Adaptations of membrane trafficking in cancer and tumorigenesis.

Membrane trafficking, a fundamental cellular process encompassing the transport of molecules to specific organelles, endocytosis at the plasma membrane and protein secretion, is crucial for cellular homeostasis and signalling. Cancer cells adapt membrane trafficking to enhance their survival and metabolism, and understanding these adaptations is vital for improving patient responses to therapy and identifying therapeutic targets. In this Review, we provide a concise overview of major membrane trafficking pathways and detail adaptations in these pathways, including COPII-dependent endoplasmic reticulum (ER)-to-Golgi vesicle trafficking, COPI-dependent retrograde Golgi-to-ER trafficking and endocytosis, that have been found in cancer. We explore how these adaptations confer growth advantages or resistance to cell death and conclude by discussing the potential for utilising this knowledge in developing new treatment strategies and overcoming drug resistance for cancer patients.

Does arthroscopic or open washout in native knee septic arthritis result in superior post-operative function? A systematic review and meta-analysis of randomised controlled trials and observational studies.

AIMS: Septic arthritis (SA) of the native knee joint is associated with significant morbidity. This review compared post-operative functional outcomes (patient-reported outcome measures (PROMs) and range of movement (ROM)) following arthroscopic washout (AW) and open washout (OW) amongst adult patients with SA of the native knee. The need for further operative intervention was also considered. METHODS: Electronic databases of PubMed, MEDLINE, Embase, Cochrane, Web of Science and Scopus were searched between 16 February 2023 and 18 March 2023. Randomised controlled trials (RCTs) and comparative observational analytic studies comparing function (reflected in PROMs or ROM) at latest follow-up following AW and OW were included. A narrative summary was provided concerning post-operative PROMs. Pooled estimates for mean ROM and re-operation rates were conducted using the random-effects model. The risk of bias was assessed using the Cochrane risk-of-bias assessment tool-2 for RCTs and the Risk of Bias in Non-Randomized Studies of Interventions tool for observational analytic studies. RESULTS: Of 2580 retrieved citations, 7 articles (1 RCT and 6 cohort studies) met the inclusion criteria. Of these, five had some concerns/moderate risk of bias, and two had serious risk. There was a slight tendency for superior mean PROMs following AW compared with OW, but due to small effect sizes, this was unlikely clinically relevant. Additionally, the use of four different PROMs scales made direct comparisons impossible. AW was associated with superior ROM (mean difference 20.18° (95% CI 14.35, 26.02; p < 0.00001)), whilst there was a tendency for lower re-operation requirements following AW (OR 0.64, 95% CI 0.26, 1.57, p = 0.44). CONCLUSIONS: AW was associated with equivalent to superior post-operative function and lower requirement for further intervention compared with OW. Results need to be interpreted cautiously, taking into consideration the methodological and clinical heterogeneity of the included studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2022, CRD42022364062.

Mitochondrial DNA D-Loop Polymorphisms among the Galla Goats Reveals Multiple Maternal Origins with Implication on the Functional Diversity of the HSP70 Gene.

Despite much attention given to the history of goat evolution in Kenya, information on the origin, demographic history, dispersal route, and genetic diversity of Galla goats remains unclear. Here, we examined the genetic background, diversity, demographic history, and population genetic variation of Galla goats using mtDNA D-loop and HSP70 single-nucleotide polymorphism markers. The results revealed 90 segregating sites and 68 haplotypes in a 600-bp mtDNA D-loop sequence. The overall mean mitochondrial haplotype diversity was 0.993. The haplotype diversities ranged between 0.8939 ± 0.0777 and 1.0000 ± 0.0221 in all populations supporting high genetic diversity. Mitochondrial phylogenetic analysis revealed three Galla goat haplogroups (A, G, and D), supporting multiple maternal ancestries, of which haplogroup A was the most predominant. Analysis of molecular variance (AMOVA) showed considerable variation within populations at 94.39%, evidence of high genetic diversity. Bimodal mismatch distribution patterns were observed while most populations recorded negative results for Tajima and Fu's Fs neutrality tests supporting population expansion. Genetic variation among populations was also confirmed using HSP70 gene fragment sequences, where six polymorphic sites which defined 21 haplotypes were discovered. Analysis of molecular variance revealed a significant FST index value of 0.134 and a high FIS index value of 0.746, an indication of inbreeding. This information will pave the way for conservation strategies and informed breeding to improve Galla or other goat breeds for climate-smart agriculture.

Validation of the Radiographic Union Score for HUmeral fractures (RUSHU): A retrospective study in an independent centre.

Background: Early diagnosis and fixation of fractures unlikely to unite can prevent months of morbidity. The Radiographic Union Score for Humeral fractures (RUSHU) is a summative scoring system developed to aid identification of patients at higher risk of developing humeral shaft non-union. Plain radiographs taken six weeks after injury are given a score between four and 12 based on signs of union. Our aim was to assess the validity of the RUSHU prognostic model in an external population. Methods: The radiographs of fifty-seven patients were scored independently according to RUSHU methodology by three reviewers (blinded to patient outcome). Interobserver intraclass correlation (ICC) was calculated. Results: Of the cohort, six (10.5%) progressed to non-union after six months. We observed an interobserver ICC co-efficient of 0.89 (95%CI0.84,0.93) in RUSHU score at six weeks. Median score was significantly higher in the union cohort (10v5 p < 0.001). Using the score of < 8 to predict non-union gave an area under the ROC curve of 0.87 (95%CI 0.83,0.90). Conclusions: In this retrospective single-centre study, we have demonstrated good inter-rater reliability. We would suggest that the RUSHU model be assessed in further external validation studies. RUSHU has the potential to reduce morbidity of delayed treatment of non-union.

Toward the validation of VR-HMDs for medical education: a systematic literature review.

The latest technological advancements in the domain of virtual reality (VR) have created new opportunities to use VR as a training platform for medical students and practitioners more broadly. Despite the growing interest in the use of VR as a training tool, a commonly identified gap in VR-training for medical education is the confidence in the long-term validity of the applications. A systematic literature review was undertaken to explore the extent of VR (in particular head-mounted displays) applications for medical training with an additional focus on validation measures. The papers included in this review discussed empirical case studies of specific applications; however, these were mostly concerned with human-computer interaction and were polarized between demonstrating that a conceptual technology solution was feasible for simulation or looked at specific areas of VR usability with little discussion on validation measures for long-term training effectiveness and outcomes. The review uncovered a wide range of ad hoc applications and studies in terms of technology vendors, environments, tasks, envisaged users and effectiveness of learning outcomes. This presents decision-making challenges for those seeking to adopt, implement and embed such systems in teaching practice. The authors of this paper then take a wider socio-technical systems perspective to understand how the holistic training system can be engineered and validated effectively as fit for purpose, through distillation of a generic set of requirements from the literature review to aid design specification and implementation, and to drive more informed and traceable validation of these types of systems. In this review, we have identified 92 requirement statements in 11 key areas against which a VR-HMD training system could be validated; these were grouped into design considerations, learning mechanisms and implementation considerations.

Synthesis and analysis of novel catecholic ligands as inhibitors of catechol-O-methyltransferase.

l-DOPA, a dopamine precursor, is commonly used as a treatment for patients with conditions such as Parkinson's disease. This therapeutic l-DOPA, as well as the dopamine derived from l-DOPA, can be deactivated via metabolism by catechol-O-methyltransferase (COMT). Targeted inhibition of COMT prolongs the effectiveness of l-DOPA and dopamine, resulting in a net increase in pharmacological efficiency of the treatment strategy. Following the completion of a previous ab initio computational analysis of 6-substituted dopamine derivatives, several novel catecholic ligands with a previously unexplored neutral tail functionality were synthesized in good yields and their structures were confirmed. The ability of the catecholic nitriles and 6-substituted dopamine analogues to inhibit COMT was tested. The nitrile derivatives inhibited COMT most effectively, in agreement with our previous computational work. pKa values were used to further examine the factors involved with the inhibition and molecular docking studies were performed to support the ab initio and experimental work. The nitrile derivatives with a nitro substituent show the most promise as inhibitors, confirming that both the neutral tail and the electron withdrawing group are essential on this class of inhibitors.

An Unusual Finding: Papillary Tumor of the Pineal Region.

A papillary tumor of the pineal region (PTPR) is a rare tumor of neuroepithelial origin formed from specialized ependymocytes of the subcommissural organ located in the lining of the posterior commissure, not the pineal gland itself. Patients with this type of tumor generally present with nonspecific symptoms secondary to obstructive hydrocephalus such as headache and vision changes. The mean age of patient presentation is 31, with a slight predominance in females. This type of tumor has a high rate of recurrence (56%) following surgical resection. This case study describes the presentation of this uncommon tumor in a 61-year-old woman, including presentation, imaging, surgery, and pathology findings.

The role of CaMKK2 in Golgi-associated vesicle trafficking.

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a serine/threonine-protein kinase, that is involved in maintaining various physiological and cellular processes within the cell that regulate energy homeostasis and cell growth. CaMKK2 regulates glucose metabolism by the activation of downstream kinases, AMP-activated protein kinase (AMPK) and other calcium/calmodulin-dependent protein kinases. Consequently, its deregulation has a role in multiple human metabolic diseases including obesity and cancer. Despite the importance of CaMKK2, its signalling pathways and pathological mechanisms are not completely understood. Recent work has been aimed at broadening our understanding of the biological functions of CaMKK2. These studies have uncovered new interaction partners that have led to the description of new functions that include lipogenesis and Golgi vesicle trafficking. Here, we review recent insights into the role of CaMKK2 in membrane trafficking mechanisms and discuss the functional implications in a cellular context and for disease.

A retrospective single-institution review of the impact of COVID-19 on severity of biliary disease.

BACKGROUND: The COVID-19 pandemic possessed far-reaching health implications beyond the public health impact that have yet to be fully elucidated. We hypothesized that the COVID-19 pandemic led to an increase in biliary disease complexity and incidence of emergency cholecystectomy. METHODS: We reviewed our institutional experience with cholecystectomy from February 2019-February 2021, n = 912. Pre COVID-19 pandemic patients were compared to patients after the onset of the pandemic. Baseline characteristics were compared between groups. A Cochran-Armitage test for trend assessed the temporal impact of COVID-19 on emergency presentation and gallbladder disease complexity. RESULTS: We identified 442 patients pre-pandemic and 470 patients during the pandemic. No significant differences were noted in demographics. COVID-19 significantly impacted emergency presentation (43.2% vs. 56.8%, p= <0.01), cholecystitis (53.2% vs 61.8%; p=<0.01), and gangrenous cholecystitis (2.8% vs 6.1%; p=<0.01). Both groups had similar clinical outcomes. CONCLUSIONS: The COVID-19 pandemic affected an increased incidence of emergency presentation and complexity of gallbladder disease but did not significantly impact clinical outcomes. These findings may have broader implications for other diseases possibly affected by COVID-19.

Comparing pinning in situ and capital realignment procedures for severe, stable slipped capital femoral epiphysis: a systematic review.

In severe, stable slipped capital femoral epiphysis, it is unclear whether pinning in situ (PIS) or capital realignment procedures (CRPs) are superior. Our primary aim was to compare patient-reported outcome measures (PROMs) following each strategy. Secondary aims were to compare rates of femoral head avascular necrosis (AVN) and complications. MEDLINE, Embase and Cochrane databases were searched according to an agreed strategy. Narrative review articles, case reports, letters to the editor and articles not written in English were excluded. The risk of bias was assessed using the Newcastle-Ottawa Scale. Of the 132 citations identified, 127 were excluded following de-duplication and application of the exclusion criteria. Three observational studies comparing PIS with CRP and two case series considering CRP alone were identified. One article was considered fair quality, and four articles were considered poor. In total, 198 hips from five studies were included (66 PIS, 132 CRP). PIS was associated with moderate-good functional outcomes, and CRP with good-high outcomes. Two comparative studies reported significantly better PROMs following CRP. AVN was reported in 1.5% following PIS and 10.6% following CRP. Regarding other complications, chondrolysis occurred in 3.0% following PIS and 2.4% following CRP. Femoroacetabular impingement rates were markedly higher following PIS (60.6% versus 2.3%). Reoperation rates were also greater following PIS (34.5% versus 13.3%). PIS tends to be associated with favourable AVN rates, but CRP with favourable PROMs and complication rates. However, comparisons were drawn from heterogeneous studies lacking long-term follow-up. Further high-quality research is required.

Central anticholinergic syndrome from hyoscine hydrobromide in an unresponsive patient.

Terminal agitation is common and causes severe distress for patients and loved ones. Careful assessment is of paramount importance in identifying a cause. PA patient with gastric adenocarcinoma who was admitted with adverse effects post-chemotherapy deteriorated acutely with a presumed intracerebral event. Secretions were an issue and hyoscine hydrobromide was commenced. Within twenty-four hours, the patient became acutely agitated and did not respond to standard treatment.After careful clinical examination out-ruling other causes, toxic psychosis secondary to hyoscine hydrobromide was felt to be most likely. Rotating anti-secretories and commencing a phenobarbitone infusion to treat severe agitation resulted in prolonged comfort before death.Inhibiting cholinergic transmission at central muscarinic receptors can cause psychosis, delirium, etc. Hyoscine hydrobromide crosses the blood brain barrier. This case demonstrates that even in unresponsive patients, it may cause agitation. If standard therapies are failing to control agitation, all possibilities must be considered. Central side effects of hyoscine hydrobromide may be a rare but under-recognised cause of agitation. This case demonstrates how through careful clinical assessment of possible differentials, and prompt and effective management of the most likely causes of distress, lasting comfort can be achieved. Patient with gastric adenocarcinoma who was admitted with adverse effects post-chemotherapy deteriorated acutely with a presumed intracerebral event. Secretions were an issue and hyoscine hydrobromide was commenced. Within twenty-four hours, the patient became acutely agitated and did not respond to standard treatment.

Evaluating the role of negative affect and negative interpretation biases in emotional eating behavior.

OBJECTIVE: The study of emotional eating, or (over)eating in response to emotions, may inform transdiagnostic interventions for eating pathology. Prior work has focused on the role of negative affect in promoting emotional eating. The present study sought to extend this work through examining the role of cognitive biases. METHOD: Women who self-reported (n = 50) and did not self-report (n = 40) emotional eating completed self-report questionnaires of negative affect and negative interpretation biases, an implicit measure of cognitive bias, and a behavioral assay of emotional eating involving an ad lib test meal following a stress induction task. RESULTS: The emotional eating group endorsed elevated trait negative affect, explicit shame biases, and implicit negative biases compared to controls. In addition, state negative affect increased after the stress induction task, and the emotional eating group endorsed greater state negative affect before and after the task and consumed more food following the stress induction. Only explicit cognitive shame biases demonstrated significant indirect effects in the association between group and food consumption. Specifically, elevated explicit shame biases were positively associated with amount of food consumed for the emotional eating group. DISCUSSION: Future research should examine whether interventions that target cognitive biases related to shame reduce emotional eating. PUBLIC SIGNIFICANCE: Individuals with emotional eating consumed more food than controls following a stress induction. Explicit shame cognitive biases were positively associated with amount of food consumed for the emotional eating group. Shame cogntiive biases may be fruitful targets for reducing emotional eating.

Leadership Development Among Junior Surgery Residents: Communication and Perception.

INTRODUCTION: Leadership is necessary for effective health care teams, particularly for surgeons. Trainees similarly must acquire foundational leadership skills to maximize effectiveness. However, surgical leadership is rarely formally assessed, particularly for junior trainees. We aimed to establish themes of communication, perception and engagement styles, as well as strengths and weaknesses among junior surgical residents at a single institution. METHODS: The Data Dome Inc. (datadome.com) DISC personality assessment was administered in 2018-2021 to junior residents at an academic general surgery training program at a single institution. Resident demographics were recorded, and themes from deidentified reports were analyzed by year (PGY-1 and PGY-2) using JMP 16 Pro Text Explorer. RESULTS: PGY-1 communication was most frequently described as "accomplished best by well-defined avenues" with "duties and responsibilities of others who will be involved explained" in "friendly terms." PGY-2 communication involved "deal [ing] with people," "strong feelings about a particular problem," and being "good at giving verbal and nonverbal feedback." In ideal environments, PGY-1s self-perceived as "good listener [s]," "good-natured," and "team player [s]." However, under stress, PGY-1s were perceived by others as "poor listener [s]," "self-promoter [s]," "detached," and "insensitive." In ideal environments, PGY-2s were also "good listener [s]," "good-natured," and "team player [s]." However, under stress, PGY-2 external perception was "overly confident," "poor listener [s]," and "self-promoter [s]." CONCLUSIONS: Clear expectations, friendly work environments, and opportunities to succeed are key to effectively train junior surgical residents. In environments where time is often a limited resource, surgical simulation, stress training, and standardized teaching methods from attending surgeons are needed to develop competent trainees.

Reliability and validity of a transdiagnostic measure of reward valuation effort.

To identify biobehavioral mechanisms underlying excessive reward consumption, reward valuation-effort (RV-E) assessments should (a) parallel measures in basic science to permit translation from preclinical to clinical studies; (b) quantify constructs dimensionally from healthy to disease states; and (c) hold relevance across different diagnostic categories. To address these aims, we developed a progressive ratio (PR) task whereby RV-E is measured as breakpoint when participants worked for access to playing a game. We evaluated test-retest reliability of breakpoint and convergent and discriminant validity of interpretations of this score against an established PR task for food. In Study 1, female undergraduates (N = 71; 33% racial minority; 28% ethnic minority) completed the game and food tasks in fasted and fed states. In Study 2, women (N = 189; 29% racial minority; 27% ethnic minority) with eating disorders (n = 158) were compared to controls (n = 31) on tasks. Game task breakpoint demonstrated excellent test-retest reliability, intraclass correlation coefficient (ICC) = .91, 95% CI [.80, -.96], over 2 weeks and convergent validity with the fasted food task (r = .51, p < .001). Consistent with animal models, breakpoint was lower in fed compared to fasted states across tasks, B (SE) = 321.01 (552.40), p < .001. Finally, the game task demonstrated discriminant validity from measurement of satiation. In Study 2, women with eating disorders demonstrated higher breakpoint on both tasks compared to controls, and game PR task breakpoint decreased from a fasted to fed state. The game PR task offers a novel approach for translating results from animal models of RV-E into testable hypotheses in nonclinical and clinical samples. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Hopelessness, Interpersonal, and Emotion Dysregulation Perspectives on Suicidal Ideation: Tests in a Clinical Sample.

OBJECTIVE: The present study directly compared three perspectives of suicidality: Interpersonal Theory of Suicide (IPTS), Hopelessness Theory, and a perspective emphasizing emotion dysregulation. METHOD: 219 adults seeking outpatient psychological services completed questionnaires during intake between November 2015 and February 2019. Patients were included if they completed surveys related to thwarted belongingness (TB), perceived burdensomeness (PB), hopelessness, depressive symptoms, negative affect, and Borderline Personality Disorder (BPD) symptoms. Analyses tested the ability of TB, PB, depressive symptoms, hopelessness, and emotion dysregulation to relate to total scores on Beck Scale for Suicide Ideation. We employed Pearson's correlations and linear regressions to investigate these relations. RESULTS: Constructs related to emotion dysregulation-negative affect (r = 0.161, p < .05) and Borderline Personality Disorder symptoms (r = 0.284, p < .01)-were significantly correlated with suicidal ideation, as were those relevant to Hopelessness Theory-depressive symptoms (r = 0.46, p < .01) and hopelessness (r = 0.45, p < .01)- and IPTS-TB (r = 0.36, p < .01) and PB (r = 0.43, p < .01). Notably the combinations of constructs as proposed by theories were significantly associated with suicidal ideation, but did not improve upon single constructs. This indicated that theoretically relevant constructs alone were strongly associated with suicidal ideation, but were not bested by interactions. CONCLUSIONS: This project compared constructs relevant to three theories of suicidality among a sample of treatment seeking outpatients. Findings indicated that suicidal ideation assessment was similarly informed by Hopelessness Theory and IPTS, and to a lesser degree emotion dysregulation. The cross sectional nature of the data and the reliance upon self-report measures limit the inferences that can be made.

Suicidal ideation, suicide attempts, and suicide death among Veterans and service members: A comprehensive meta-analysis of risk factors.

Suicide is the tenth leading cause of death in America. Particularly at risk, Veterans are 1.5 times more likely to die by suicide than non-Veterans, and the suicide rate among service members has risen over the last decade. In the present study, we (1) assessed risk factors for suicidal ideation, suicide attempts, and suicide death within and between Veterans and service members, (2) identified the most commonly studied and (3) the strongest risk factors for suicide-related outcomes among Veterans and service members, and (4) compared overall and risk factor-specific meta-analytic prediction of suicide-related outcomes in Veterans and service members, as determined in the present meta-analysis, to that of the general population. Authors harvested longitudinal effects predicting suicidal ideation, suicide attempts, or suicide deaths in Veterans or service members until May 1, 2020. Traumatic Brain Injury, substance/alcohol use disorders, prior Self-Injurious Thoughts and Behavior, PTSD, and depressive symptoms were among the most commonly studied risk factors. Anger/aggression was particularly strong risk factors, providing a source for future study and intervention efforts. When combined, risk factors conferred similar risk for suicide attempts and suicide death among Veterans, service members, and the general population. However, when analyzing p-values, factors conferred significantly more risk of suicidal ideation among Veterans and service members as compared to the general population. That is, p-values for risk factors were lower in an absolute sense but not necessarily to a statistically significant degree.

Generation of an Lpar1-EGFP Fusion Knock-in Transgenic Mouse Line.

Lysophosphatidic acid (LPA) is a lysophospholipid that acts as an extracellular signal through the activation of cognate G protein-coupled receptors (GPCRs). There are six known LPA receptors (LPA1-6). The first such receptor, LPA1, was identified in the embryonic brain and has been studied extensively for gene expression throughout the body, including through studies of receptor-null mice. However, identifying receptor protein expression in situ and in vivo within living cells and tissues has been difficult because of biologically low receptor expression and variable antibody specificity. To visualize native LPA1 receptor expression in situ, we generated a knock-in mouse produced by homologous recombination in murine embryonic stem (ES) cells to replace a wildtype Lpar1 allele with a mutant allele created by in-frame fusion of EGFP to the 4th exon of Lpar1 (Lpar1-EGFP knock-in allele). Homozygous knock-in mice appeared normal and the expected mendelian ratios of knock-in allele transmission were present in females and males. Histological assessments of the fetal and adult central nervous system (CNS) demonstrated expression patterns that were consistent with prior in situ hybridization studies. This new mouse line will be useful for studies of LPA1 in the developing and adult CNS, as well as other tissues, and for receptor assessments in living tissues and disease models.

Does Chair of Surgery Gender Influence Divisional or Residency Program Director Gender Diversity?

BACKGROUND: Workplace diversity is beneficial and results in new ideas and improved performance. Within surgery leadership, the gender gap is improving, but still present. Given the increasing number of women surgery department chairs, we aimed to examine the association of surgery chair gender with division and residency program director gender. We hypothesized that surgery departments with female leadership would have an increase in gender diversity compared to departments led by male chairs. MATERIALS AND METHODS: A list of all surgery departments were compiled from the Society of Surgical Chairs website. Gender of department chair, division director and residency program director were examined and compared. Chair position term length was determined based on online public announcements, publicly available curriculum vitae, and institutional profile biographies. RESULTS: Of 178 department chairs included, 10.7% were female, and 89.3% were male. There was no difference in female residency program director leadership between female versus male led programs (42.1 versus 26.1%, P= 0.147). Of the programs with female department chairs, only 29.4% had any female division directors compared to 54.6% led by male chairs (P= 0.055). When examining departments with ≥5 division directors, there was no difference in the average number of female division directors within departments led by female versus male chairs. There was a significant difference in length of surgery chairship, with female chairs holding the position for fewer years than male chairs (median time 5.3 (IQR = 3.4-5.8) versus 7.0 (IQR=4.3-12.3) years, P= 0.032). CONCLUSIONS: Female department chair leadership was not associated with increased diversity in divisional leadership compared to departments of surgery led by males.