New therapies on the horizon: Targeted protein degradation in neuroscience.

This minireview explores the burgeoning field of targeted protein degradation (TPD) and its promising applications in neuroscience and clinical development. TPD offers innovative strategies for modulating protein levels, presenting a paradigm shift in small-molecule drug discovery and therapeutic interventions. Importantly, small-molecule protein degraders specifically target and remove pathogenic proteins from central nervous system cells without the drug delivery challenges of genomic and antibody-based modalities. Here, we review recent advancements in TPD technologies, highlight proteolysis targeting chimera (PROTAC) protein degrader molecules with proximity-induced degradation event-driven and iterative pharmacology, provide applications in neuroscience research, and discuss the high potential for translation of TPD into clinical settings.

Psychological Factors Protecting Against Suicidality in Older Adults: A Systematic Review.

OBJECTIVE: Suicide rates in older adults are often the highest of any age group, particularly among high income countries. However, there is a limited understanding of the factors that could protect against suicidality in older age. This systematic review aimed to identify and evaluate the psychological factors that protect against suicidality in older age. METHOD: An a priori protocol was established and registered on PROSPERO (CRD42022343694). EMBASE, MEDLINE, PsycINFO, Web of Science and Scopus were searched. Papers were quality assessed using the Quality Assessment with Diverse Studies (QuADSs) tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Seventeen papers were included and narratively synthesised. RESULTS: The initial searches identified 10,673 records, resulting in the screening of 5441 records after the removal of duplicates. The protective factors identified were (1) meaning/purpose in life, (2) reasons for living, (3) coping styles, (4) psychological wellbeing, (5) life satisfaction, (6) personality factors, (7) cognitive functioning, and (8) sense of belonging. The factors with the most empirical support were meaning in life, followed by psychological wellbeing and coping responses, such as primary control strategies, and personality traits, such as positive affect and agency. There was also evidence to suggest that the influence of some protective factors, for example meaning in life, may depend upon stage in older life and gender. CONCLUSION: This review identified several psychological factors that have been found to protect against suicidal ideation in older adults, representing potential treatment targets for reducing suicide in older adults. Recommendations for future research includes greater use of longitudinal and case-control designs, measuring outcomes across the continuum of suicidality and using samples that allow comparison between younger and older adults and within the spectrum of old age.

Reverse takotsubo induced cardiogenic shock in the peripartum period: A case report and literature review.

Reverse takotsubo cardiomyopathy is a rare variant of a rare disease characterized by basal ballooning and dysfunction of the left ventricle. While it can render patients profoundly unwell and reliant on intensivist care, it is a transient phenomenon, with the worst symptoms subsiding after 2-3 days. At term, a young woman spontaneously entered labor prior to a planned repeat cesarean section. After experiencing physical and psychological distress during labor and a vacuum extraction, she developed cardiogenic shock from reverse takotsubo cardiomyopathy, quickly diagnosed with transthoracic echocardiogram. She required 2 days of intensive care support and made an excellent recovery. This very rare condition should be considered in systemically unwell women in the peripartum as it can be quickly diagnosed, providing patients with the best appropriate care.

Feasibility and acceptability of general practitioners using sit-stand desks: a feasibility trial.

OBJECTIVES: The primary aim of this study was to investigate the feasibility and acceptability of general practitioners (GPs) using sit-stand desks to facilitate standing during consultations. A further aim was to examine the views of patients about GPs standing for their consultations. DESIGN: A pre-post single-group experimental trial design. SETTING: General practices in England, UK. PARTICIPANTS: 42 GPs (working a minimum of five clinical sessions per week) and 301 patients (aged ≥18 years). INTERVENTIONS: The intervention consisted of each GP having a sit-stand desk (Opløft Sit-Stand Platform) installed in their consultation room for 4 working weeks. Sit-stand desks allow users to switch, in a few seconds, between a sitting and standing position and vice versa, by adjusting the height of the desk. MAIN OUTCOME MEASURES: To test feasibility and acceptability, GPs reported their views about using sit-stand desks at work at baseline and follow-up. Sitting time and physical activity were also measured via accelerometer at baseline and follow-up. Patients who attended a consultation where their GP was standing were asked to complete an exit questionnaire about the perceived impact on the consultation. RESULTS: Most GPs reported using their sit-stand desk daily (n=28, 75.7%). 16 GPs (44.4%) used their sit-stand desk during face-to-face consultations every day. Most GPs and patients did not view that GPs standing during face-to-face consultations impacted the doctor-patient relationship (GPs; 73.5%, patients; 83.7%). GPs' sitting time during work was 121 min per day lower (95% CI: -165 to -77.58) at follow-up compared with baseline. CONCLUSIONS: Use of sit-stand desks is acceptable within general practice and may reduce sitting time in GPs. This may benefit GPs and help reduce sitting time in patients. TRIAL REGISTRATION NUMBER: ISRCTN76982860.

Nutrient Intake, Performance, and Body Composition of Preseason Wrestlers.

College athletes, especially in weight class sports, often experience energy deficits. Athletes competing in weight class sports such as wrestling are at greatest risk for deficiencies and little is known about the relationships between body composition, nutrient intake, and performance in these athletes. The purposes of this study were to (1) quantify macronutrient and micronutrient intake of pre-season male collegiate wrestlers and compare to estimated needs, and (2) examine relationships among nutritional intakes, body composition, and performance measurements of strength and anaerobic capacity. Male Division I wrestlers (n = 11, age: 21.3 ± 1.7 years, wrestling experience: 14.9 ± 2.5 years) were recruited during pre-season. Nutrient intake was collected from a 3-day food diary. A 7-site skinfold assessment determined fat-free mass (FFM) to estimate total daily energy expenditure (eTEE). Isokinetic and isometric strength were evaluated by a Biodex dynamometer. Anaerobic capacity was tested on a stationary cycle ergometer. Eight of eleven wrestlers were energy deficient based on estimated needs. Mean intake of four micronutrients fell below the Recommended Dietary Allowances (RDA). Significant correlations were found between dietary intake, strength and anaerobic performance variables (r = 0.603 - 0.902, p = 0.0001 - 0.05). However, after accounting for FFM, these relationships were no longer significant. Nutrient intake in tandem with body composition affects performance for weight class athletes. Achieving high FFM during the preseason may be advantageous for wrestling performance. Nutrient intake and body composition should be monitored so coaches and health professionals can create individualized recommendations to help athletes optimize performance.

Parental Expressed Emotion and Behavioural Outcomes in Autistic Children and Adolescents: A Systematic Review.

Growing interest in the links between parent-child relationships and child behavioural presentations in families of autistic children has led to an increased use of the Five Minute Speech Sample (FMSS) measure of parental expressed emotion (EE) in autism research. This review focuses on studies exploring the relationships between parental EE and behavioural outcomes in autistic children. Electronic searches of six databases and grey literature wielded eight studies that met eligibility criteria. Study designs were a mixture of cross-sectional and longitudinal and quality of studies was variable. Parental criticism was largely positively related to, and showed some predictive value for, child behaviour problems. Warmth was mostly negatively related to, and showed some predictive value for, child behaviour problems. Preliminary evidence from one study showed paternal warmth to be significantly related to child behaviours, whilst child behaviours were also significantly related to paternal warmth, suggesting a bidirectional relationship. Analysis of additional EE components produced variable results, however parental stress and depressive symptoms were consistently related to child behaviour, and preliminary evidence suggests a possible role of maternal education level and family cohesion. Outcomes were variable across FMSS coding systems and greater consistency in their application is needed in future research. The current findings suggest that parental EE has an important relationship with child behaviour and future intervention efforts may benefit from aiming to reduced EE in order to improve child outcomes.

Tunnel-free acromioclavicular joint reconstruction is associated with improved initial reduction and higher patient satisfaction.

Background: Many surgical techniques have been described for acromioclavicular (AC) joint reconstruction. Creation of bone tunnels through the clavicle or coracoid has been shown to be a risk factor for fracture. Use of an AC reconstruction technique that does not create bone tunnels may obviate this risk. This study aims to evaluate clinical outcomes of AC joint reconstruction using a tunnel-free technique compared to reconstruction using a cortical button and clavicular drill holes. Methods: Consecutive patients who underwent AC joint reconstruction by a single surgeon in a subspecialty referral practice were included. One group of patients received cortical button fixation (button group), in which sutures were passed around the coracoid, brought up through a drill hole in the clavicle, and tied over a cortical button. The other group of patients received tunnel-free fixation, in which a self-locking tape suture was passed in a cerclage fashion around the base of the coracoid and the clavicle and tensioned with a tensioning device (cerclage group). Both groups underwent reconstruction of the coracoclavicular (CC) ligament and AC joint capsule using tibialis anterior allograft. Patient-reported outcome scores and satisfaction were collected and compared between groups. Radiographs were reviewed to evaluate CC ligament distance and loss of reduction. Results: Twenty-two patients were included in the study (button n = 10, cerclage n = 12). Preoperative demographics and injury characteristics were not different between groups. Average radiographic follow-up was not different between groups (button: 231 days, cerclage: 105 days). Postoperative American Shoulder and Elbow Surgeons, visual analog scale, and Single Assessment Numeric Evaluation scores were similar between groups. Two postoperative clavicle fractures were sustained in the button group. These occurred through clavicular drill holes and were preceded by tunnel widening. No fractures occurred in the cerclage group. CC distance at initial follow-up was significantly less in the cerclage group (button: 11.2 ± 4.5 mm, cerclage: 7.0 ± 2.9 mm, P =.023). Loss of reduction was similar throughout the postoperative period (button: 4.3 ± 2.6 mm, cerclage: 4.8 ± 4.1 mm, P >.05. Forty percent of patients were unsatisfied with their clavicle after button fixation (n = 4/10), compared with zero after cerclage fixation (n = 0/12, P =.03). Reasons for dissatisfaction were fracture (n = 2) and persistent cosmetic deformity (n = 2). Conclusion: Tunnel-free AC joint reconstruction is associated with improved initial radiographic appearance and patient satisfaction compared to single cortical button fixation. Postoperative clavicle fracture and persistent cosmetic deformity drive patient dissatisfaction, which may be minimized by avoiding clavicular drill holes and using a tensioned self-locking cerclage suture to improve initial reduction.

Clinical outcomes of rotator cuff repair with subacromial bursa reimplantation: a retrospective cohort study.

Background: The subacromial bursa has been found to be a rich, local, source of mesenchymal stem cells but is removed for visualization during rotator cuff repair. Reimplantation of this tissue may improve rotator cuff healing. The purpose of this study is to evaluate clinical outcomes of rotator cuff repair with and without subacromial bursa reimplantation. Methods: Patients aged 37-77 with a full-thickness or near full-thickness supraspinatus tears underwent arthroscopic transosseous-equivalent double row rotator cuff repair. In patients prior to July 2019, the subacromial bursa was resected for visualization, and discarded. In patients after July 2019, the subacromial bursa was collected using a filtration device connected to an arthroscopic shaver and reapplied to the bursal surface of the tendon at the completion of the rotator cuff repair. Rotator cuff integrity was evaluated via magnetic resonance imaging on bursa patients at 6 months postoperatively. Minimum 18-month clinical outcomes (Single Assessment Numeric Evaluation, American Shoulder and Elbow Surgeons, patient satisfaction) were compared between bursa and nonbursa cohorts. Results: A total of 136 patients were included in the study (control n = 110, bursa n = 26). Preoperative demographics and tear characteristics were not different between groups. Average follow-up was significantly longer in the control group (control: 3.2 ± 0.7 years; bursa: 1.8 ± 0.3 years; P < .001). The control group showed a significantly higher Single Assessment Numeric Evaluation score (control: 87.9 ± 15.8, bursa: 83.6 ± 15.1, P = .037) that did not meet minimum clinically important difference. The American Shoulder and Elbow Surgeons and patient satisfaction scores were similar between the groups. Symptomatic retears were not significantly different between groups (control: 9.1%, bursa 7.7%, P = .86). Seven patients in the control group underwent reoperation (6.4%), compared to 0 patients in the bursa group (0%, P = .2). Six-month postoperative magnetic resonance images obtained on bursa patients demonstrated 85% rotator cuff continuity (n = 17/20) as defined via Sugaya classification. Conclusion: Augmentation of rotator cuff repair with bursal tissue does not appear to have negative effects, and given the accessibility and ease of harvest of this tissue, further research should be performed to evaluate its potential for improved tendon healing or clinical outcomes.

Preoperative metaphyseal cancellous bone density is associated with intraoperative conversion to stemmed total shoulder arthroplasty.

Background: Methods to determine whether a stemless humeral component is appropriate for anatomic total shoulder arthroplasty are varied and often subjective. Objective preoperative data regarding metaphyseal bone quality may help guide surgical decision-making. This study sought to evaluate preoperative proximal humeral bone quality and determine whether it is predictive of intraoperative conversion to a stemmed humeral component. Methods: Consecutive patients who underwent primary anatomic total shoulder arthroplasty from a single-surgeon practice were enrolled. All patients received a preoperative computed tomography (CT) scan for surgical templating purposes. The exclusion criteria were lack of a preoperative CT scan, preoperative plan for a stemmed component, and intraoperative conversion to a stem for a reason other than bone quality (ie, fracture). Preoperative CT scans were analyzed with an automated templating software. Cortical index and thickness were calculated, and bone density of the proximal diaphysis, cancellous metaphysis, and cortical metaphysis was obtained by averaging Hounsfield units (HU) across anatomically defined regions using a previously validated technique. The decision to convert to a stemmed humeral component was made intraoperatively based on a lack of stability of the trial stemless component. Bone quality measurements were compared between stemless and stemmed groups. An exact logistic regression was used incorporating gender and age. Results: A total of 79 patients who underwent primary anatomic total shoulder arthroplasty were included in this study. Of these patients, 6 underwent intraoperative conversion to a stemmed humeral component (7.6%). There was no significant difference between cohorts in terms of cortical index and bone density within the proximal diaphysis and cortical metaphysis. On univariate analysis, cortical thickness, metaphyseal cancellous bone density, and gender were significantly different between groups. Patients receiving a stem had significantly lower metaphyseal cancellous bone density than those receiving stemless components (5.5 ± 11.2 HU vs. 47.6 ± 29.4 HU, P<.001). All patients converted to stems were female individuals (P = .01) and had metaphyseal cancellous bone density less than 20 HU (P<.001). Conclusions: Metaphyseal cancellous bone density can be calculated on preoperative CT scans and is associated with intraoperative conversion to a stemmed humeral component in anatomic shoulder arthroplasty. A threshold of 20 HU can be used to predict which patients are more likely to require stemmed components.

Predictors of the rate of cognitive decline in older adults using machine learning.

BACKGROUND: The longitudinal rates of cognitive decline among aging populations are heterogeneous. Few studies have investigated the possibility of implementing prognostic models to predict cognitive changes with the combination of categorical and continuous data from multiple domains. OBJECTIVE: Implement a multivariate robust model to predict longitudinal cognitive changes over 12 years among older adults and to identify the most significant predictors of cognitive changes using machine learning techniques. METHOD: In total, data of 2733 participants aged 50-85 years from the English Longitudinal Study of Ageing are included. Two categories of cognitive changes were determined including minor cognitive decliners (2361 participants, 86.4%) and major cognitive decliners (372 participants, 13.6%) over 12 years from wave 2 (2004-2005) to wave 8 (2016-2017). Machine learning methods were used to implement the predictive models and to identify the predictors of cognitive decline using 43 baseline features from seven domains including sociodemographic, social engagement, health, physical functioning, psychological, health-related behaviors, and baseline cognitive tests. RESULTS: The model predicted future major cognitive decliners from those with the minor cognitive decline with a relatively high performance. The overall AUC, sensitivity, and specificity of prediction were 72.84%, 78.23%, and 67.41%, respectively. Furthermore, the top 7 ranked features with an important role in predicting major vs minor cognitive decliners included age, employment status, socioeconomic status, self-rated memory changes, immediate word recall, the feeling of loneliness, and vigorous physical activity. In contrast, the five least important baseline features consisted of smoking, instrumental activities of daily living, eye disease, life satisfaction, and cardiovascular disease. CONCLUSION: The present study indicated the possibility of identifying individuals at high risk of future major cognitive decline as well as potential risk/protective factors of cognitive decline among older adults. The findings could assist in improving the effective interventions to delay cognitive decline among aging populations.

From a genome-wide screen of RNAi molecules against SARS-CoV-2 to a validated broad-spectrum and potent prophylaxis.

Expanding the arsenal of prophylactic approaches against SARS-CoV-2 is of utmost importance, specifically those strategies that are resistant to antigenic drift in Spike. Here, we conducted a screen of over 16,000 RNAi triggers against the SARS-CoV-2 genome, using a massively parallel assay to identify hyper-potent siRNAs. We selected Ten candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity (IC50 < 20 pM) and strong blockade of infectivity in live-virus experiments. We further enhanced this activity by combinatorial pairing of the siRNA candidates and identified cocktails that were active against multiple types of variants of concern (VOC). We then examined over 2,000 possible mutations in the siRNA target sites by using saturation mutagenesis and confirmed broad protection of the leading cocktail against future variants. Finally, we demonstrated that intranasal administration of this siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the gold-standard Syrian hamster model. Our results pave the way for the development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies.

Increasing rates of ulnar collateral ligament repair outpace reconstruction in isolated injuries: review of a Texas surgical database.

Background: The gold standard of treatment for ulnar collateral ligament (UCL) injuries has been reconstruction. Despite early repair studies yielding less than satisfactory results, there has been recent renewed interest in UCL repair due to improved outcomes and new technologies. Data regarding clinical use of these procedures are lacking. The purpose of this study was to define the epidemiological trends of UCL repair and reconstruction surgery from 2010 to 2019, compare demographic characteristics of patients undergoing either procedure, and determine incidence of concomitant procedures in each surgical group as well as comparing respective patient-level charges. Methods: A retrospective database analysis of UCL surgeries was performed through the Texas Healthcare Information Collection database, a comprehensive and publicly available statewide billing dataset. Inclusion criteria were defined using Current Procedural Terminology billing codes for elbow UCL repair and reconstruction between 2010 through 2019, excluding patients who had concomitant elbow fractures or lateral collateral ligament tears indicative of high-energy trauma. Procedural volume changes, patient demographics, and commonly performed concomitant procedures including elbow arthroscopy, ulnar nerve surgery, and platelet-rich plasma injection were compared. Total patient-level charges were compared across groups. Results: A total of 1664 patients were included, consisting of 484 UCL repairs and 1180 reconstructions. Total UCL surgeries increased eleven-fold when corrected for population growth from 2010 (N = 25) to 2019 (N = 315). In 2010, repair constituted 23% of all UCL tear surgeries and increased to 40% by the end of 2019. The annual frequency of UCL repair increased at a 5.4% faster rate than UCL reconstruction from 2010 to 2019 (P < .001). There were no significant differences between any demographic data between UCL repair and reconstruction except for rural surgical settings which demonstrated 1.8 times greater odds of undergoing reconstruction (P = .05). There were no differences among commonly associated procedures including ulnar nerve surgery (P = .217), elbow arthroscopy (P = .092), and platelet-rich plasma injection (P = .837) with no differences in patient-level charges at any time point (P = .47). Conclusion: While reconstruction remains more common, the annual frequency of UCL repair is increasing at a faster rate. Since were no demographic differences aside from surgical setting, it can be inferred that patients who were previously receiving reconstruction are instead undergoing repair. This highlights the need for future studies to further identify surgical indications for the two interventions.

Use of intraoperative platelet-rich plasma during rotator cuff repair is correlated with increased patient-level charges across multiple categories.

BACKGROUND: As the efficacy of platelet-rich plasma (PRP) as an adjunct in rotator cuff repair (RCR) is debated, the decision to use PRP may be more heavily affected by its cost. We sought to quantify whether augmenting arthroscopic RCR with PRP injections at the time of surgery is correlated with increased patient-level charges. METHODS: All outpatient records reported in Texas from 2010 to 2018 were obtained from the publicly available Texas Healthcare Information Collection database through the Texas Department of State Health Services. All records including a Current Procedural Terminology code for arthroscopic RCR were included. Of the 139,587 records identified within this group, 1662 also contained a Current Procedural Terminology code for intraoperative PRP injection. Patient-level charge data were compared between those who received and those who did not receive concomitant PRP injection during the same outpatient surgical encounter. Subgroup analyses were performed across surgical facilities and insurance types. Mann-Whitney U tests were used to compare charges between PRP and non-PRP cases. Linear regression was used to predict the change in billed charges according to standard charge categories. P values less than .05 were considered statistically significant. RESULTS: The total charges for arthroscopic RCR over the 8-year period were $4.66 billion, coming to $33,371 ± $22,118 per case. Cases that included PRP injection were found to have significantly greater overall charges than cases that did not ($54,452 ± $33,637 vs. $33,117 ± $21,818; P < .001). Linear regression indicated that concomitant PRP injections predicted an increase in combined total charges by $22,027 (95% confidence interval, $20,425-$23,628; P < .001). CONCLUSIONS: PRP utilization at the time of rotator cuff surgery is correlated with increased patient-level charges overall, which occur across all charge subcategories and persist across surgical facility, surgeon volume, and insurance type. Detailed cost analysis is recommended to explore this charge correlation, and future cost-benefit analyses of PRP use in RCR should explore costs beyond that solely associated with PRP preparation, as these may have previously been overlooked.

Optimization of Low-Biomass Sample Collection and Quantitative PCR-Based Titration Impact 16S rRNA Microbiome Resolution.

The major aquatic interface between host and environment in teleost finfish species is the gill. The diversity of this infraclass, high complexity of the organ, and its direct exposure to the surrounding environment make it an ideal candidate for furthering our understanding of the intertwined relationships between host and microbiome. Capturing the structure and diversity of bacterial communities from this low-biomass, inhibitor-rich tissue can, however, prove challenging. Lessons learned in doing so are directly applicable to similar sample types in other areas of microbiology. Through the development of a quantitative PCR assay for both host material and 16S rRNA genes, we tested and developed a robust method for low-biomass sample collection which minimized host DNA contamination. Quantification of 16S rRNA facilitated not only the screening of samples prior to costly library construction and sequencing but also the production of equicopy libraries based on 16S rRNA gene copies. A significant increase in diversity of bacteria captured was achieved, providing greater information on the true structure of the microbial community. Such findings offer important information for determining functional processes. Results were confirmed across fresh, brackish, and marine environs with four different fish species, with results showing broad homology between samples, demonstrating the robustness of the approach. Evidence presented is widely applicable to samples similar in composition, such as sputum or mucus, or those that are challenging due to the inherent inclusion of inhibitors. IMPORTANCE The interaction between the fish gill and surrounding bacteria-rich water provides an intriguing model for examining the interaction between the fish, free-floating bacteria, and the bacterial microbiome on the gill surface. Samples that are inherently low in bacteria, or that have components that inhibit the ability to produce libraries that identify the components of microbial communities, present significant challenges. Gill samples present both of these types of challenges. We developed methods for quantifying both the bacterial and host DNA material and established a sampling method which both reduced inhibitor content and maximized bacterial diversity. By quantifying and normalizing bacteria prior to library construction, we showed significant improvements with regards to the fidelity of the final data. Our results support wide-ranging applications for analyzing samples of similar composition, such as mucus and sputum, in other microbiological spheres.

Transcriptional and Translational Dynamics of Zika and Dengue Virus Infection.

Zika virus (ZIKV) and dengue virus (DENV) are members of the Flaviviridae family of RNA viruses and cause severe disease in humans. ZIKV and DENV share over 90% of their genome sequences, however, the clinical features of Zika and dengue infections are very different reflecting tropism and cellular effects. Here, we used simultaneous RNA sequencing and ribosome footprinting to define the transcriptional and translational dynamics of ZIKV and DENV infection in human neuronal progenitor cells (hNPCs). The gene expression data showed induction of aminoacyl tRNA synthetases (ARS) and the translation activating PIM1 kinase, indicating an increase in RNA translation capacity. The data also reveal activation of different cell stress responses, with ZIKV triggering a BACH1/2 redox program, and DENV activating the ATF/CHOP endoplasmic reticulum (ER) stress program. The RNA translation data highlight activation of polyamine metabolism through changes in key enzymes and their regulators. This pathway is needed for eIF5A hypusination and has been implicated in viral translation and replication. Concerning the viral RNA genomes, ribosome occupancy readily identified highly translated open reading frames and a novel upstream ORF (uORF) in the DENV genome. Together, our data highlight both the cellular stress response and the activation of RNA translation and polyamine metabolism during DENV and ZIKV infection.

What is underneath all that stuff? A Q-methodological exploration of profiles of beliefs and vulnerabilities in hoarding disorder.

BACKGROUND: Hoarding disorder (HD) can be understood through the cognitive behavioural model in the context of vulnerability factors (for example, personality traits, co-morbidities, traumatic life events) and beliefs about possessions (for example, identity, emotional attachment, memory, utility). Less is known about the strength of these hypothesised beliefs, or how they interact within the hoarding population, with researchers suggesting that specifying beliefs would improve treatment outcomes. AIM: The current study explored beliefs in HD, utilising Q-methodology to explore both categories of beliefs and the interactions between these. Moreover, Q-methodology allowed for comparison of the individuals endorsing specific categories of beliefs. METHOD: A comprehensive list of beliefs about possessions was developed. Thirty-two adults with clinically significant levels of HD completed a Q-sort task, alongside measures of proposed vulnerabilities, including co-morbidity, trauma and attachment style. RESULTS: Q-factor analysis produced four profiles consisting of groups of participants who endorsed the same beliefs and had shared characteristics: (1) 'Expression of identity', (2) 'Responsibility and morality', (3) 'Stability and predictability', and (4) 'Objects as emotional and meaningful beings'. DISCUSSION: The profiles were distinguished by different categories of beliefs and co-morbid symptoms, suggesting that more targeted assessment tools and interventions would be beneficial to account for this heterogeneity within the clinical population. In particular, beliefs about identity and self-concept formed the largest profile, and beliefs about stability and predictability introduce a novel category of beliefs.

The socioeconomic gradient in mortality from ovarian, cervical, and endometrial cancer in Australian women, 2001-2018: A population-based study.

BACKGROUND: Socio-economic (SE) status is closely linked to health status and the mechanisms of this association are complex. One important adverse effect of SE disadvantage is vulnerability to cancer and cancer is a major cause of morbidity and mortality in Australia. AIMS: We aimed to estimate the effect of SE status on mortality rates from ovarian, cervical, and endometrial cancer. MATERIALS AND METHODS: National mortality data were obtained from the Australian Bureau of Statistics (ABS) for the calendar years from 2001 to 2018, inclusive. Individual deaths were grouped by the ABS Index of Relative Socio-economic Advantage and Disadvantage. Population data were obtained to provided denominators allowing calculation of mortality rates (deaths per 100 000 women aged 30-79 years). Statistical analyses performed included tabulating point-estimates of mortality rates and their changes over time and modelling the trends of rates using maximum likelihood method. RESULTS: Age-standardised mortality rates for ovarian and cervical cancer fell over the study period but increased for endometrial cancer. There was clear evidence of a SE gradient in the mortality rate for all three cancers. This SE gradient increased over the study period for ovarian and cervical cancer but remained unchanged for endometrial cancer. CONCLUSIONS: Women at greater SE disadvantage have higher rates of death from the commonest gynaecological cancers and this gradient has not reduced over the last two decades. After the COVID-19 pandemic efforts must be redoubled to ensure that Australians already at risk of ill health do not face even greater risks because of their circumstances.

Treatment of Acromioclavicular Joint Instability With a Tunnel-Free Reconstruction Technique.

Acromioclavicular joint injuries are a common shoulder injury encountered by orthopaedic surgeons. Many different surgical techniques have been described for the operative treatment of these injuries with no single, clear gold standard technique on which surgeons agree. Among the most common complications after surgical management of acromioclavicular injuries are loss of reduction, infection, fracture of clavicle or coracoid, and need for reoperation. We propose an arthroscopic-assisted, tunnel-free surgical technique using a tibialis anterior allograft combined with a FiberTape Cerclage (Arthrex, Naples, FL) to manage both acute and chronic acromioclavicular joint injuries. No bony tunnels are drilled and no hardware is implanted, which should obviate the risk for subsequent bony failure through a fracture, nor require subsequent hardware removal. In addition, the combination of suspensory and allograft fixation should impart sufficient stability to maintain an adequate reduction even in the face of failure of one of the fixation methods.

A Comprehensive Review of PCSK9 Inhibitors.

Cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. A major risk factor for this condition is increased serum low-density lipoprotein cholesterol (LDL-C) levels for which statins have been successful in reducing serum LDL-C to healthy concentrations. However, patients who are statin intolerant or those who do not achieve their treatment goals while on high-intensity statin therapy, such as those with familial hypercholesterolemia, remain at risk. With the discovery of PCSK9 inhibitors, the ability to provide more aggressive treatment for patients with homozygous and heterozygous familial hypercholesterolemia has increased. Ezetimibe reduces LDL-C by 15%-20% when combined with statin.2,3 Protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been found to achieve profound reductions in LDL-C (54%-74%) when added to statins. They have shown dramatic effects at lowering major adverse cardiovascular events (MACE) in high-risk patients4 with LDL-C levels ≥70 mg/dL and can be used in populations that are statin intolerant or not at goal levels with maximally tolerated statin therapy. PCSK9 inhibitors also produce minimal side effects. Myopathy, a common side effect for patients on statins, has been rare in patients on PCSK9 inhibitors. Randomized trials have shown that reduction in LDL-C has translated to clinical benefits even in patients who have not achieved their LDL-C target.