatment providers. Interviews aimed to elicit participants' experiences either receiving or providing care. The study team analyzed data in NVivo-12 using a deductive codebook based on the six principles of trauma informed care (TIC). RESULTS: We conducted a total of 32 interviews (WWLE =13, SUD providers =19). The study identified four major themes: 1) peer relationships provide inspiration and diminish shame; 2) providing individuals safe space to stumble in recovery creates opportunities for growth and builds self-efficacy; 3) reasonable, clear boundaries create a structured, protective environment for early recovery; 4) nonjudgmental connections facilitate engagement and build trust. We identified small pivotal moments along the continuum of care that showed how the elements in the four themes enhanced engagement and retention in treatment. These interactions, along the care continuum, are either structural (workflow process) or relational (interpersonal). CONCLUSION: This research increases understanding of the interplay of the structural and relational barriers and facilitators to engagement and retention in treatment. These seemingly minor positive or negative interactions along the care continuum are pivotal to fully operationalizing TIC and optimizing women's engagement in treatment. Improvement strategies that integrate the voices of WWLE and collaboratively co-design a more patient-centered system are critical steps to improving engagement in SUD treatment and more equitable SUD treatment services.

Reporting standard for describing first responder systems, smartphone alerting systems, and AED networks.

Standardized reporting of data is crucial for out-of-hospital cardiac arrest (OHCA) research. While the implementation of first responder systems dispatching volunteers to OHCA is encouraged, there is currently no uniform reporting standard for describing these systems. A steering committee established a literature search to identify experts in smartphone alerting systems. These international experts were invited to a conference held in Hinterzarten, Germany, with 40 researchers from 13 countries in attendance. Prior to the conference, participants submitted proposals for parameters to be included in the reporting standard. The conference comprised five workshops covering different aspects of smartphone alerting systems. Proposed parameters were discussed, clarified, and consensus was achieved using the Nominal Group Technique. Participants voted in a modified Delphi approach on including each category as a core or supplementary element in the reporting standard. Results were presented, and a writing group developed definitions for all categories and items, which were sent to participants for revision and final voting using LimeSurvey web-based software. The resulting reporting standard consists of 68 core items and 21 supplementary items grouped into five topics (first responder system, first responder network, technology/algorithm/strategies, reporting data, and automated external defibrillators (AED)). This proposed reporting standard generated by an expert opinion group fills the gap in describing first responder systems. Its adoption in future research will facilitate comparison of systems and research outcomes, enhancing the transfer of scientific findings to clinical practice.

Social operant conditioning of autobiographical memory sharing.

The memories for past autobiographical experiences that we share can influence relationship formation and consolidation with important implications for our mental health. However, little is known about how people's responses to our memories can influence subsequent memory sharing. Previous research examined how operant processes (i.e., punishment with aversive sounds) influence the sharing of memories for specific events from our past. Understanding the (social) mechanisms associated with difficulty sharing specific autobiographical memories is important given the association between these difficulties and a range of psychiatric diagnoses. We investigate the effects of verbal and non-verbal social operants on the willingness to share specific autobiographical memories. Participants shared memories with a confederate who coded their memories as specific or non-specific and responded in either an engaged/attentive, dismissive manner or gave no feedback depending on participants' assigned condition. Participants who were reinforced for sharing specific memories and punished for sharing non-specific memories, were more likely to share specific than non-specific memories compared to those who received no feedback. Reinforcement alone was not sufficient for modifying specificity. The ways that we respond to people when they share memories with us can influence their subsequent willingness to share specific events from their past.

Adverse effect of VEGFR-2 (rs1870377) polymorphism on the clinical course of COVID-19 in females and males in an age-dependent manner.

The COVID-19 pandemic has affected people worldwide with varying clinical presentations ranging from mild to severe or fatal, and studies have found that age, gender, and some comorbidities can influence the severity of the disease. It would be valuable to have genetic markers that might help predict the likely outcome of infection. For this objective, genes encoding VEGFR-2 (rs1870377), CCR5Δ32 (rs333), and TLR3 (rs5743313) were analyzed for polymorphisms in the peripheral blood of 160 COVID-19 patients before COVID-19 vaccine was available in Türkiye. We observed that possession of the VEGFR-2 rs1870377 mutant allele increased the risk of severe/moderate disease in females and subjects ≥65 years of age, but was protective in males <65 years of age. Other significant results were that the CCR5Δ32 allele was protective against severe disease in subjects ≥65 years of age, while TLR3 rs5743313 polymorphism was found to be protective against severe/moderate illness in males <65 years of age. The VEGFR-2 rs1870377 mutant allele was a risk factor for severe/moderate disease, particularly in females over the age of 65. These findings suggest that genetic polymorphisms have an age- and sex-dependent influence on the severity of COVID-19, and the VEGFR-2 rs1870377 mutant allele could be a potential predictor of disease severity.

Collective cell dynamics and luminal fluid flow in the epididymis: A mechanobiological perspective.

BACKGROUND: The mammalian epididymis is a specialized duct system that serves a critical role in sperm maturation and storage. Its distinctive, highly coiled tissue morphology provides a unique opportunity to investigate the link between form and function in reproductive biology. Although recent genetic studies have identified key genes and signaling pathways involved in the development and physiological functions of the epididymis, there has been limited discussion about the underlying dynamic and mechanical processes that govern these phenomena. AIMS: In this review, we aim to address this gap by examining two key aspects of the epididymis across its developmental and physiological phases. RESULTS AND DISCUSSION: First, we discuss how the complex morphology of the Wolffian/epididymal duct emerges through collective cell dynamics, including duct elongation, cell proliferation, and arrangement during embryonic development. Second, we highlight dynamic aspects of luminal fluid flow in the epididymis, essential for regulating the microenvironment for sperm maturation and motility, and discuss how this phenomenon emerges and interplays with epididymal epithelial cells. CONCLUSION: This review not only aims to summarize current knowledge but also to provide a starting point for further exploration of mechanobiological aspects related to the cellular and extracellular fluid dynamics in the epididymis.

Effect of Two Years of Doxycycline Treatment on Infrarenal Aortic Neck Diameter.

Objective: Endovascular aneurysm repair (EVAR) is a widely used option for patients with suitable vascular anatomy who have a large infrarenal abdominal aortic aneurysm (AAA). Neck diameter is the primary anatomical determinant of EVAR eligibility and device durability. Doxycycline has been proposed to stabilise the proximal neck after EVAR. This study explored doxycycline mediated aortic neck stabilisation in patients with small AAA, monitored by computed tomography over two years. Methods: This was a multicentre prospective randomised clinical trial. Subjects from the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT, NCT01756833) were included in this secondary a priori analysis. Female baseline AAA maximum transverse diameter was between 3.5 and 4.5 cm, and male was between 3.5 and 5.0 cm. Subjects were included if they completed pre-enrolment and two year follow up computed tomography (CT) imaging. Proximal aortic neck diameter was measured at the lowest renal artery, and 5, 10, and 15 mm caudal to this point; mean neck diameter was calculated from these values. Unpaired, two tailed parametric t test analysis with post hoc Bonferroni correction was used to detect differences between neck diameters in subjects treated with placebo vs. doxycycline at baseline and two years. Results: One hundred and ninety-seven subjects (171 male, 26 female) were included in the analysis. All patients, regardless of treatment arm, demonstrated larger neck diameter caudally, a slight increase in diameter at all anatomical levels over time, and greater growth caudally. There was no statistically significant difference in infrarenal neck diameter between treatment arms at any anatomical level at any time point, nor mean change in neck diameter over two years. Conclusion: Doxycycline does not demonstrate infrarenal aortic neck growth stabilisation in small AAA followed for two years by thin cut CT imaging using a standardised acquisition protocol and cannot be recommended for mitigation of growth of the aortic neck in patients with untreated small abdominal aortic aneurysms.

Chemical Tools for Studying Phosphohistidine: Generation of Selective τ-Phosphohistidine and π-Phosphohistidine Antibodies.

Nonhydrolysable stable analogues of τ-phosphohistidine (τ-pHis) and π-pHis have been designed, aided by electrostatic surface potential calculations, and subsequently synthesized. The τ-pHis and π-pHis analogues (phosphopyrazole 8 and pyridyl amino amide 13, respectively) were used as haptens to generate pHis polyclonal antibodies. Both τ-pHis and π-pHis conjugates in the form of BSA-glutaraldehyde-τ-pHis and BSA-glutaraldehyde-π-pHis were synthesized and characterized by 31 P NMR spectroscopy. Commercially available τ-pHis (SC56-2) and π-pHis (SC1-1; SC50-3) monoclonal antibodies were used to show that the BSA-G-τ-pHis and BSA-G-π-pHis conjugates could be used to assess the selectivity of pHis antibodies in a competitive ELISA. Subsequently, the selectivity of the pHis antibodies generated by using phosphopyrazole 8 and pyridyl amino amide 13 as haptens was assessed by competitive ELISA against His, pSer, pThr, pTyr, τ-pHis and π-pHis. Antibodies generated by using phosphopyrazole 8 as a hapten were found to be selective for τ-pHis, and antibodies generated by using pyridyl amino amide 13 were found to be selective for π-pHis. Both τ- and π-pHis antibodies were shown to be effective in immunological experiments, including ELISA, western blot, and immunofluorescence. The τ-pHis antibody was also shown to be useful in the immunoprecipitation of proteins containing pHis.

Controlling viral inflammatory lesions by inhibiting fatty acid metabolism.

Herpes simplex virus infection is a major cause of vision loss in humans. Eye damaging consequences are often driven by inflammatory cells as a result of an immune response to the virus. In the present report, we have compared the effect of inhibiting energy metabolism with etomoxir (Etox), which acts on the fatty acid oxidation pathway and 2-Deoxy-d-glucose (2DG), which acts on glycolysis for their inhibitory effects on herpetic ocular lesions. Both drugs showed similar protective effects when therapy was started on the day of infection, but some 2DG recipients succumbed to encephalitis. In contrast, all Etox recipients remained healthy. Both drugs were compared for effects on inflammatory reactions in the trigeminal ganglion (TG), where virus replicates and then establishes latency. Results indicate that 2DG significantly reduced CD8 and CD4 Th1 T cells in the TG, whereas Etox had minimal or no effect on such cells, perhaps explaining why encephalitis occurred only in 2DG recipients. Unlike treatment with 2DG, Etox therapy was largely ineffective when started at the time of lesion expression. Reasons for the differential effects were discussed as was the relevance of combining metabolic reprogramming approaches to combat viral inflammatory lesions.

Role of Innate Interferon Responses at the Ocular Surface in Herpes Simplex Virus-1-Induced Herpetic Stromal Keratitis.

Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that primarily infects epithelial cells of the orofacial mucosa. After initial lytic replication, HSV-1 enters sensory neurons and undergoes lifelong latency in the trigeminal ganglion (TG). Reactivation from latency occurs throughout the host's life and is more common in people with a compromised immune system. HSV-1 causes various diseases depending on the site of lytic HSV-1 replication. These include herpes labialis, herpetic stromal keratitis (HSK), meningitis, and herpes simplex encephalitis (HSE). HSK is an immunopathological condition and is usually the consequence of HSV-1 reactivation, anterograde transport to the corneal surface, lytic replication in the epithelial cells, and activation of the host's innate and adaptive immune responses in the cornea. HSV-1 is recognized by cell surface, endosomal, and cytoplasmic pattern recognition receptors (PRRs) and activates innate immune responses that include interferons (IFNs), chemokine and cytokine production, as well as the recruitment of inflammatory cells to the site of replication. In the cornea, HSV-1 replication promotes type I (IFN-α/ß) and type III (IFN-λ) IFN production. This review summarizes our current understanding of HSV-1 recognition by PRRs and innate IFN-mediated antiviral immunity during HSV-1 infection of the cornea. We also discuss the immunopathogenesis of HSK, current HSK therapeutics and challenges, proposed experimental approaches, and benefits of promoting local IFN-λ responses.

Evidence for distinct genetic and environmental influences on fear acquisition and extinction.

BACKGROUND: Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction. METHODS: In total, 1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase. RESULTS: Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4-0.5). CONCLUSIONS: Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

Introducing the Fear Learning and Anxiety Response (FLARe) app and web portal for the remote delivery of fear conditioning experiments.

Experimental paradigms measuring key psychological constructs can enhance our understanding of mechanisms underlying human psychological well-being and mental health. Delivering such paradigms remotely affords opportunities to reach larger, more representative samples than is typically possible with in-person research. The efficiency gained from remote delivery makes it easier to test replication of previously established effects in well-powered samples. There are several challenges to the successful development and delivery of remote experimental paradigms, including use of an appropriate delivery platform, identifying feasible outcome measures, and metrics of participant compliance. In this paper, we present FLARe (Fear Learning and Anxiety Response), open-source software in the form of a smartphone app and web portal for the creation and delivery of remote fear conditioning experiments. We describe the benefits and challenges associated with the creation of a remote delivery platform for fear conditioning, before presenting in detail the resultant software suite, and one instance of deploying this using the FLARe Research infrastructure. We provide examples of the application of FLARe to several research questions which illustrate the benefits of the remote approach to experiment delivery. The FLARe smartphone app and web portal are available for use by other researchers and have been designed to be user-friendly and intuitive. We hope that FLARe will be a useful tool for those interested in conducting well-powered fear conditioning studies to inform our understanding of the development and treatment of anxiety disorders.

Hedgehog signaling regulates Wolffian duct development through the primary cilium†.

Primary cilia play pivotal roles in embryonic patterning and organogenesis through transduction of the Hedgehog signaling pathway (Hh). Although mutations in Hh morphogens impair the development of the gonads and trigger male infertility, the contribution of Hh and primary cilia in the development of male reproductive ductules, including the epididymis, remains unknown. From a Pax2Cre; IFT88fl/fl knock-out mouse model, we found that primary cilia deletion is associated with imbalanced Hh signaling and morphometric changes in the Wolffian duct (WD), the embryonic precursor of the epididymis. Similar effects were observed following pharmacological blockade of primary cilia formation and Hh modulation on WD organotypic cultures. The expression of genes involved in extracellular matrix, mesenchymal-epithelial transition, canonical Hh and WD development was significantly altered after treatments. Altogether, we identified the primary cilia-dependent Hh signaling as a master regulator of genes involved in WD development. This provides new insights regarding the etiology of sexual differentiation and male infertility issues.

Can the triumph of mRNA vaccines against COVID-19 be extended to other viral infections of humans and domesticated animals?

The unprecedented success of mRNA vaccines in managing the COVID-19 pandemic raises the prospect of applying the mRNA platform to other viral diseases of humans and domesticated animals, which may lead to more efficacious vaccines for some agents. We briefly discuss reasons why mRNA vaccines achieved such success against COVID-19 and indicate what other virus infections and disease conditions might also be ripe for control using mRNA vaccines. We also evaluate situations where mRNA could prove valuable to rebalance the status of immune responsiveness and achieve success as a therapeutic vaccine approach against infections that induce immunoinflammatory lesions.