Utility of Intraoperative Neuromonitoring to Protect Against Adjacent Nerve Injury in Musculoskeletal and Lymph Nodal Cryoablation.

PURPOSE: To demonstrate the utility of intraoperative neuromonitoring (IONM) as an effective method of passive thermoprotection against cryogenic injury of neural structures during musculoskeletal and lymph node cryoablation. MATERIAL AND METHODS: 29 patients (16 male, mean age and range, M: 68.6 and 45-90, F: 62.6 and 28-88) underwent 33 cryoablations of musculoskeletal and lymph node lesions. Transcranial electrical motor evoked potentials (MEPs) and somatosensory evoked potentials (SSEPs) of target nerves were recorded throughout the ablations. Significant change was defined as waveform amplitude reduction greater than 30% (MEP) and 50% (SSEP). The primary outcomes of this study were immediate post-procedural neurological deficits and frequency of significant MEP and SSEP amplitude reductions. RESULTS: Significant amplitude reductions were detected in 54.5% (18/33) of MEP tracings and 0% (0/33) of SSEP tracings. Following each occurrence of significant amplitude reductions, freeze cycles were promptly terminated. Intra-procedurally, 13 patients had full recovery of amplitudes to baseline, 11 of which had additional freeze cycles completed. In 5/33 (15.2%) of cryoablations, there were immediate post-procedure neurological deficits (Moderate Adverse Events). Unrecovered MEPs conferred a relative risk for neurological sequela of 23.2 (95% confidence interval [CI], 3.22-167.21; P=0.0009) vs. those with recovered MEPs. All five patients had complete neurologic recovery by twelve months. CONCLUSION: IONM is a reliable, safe method of passive thermoprotection of neurological structures during cryoablation. It provides early detection of changes in nerve conduction, which when addressed quickly, may result in complete restoration of MEP signals within the procedure and minimize risk of cryogenic neural injury.

The benefit of adjuvant chemotherapy following pancreaticoduodenectomy for pancreatic adenocarcinoma depends on response to neoadjuvant therapy.

BACKGROUND: The benefit of adjuvant therapy (AT) remains unclear in pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and surgical resection. METHODS: The 2019 National Cancer Database was queried for patients with non-metastatic PDAC who received NAT followed by pancreaticoduodenectomy. Only patients with data regarding receipt of AT were included. Patients were classified if they had nodal down-staging specifically, or any downstaging (Tumor, Nodal, or overall). Propensity score matching (PSM) adjusted for pretreatment covariate imbalance between groups. The weighted Kaplan-Meier method and log-rank test were used to estimate the cumulative survival. RESULTS: After exclusion criteria and PSM, a total of 2784 patients remained; 1689 (60.7%) received AT and 1095 (39.3%) did not receive AT. Among all, those with additional AT had a significantly improved overall survival (OS) (p < 0.001). Upon evaluation of patients without downstaging after NAT, those who received AT had improved OS (no nodal downstaging or any downstaging; p = 0.002; p = 0.001). When evaluating patients with downstaging after NAT, those receiving AT did not have improved OS (nodal downstaging or any downstaging: p = 0.352; p = 0.99). CONCLUSION: Response to NAT appears to correlate with the benefit of AT following pancreaticoduodenectomy; patients who have a favorable response to NAT may not benefit from AT.

High-pressure studies of size dependent yield strength in rhenium diboride nanocrystals.

The superhard ReB2 system is the hardest pure phase diboride synthesized to date. Previously, we have demonstrated the synthesis of nano-ReB2 and the use of this nanostructured material for texture analysis using high-pressure radial diffraction. Here, we investigate the size dependence of hardness in the nano-ReB2 system using nanocrystalline ReB2 with a range of grain sizes (20-60 nm). Using high-pressure X-ray diffraction, we characterize the mechanical properties of these materials, including bulk modulus, lattice strain, yield strength, and texture. In agreement with the Hall-Petch effect, the yield strength increases with decreasing size, with the 20 nm ReB2 exhibiting a significantly higher yield strength than any of the larger grained materials or bulk ReB2. Texture analysis on the high pressure diffraction data shows a maximum along the [0001] direction, which indicates that plastic deformation is primarily controlled by the basal slip system. At the highest pressure (55 GPa), the 20 nm ReB2 shows suppression of other slip systems observed in larger ReB2 samples, in agreement with its high yield strength. This behavior, likely arises from an increased grain boundary concentration in the smaller nanoparticles. Overall, these results highlight that even superhard materials can be made more mechanically robust using nanoscale grain size effects.

Suicide and the COVID-19 pandemic: A qualitative study of discourse on an online pro-choice for suicide discussion forum.

The COVID-19 pandemic had a widespread impact on millions of individuals. Many turned to social media as an outlet for sharing personal experiences, such as the impact of the pandemic on suicidality. The purpose of this study was to understand the pandemic's impact on individuals who discuss their suicidality on social media. Keywords were used to search for discussion threads (N = 118) related to the pandemic on an online pro-choice for suicide forum. Using reflexive thematic analysis, six themes related to the pandemic's impact on mental health, suicidality, living conditions, and optimism were identified. Examination of the content from pro-choice for suicide forums may yield authentic information on the impact of the pandemic on those considering suicide. This study contributes to our understanding of the nuances of factors impacting mental health and suicidality during the pandemic, including unique risk and protective factors.

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer.

In the realm of cancer therapeutics, targeting the hypoxia-inducible factor (HIF) pathway has emerged as a promising strategy. This study delves into the intricate web of HIF-associated mechanisms, exploring avenues for future anticancer therapies. Framing the investigation within the broader context of cancer progression and hypoxia response, this article aims to decipher the pivotal role played by HIF in regulating genes influencing angiogenesis, cell proliferation, and glucose metabolism. Employing diverse approaches such as HIF inhibitors, anti-angiogenic therapies, and hypoxia-activated prodrugs, the research methodologically intervenes at different nodes of the HIF pathway. Findings showcase the efficacy of agents like EZN-2968, Minnelide, and Acriflavine in modulating HIF-1α protein synthesis and destabilizing HIF-1, providing preliminary proof of HIF-1α mRNA modulation and antitumor activity. However, challenges, including toxicity, necessitate continued exploration and development, as exemplified by ongoing clinical trials. This article concludes by emphasizing the potential of targeted HIF therapies in disrupting cancer-related signaling pathways.

A giant tyrannosaur from the Campanian-Maastrichtian of southern North America and the evolution of tyrannosaurid gigantism.

Tyrannosaurid dinosaurs dominated as predators in the Late Cretaceous of Laurasia, culminating in the evolution of the giant Tyrannosaurus rex, both the last and largest tyrannosaurid. Where and when Tyrannosaurini (T. rex and kin) originated remains unclear. Competing hypotheses place tyrannosaurin origins in Asia, or western North America (Laramidia). We report a new tyrannosaurin, Tyrannosaurus mcraeensis, from the Campanian-Maastrichtian Hall Lake Formation of New Mexico, based on a fossil previously referred to T. rex. T. mcraeensis predates T. rex by ~ 6-7 million years, yet rivaled it in size. Phylogenetic analysis recovers T. mcraeensis as sister to T. rex and suggests Tyrannosaurini originated in southern Laramidia. Evolution of giant tyrannosaurs in southern North America, alongside giant ceratopsians, hadrosaurs, and titanosaurs suggests large-bodied dinosaurs evolved at low latitudes in North America.

Uric acid formation is driven by crosstalk between skeletal muscle and other cell types.

Hyperuricemia is implicated in numerous pathologies, but the mechanisms underlying uric acid production are poorly understood. Using a combination of mouse studies, cell culture studies, and human serum samples, we sought to determine the cellular source of uric acid. In mice, fasting and glucocorticoid treatment increased serum uric acid and uric acid release from ex vivo-incubated skeletal muscle. In vitro, glucocorticoids and the transcription factor FoxO3 increased purine nucleotide degradation and purine release from differentiated muscle cells, which coincided with the transcriptional upregulation of AMP deaminase 3, a rate-limiting enzyme in adenine nucleotide degradation. Heavy isotope tracing during coculture experiments revealed that oxidation of muscle purines to uric acid required their transfer from muscle cells to a cell type that expresses xanthine oxidoreductase, such as endothelial cells. Last, in healthy women, matched for age and body composition, serum uric acid was greater in individuals scoring below average on standard physical function assessments. Together, these studies reveal skeletal muscle purine degradation is an underlying driver of uric acid production, with the final step of uric acid production occurring primarily in a nonmuscle cell type. This suggests that skeletal muscle fiber purine degradation may represent a therapeutic target to reduce serum uric acid and treat numerous pathologies.

The role of co-occurring disorders in criminal recidivism and psychiatric recovery among adults with opioid use disorder and criminal-legal involvement: A statewide retrospective cohort study.

INTRODUCTION: Individuals with opioid use disorder (OUD) in the criminal-legal system commonly present co-occurring mental health disorders. However, evidence-based treatment for high-risk populations such as those with co-occurring disorders is often unavailable within jails and prisons. Coordination of timely and affordable access to behavioral health treatment following incarceration is critical to address the multidimensional needs of people with co-occurring needs. However, the role of co-occurring disorders among adults with OUD and criminal-legal involvement who are accessing community-based treatment is understudied. METHODS: This retrospective cohort study investigated community and recovery outcomes among 2039 adults with OUD and criminal-legal involvement enrolled in a statewide forensic treatment initiative between October 2015 to March 2018. Using court records and clinical data, we assessed the impact of co-occurring OUD and mental health disorders on criminal recidivism and psychiatric recovery and the moderating role of co-occurring disorders on the relationship between community-based treatment and these outcomes. RESULTS: We found that 47 % of those with OUD also had an underlying mental health disorder. Co-occurring OUD and mental health disorders predicted higher rates of recidivism during the early stages of treatment. Furthermore, group and individual therapy services were associated with lower odds of recidivism. A co-occurring disorder was an important predictor of more severe behavioral health needs when exiting community-based services and did moderate the relationship between service utilization-specifically group therapy and substance use outpatient services-and psychiatric recovery (i.e., behavioral health needs at exit). CONCLUSIONS: Co-occurring mental health disorders are highly prevalent among adults with OUD who have criminal-legal involvement, but it appears that they can benefit from social support services in the community. Given the multidimensional needs of this high-risk population, criminal-legal stakeholders and community-based clinicians must work in tandem to develop tailored treatment plans that give individuals with co-occurring OUD and mental health disorders the best chance for success post-incarceration rather than a siloed approach to overlapping disorders.

Synthesis, Structure, and Heat Capacity of Some Basic Hydroxohalide Glasses of Zirconium and Hafnium.

This work highlights the synthesis and properties of novel basic hydroxohalide glasses of zirconium and hafnium. The hydroxohalide glasses are M(OH)4-αXα·(n)H2O where M represents either zirconium or hafnium, and X represents either chloride or bromide. The chemical structure is investigated using X-ray diffraction, total scattering, and the pair distribution function method to identify the local structure and any short-range connectivity. The thermodynamic properties of the glasses are probed using low-temperature heat capacity, where a gap in the phonon density of states is discussed and related to boson peaks in the heat capacity of the glasses. These results represent the first published synthesis and thermodynamic properties of zirconium and hafnium basic hydroxohalide glasses. Synthesis methods, structural determination, and analysis of the heat capacity data allow for a comprehensive look at the makeup and unique properties of these novel glassy materials. Values of the standard thermodynamic functions Cp,m°, Δ0TSm°, Δ0THm°, and Φm° are also reported.

Building the synaptonemal complex: Molecular interactions between the axis and the central region.

The successful delivery of genetic material to gametes requires tightly regulated interactions between the parental chromosomes. Central to this regulation is a conserved chromosomal interface called the synaptonemal complex (SC), which brings the parental chromosomes in close proximity along their length. While many of its components are known, the interfaces that mediate the assembly of the SC remain a mystery. Here, we survey findings from different model systems while focusing on insight gained in the nematode C. elegans. We synthesize our current understanding of the structure, dynamics, and biophysical properties of the SC and propose mechanisms for SC assembly.

Cardiac Sarcoidosis: A Case Report on the Role of Cardiac Computed Tomography (CT) in the Evaluation of Advanced Atrioventricular Block.

Cardiac sarcoidosis is a rare autoimmune condition that is characterized by the presence of non-caseating granulomas in the cardiac tissue. We present the case of a 31-year-old male with no significant past medical history who presented with palpitations and lightheadedness during exertion for two to three months and was found to have complete heart block on his 12-lead electrocardiogram. A cardiac CT was obtained to rule out an ischemic event, but it indicated findings suggestive of pulmonary sarcoidosis. The CT findings helped tremendously with narrowing down the differential diagnosis and providing efficient diagnostic and therapeutic management.

SOX9 Governs Gastric Mucous Neck Cell Identity and Is Required for Injury-Induced Metaplasia.

BACKGROUND & AIMS: Acute and chronic gastric injury induces alterations in differentiation within the corpus of the stomach called pyloric metaplasia. Pyloric metaplasia is characterized by the death of parietal cells and reprogramming of mitotically quiescent zymogenic chief cells into proliferative, mucin-rich spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Overall, pyloric metaplastic units show increased proliferation and specific expansion of mucous lineages, both by proliferation of normal mucous neck cells and recruitment of SPEM cells. Here, we identify Sox9 as a potential gene of interest in the regulation of mucous neck and SPEM cell identity in the stomach. METHODS: We used immunostaining and electron microscopy to characterize the expression pattern of SRY-box transcription factor 9 (SOX9) during murine gastric development, homeostasis, and injury in homeostasis, after genetic deletion of Sox9 and after targeted genetic misexpression of Sox9 in the gastric epithelium and chief cells. RESULTS: SOX9 is expressed in all early gastric progenitors and strongly expressed in mature mucous neck cells with minor expression in the other principal gastric lineages during adult homeostasis. After injury, strong SOX9 expression was induced in the neck and base of corpus units in SPEM cells. Adult corpus units derived from Sox9-deficient gastric progenitors lacked normal mucous neck cells. Misexpression of Sox9 during postnatal development and adult homeostasis expanded mucous gene expression throughout corpus units including within the chief cell zone in the base. Sox9 deletion specifically in chief cells blunts their reprogramming into SPEM. CONCLUSIONS: Sox9 is a master regulator of mucous neck cell differentiation during gastric development. Sox9 also is required for chief cells to fully reprogram into SPEM after injury.

A Rare Case of Leuconostoc pseudomesenteroides Bacteremia and Refractory Septic Shock.

Leuconostoc species are rare causes of bacteremia and are commonly mistaken for Streptococcus species. Due to their inherent resistance to commonly used drugs, they are often overlooked resulting in poor and sometimes lethal outcomes. While there are not many reported cases of this bacterial infection, Leuconostoc species are important to consider when faced with a highly drug-resistant bacterial strain. We present here a case of a 29-year-old male who presented with an out-of-hospital cardiac arrest, initially resuscitated but ultimately succumbing to his illness. This is a unique case in which our patient was subsequently found to have a rare bloodstream infection with Leuconostoc pseudomesenteroides.

Unusual Instance of Primary Diffuse Large B-cell Lymphoma of the Colon.

Diffuse large B-cell lymphoma (DLBCL) commonly affects the gastrointestinal (GI) tract, although primary DLBCL rarely occurs in the colon. Primary colorectal lymphoma is a surprisingly rare diagnosis, accounting for a minute percentage of GI lymphomas and colorectal malignancies. We present an interesting case of an immunocompromised young adult female who was diagnosed with DLBCL confined to a cecum polyp after she underwent a colonoscopy for a GI bleed. The lymphoma presented endoscopically as a semi-sessile polyp in the cecum that was successfully removed. The patient was treated with appropriate therapy of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

Meiotic DNA exchanges in C. elegans are promoted by proximity to the synaptonemal complex.

During meiosis, programmed double-strand DNA breaks are repaired to form exchanges between the parental chromosomes called crossovers. Chromosomes lacking a crossover fail to segregate accurately into the gametes, leading to aneuploidy. In addition to engaging the homolog, crossover formation requires the promotion of exchanges, rather than non-exchanges, as repair products. However, the mechanism underlying this meiosis-specific preference is not fully understood. Here, we study the regulation of meiotic sister chromatid exchanges in Caenorhabditis elegans by direct visualization. We find that a conserved chromosomal interface that promotes exchanges between the parental chromosomes, the synaptonemal complex, can also promote exchanges between the sister chromatids. In both cases, exchanges depend on the recruitment of the same set of pro-exchange factors to repair sites. Surprisingly, although the synaptonemal complex usually assembles between the two DNA molecules undergoing an exchange, its activity does not rely on a specific chromosome conformation. This suggests that the synaptonemal complex regulates exchanges-both crossovers and sister exchanges-by establishing a nuclear domain conducive to nearby recruitment of exchange-promoting factors.

Skeletal muscle contraction kinetics and AMPK responses are modulated by the adenine nucleotide degrading enzyme AMPD1.

AMP deaminase 1 (AMPD1; AMP → IMP + NH3) deficiency in skeletal muscle results in an inordinate accumulation of AMP during strenuous exercise, with some but not all studies reporting premature fatigue and reduced work capacity. To further explore these inconsistencies, we investigated the extent to which AMPD1 deficiency impacts skeletal muscle contractile function of different muscles and the [AMP]/AMPK responses to different intensities of fatiguing contractions. To reduce AMPD1 protein, we electroporated either an inhibitory AMPD1-specific miRNA encoding plasmid or a control plasmid, into contralateral EDL and SOL muscles of C57BL/6J mice (n = 48 males, 24 females). After 10 days, isolated muscles were assessed for isometric twitch, tetanic, and repeated fatiguing contraction characteristics using one of four (None, LOW, MOD, and HIGH) duty cycles. AMPD1 knockdown (∼35%) had no effect on twitch force or twitch contraction/relaxation kinetics. However, during maximal tetanic contractions, AMPD1 knockdown impaired both time-to-peak tension (TPT) and half-relaxation time (½ RT) in EDL, but not SOL muscle. In addition, AMPD1 knockdown in EDL exaggerated the AMP response to contractions at LOW (+100%) and MOD (+54%) duty cycles, but not at HIGH duty cycle. This accumulation of AMP was accompanied by increased AMPK phosphorylation (Thr-172; LOW +25%, MOD +34%) and downstream substrate phosphorylation (LOW +15%, MOD +17%). These responses to AMPD1 knockdown were not different between males and females. Our findings demonstrate that AMPD1 plays a role in maintaining skeletal muscle contractile function and regulating the energetic responses associated with repeated contractions in a muscle- but not sex-specific manner.NEW & NOTEWORTHY AMP deaminase 1 (AMPD1) deficiency has been associated with premature muscle fatigue and reduced work capacity, but this finding has been inconsistent. Herein, we report that although AMPD1 knockdown in mouse skeletal muscle does not change maximal isometric force, it negatively impacts muscle function by slowing contraction and relaxation kinetics in EDL muscle but not SOL muscle. Furthermore, AMPD1 knockdown differentially affects the [AMP]/AMPK responses to fatiguing contractions in an intensity-dependent manner in EDL muscle.

Patient-centered quality measurement for opioid use disorder: Development of a taxonomy to address gaps in research and practice.

Background: Evidence-based treatment is provided infrequently and inconsistently to patients with opioid use disorder (OUD). Treatment guidelines call for high-quality, patient-centered care that meets individual preferences and needs, but it is unclear whether current quality measures address individualized aspects of care and whether measures of patient-centered OUD care are supported by evidence. Methods: We conducted an environmental scan of OUD care quality to (1) evaluate patient-centeredness in current OUD quality measures endorsed by national agencies and in national OUD treatment guidelines; and (2) review literature evidence for patient-centered care in OUD diagnosis and management, including gaps in current guidelines, performance data, and quality measures. We then synthesized these findings to develop a new quality measurement taxonomy that incorporates patient-centered aspects of care and identifies priority areas for future research and quality measure development. Results: Across 31 endorsed OUD quality measures, only two measures of patient experience incorporated patient preferences and needs, while national guidelines emphasized providing patient-centered care. Among 689 articles reviewed, evidence varied for practices of patient-centered care. Many practices were supported by guidelines and substantial evidence, while others lacked evidence despite guideline support. Our synthesis of findings resulted in EQuIITable Care, a taxonomy comprised of six classifications: (1) patient Experience and engagement, (2) Quality of life; (3) Identification of patient risks; (4) Interventions to mitigate patient risks; (5) Treatment; and (6) Care coordination and navigation. Conclusions: Current quality measurement for OUD lacks patient-centeredness. EQuIITable Care for OUD provides a roadmap to develop measures of patient-centered care for OUD.

Correlates of suicide risk among Black and White adults with behavioral health disorders in criminal-legal systems.

BACKGROUND: Adults with behavioral health disorders in criminal-legal systems are at heightened risk of suicide relative to the general population. Despite documented racial disparities in criminal processing and behavioral health treatment, few studies have examined racial differences in suicide risk in this already high-risk population. This study examined 1) the correlates of suicide risk in this population overall and by race and 2) the moderating role of race in these associations. METHODS: We investigated correlates of clinician-rated suicide risk at baseline in a statewide sample of 2,827 Black and 14,022 White adults with criminal-legal involvement who engaged in community-based behavioral health treatment. Regression-based approaches were used to model suicide risk and test for evidence of interaction effects. RESULTS: Findings showed the strongest correlates of suicide risk were greater behavioral health needs, evidence of self-harm, and a primary mental health diagnosis or co-occurring diagnosis. In race-specific analyses, correlates of suicide risk were mostly similar for both Black and White clients, with a couple exceptions. Interaction terms testing between-group effects on correlates of suicide risk were non-significant. CONCLUSIONS: Adults with behavioral health disorders in criminal-legal systems experience similar risk factors for suicide as the general population. Similar to prior research, we found that Black adults, in particular, are at lower risk for suicide overall. Contrary to expectations, we found similarities in correlates of suicide risk across race in our sample of felony-level adults with behavioral health disorders in the criminal-legal system. Prior research shows that behavioral health professionals should be cognizant of cultural factors when developing a comprehensive approach to suicide care and treatment. Our findings show correlates of suicide risk are largely stable in Black and White adults involved in criminal-legal systems, suggesting culturally responsive treatment for suicide risk should target shared risk factors.