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Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Abstract Objectives Osteoarthritis (OA) is a joint disease with a heritable component. Genetic loci identified via genome-wide association studies (GWAS) account for an estimated 26.3% of the disease trait variance in humans. Currently, there is no method for predicting the onset or progression of OA. We describe the first use of the Collaborative Cross (CC), a powerful genetic resource, to investigate knee OA in mice, with follow-up targeted multi-omics analysis of homologous regions of the human genome. Methods We histologically screened 275 mice for knee OA and conducted quantitative trait locus (QTL) mapping in the complete cohort (> 8 months) and the younger onset sub-cohort (8–12 months). Multi-omic analysis of human genetic datasets was conducted to investigate significant loci. Results We observed a range of OA phenotypes. QTL mapping identified a genome-wide significant locus on mouse chromosome 19 containing Glis3, the human equivalent of which has been identified as associated with OA in recent GWAS. Mapping the younger onset sub-cohort identified a genome-wide significant locus on chromosome 17. Multi-omic analysis of the homologous region of the human genome (6p21.32) indicated the presence of pleiotropic effects on the expression of the HLA − DPB2 gene and knee OA development risk, potentially mediated through the effects on DNA methylation. Conclusions The significant associations at the 6p21.32 locus in human datasets highlight the value of the CC model of spontaneous OA that we have developed and lend support for an immune role in the disease. Our results in mice also add to the accumulating evidence of a role for Glis3 in OA.

Abstract Background There is a paucity of research investigating the harms associated with orthopaedic knee scooter (OKS) use and patient safety perceptions. This prospective study aimed to define the prevalence of OKS-related injuries, describe the patient perceptions of OKS safety, and identify potential risk factors. Methods This study was conducted at a single foot and ankle fellowship-trained surgeon’s community-based clinic from 6/2020 to 4/2021 and enrolled 134 patients. Our primary outcome was an OKS-related event (injury or fall) and informed an a priori power analysis. Point estimate of association magnitude was calculated as an odds ratio (OR) for statistically and clinically significant associations. Results There were 118 (88%) patients eligible for analysis; fourteen enrolled patients did not use OKS, and two withdrew. The prevalence of patient falls was 37% (44/118), and the prevalence of patient injury was 15% (18/118). Four percent of patients would not recommend OKS and 8% would not use an OKS again. Sedentary lifestyle increased risk (OR = 4.67, 1.52–14.35 95 CI) for OKS-related injury. Conclusions Despite a high prevalence of patient falls (37%), there is a low prevalence of injury (15%) and a favorable perception of OKS safety. Sedentary lifestyles may be a risk factor for OKS-related injury and should be considered in the development of a risk model.

Abstract Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.

Background. Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion. This study shows the importance of examining patient’s family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister’s unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.

Gastropulmonary fistula represents a late complication of sleeve gastrectomy and, if untreated, has high morbidity and mortality. We present a case report of a 29-year-old female who developed a gastropulmonary fistula 3 years after a sleeve gastrectomy. Dual energy CT of the chest and upper abdomen demonstrated a cavitary left lower lobe lesion associated with a focal complex pleural effusion; iodinated oral contrast confirmed the presence of a fistulous connection through the left hemidiaphragm. The patient underwent a thoracotomy, left lower lobectomy, resection of the infected segment of the left hemidiaphragm with primary repair, drainage of a subphrenic abscess and a gastric repair; the patient was discharged 2-weeks postprocedure.

Circulating concentrations of thyrotropin (TSH) and thyroxine (T4) are tightly regulated. Each individual has setpoints for TSH and free T4 which are genetically determined, and subject to environmental and epigenetic influence. Pituitary-thyroid axis setpoints are probably established in utero, with maturation of thyroid function continuing until late gestation. From neonatal life (characterized by a surge of TSH and T4 secretion) through childhood and adolescence (when free triiodothyronine levels are higher than in adults), thyroid function tests display complex, dynamic patterns which are sexually dimorphic. In later life, TSH increases with age in healthy older adults without an accompanying fall in free T4, indicating alteration in TSH setpoint. In view of this, and evidence that mild subclinical hypothyroidism in older people has no health impact, a strong case can be made for implementation of age-related TSH reference ranges in adults, as is routine in children.

Category: Trauma; Ankle; Ankle Arthritis; Diabetes Introduction/Purpose: What level I evidence exists to support the use of FNF for surgical management of ankle fractures in high risk patients? The purpose of this study was to compare clinical outcomes following fibular intramedullary nail fixation (FNF) and open reduction and internal fixation (ORIF) of ankle fractures. Methods: A systematic review of the current literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Certainty of evidence reported according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Our primary hypothesis was that patients undergoing FNF procedures to manage an ankle fracture would have significantly higher patient reported outcome scores (PROs) than patients undergoing ORIF. Primary study outcome measures were validated PROs. Secondary outcome measures included complication rate, secondary surgery rate, and bony union. Results: The primary outcome analysis revealed no evidence of a significant effect difference on Olerud and Molander Ankle Score (OMAS) PRO and no evidence of statistical heterogeneity. Secondary outcome analysis revealed a significant 0.30 (0.12-0.74 95CI) relative risk reduction for complications in FNF (P=0.008). No evidence of an effect difference for bony union. No evidence of reporting bias was appreciated. Sensitivity analyses did not significantly alter effect estimates. Conclusion: The quality of evidence is reasonably strong and likely sufficient to conclude: (1) there is likely no clinically important difference between FNF and ORIF up to 12 months post-operatively, as defined by OMS (moderate certainty); (2) surgeons may reasonably expect reduced complications in 14 out of every 100 patients treated with FNF (moderate certainty); (3) there is likely no difference in bony union (low certainty). Future studies should investigate more patient-centered outcomes and if short-term findings are durable over time if these findings apply to lower risk populations.

Category: Other; Trauma Introduction/Purpose: There is a paucity of research investigating the harms associated with the orthopaedic knee scooter (OKS) and patient safety perceptions. This prospective study aimed to define the prevalence of OKS-related injuries, identify patient risk factors and describe the patient perceptions of OKS safety. Methods: This single-surgeon prospective study recruited a cohort of 134 consecutive patients undergoing surgery at a community-based orthopaedic clinic from 6/2020 to 4/2021. Our primary outcome informed an a priori power analysis. Standardized data collection protocol included three forms that patients completed. The prevalence of OKS-related injury, patient risk factors, and patient perceptions were analyzed. Alpha values of P

Abstract Background and objective Chronic medical conditions accumulate within individuals with age. However, knowledge concerning the trends, patterns and determinants of multimorbidity remains limited. This study assessed the prevalence and patterns of multimorbidity using extensive individual phenotyping in a general population of Australian middle-aged adults. Methods Participants (n = 5029, 55% female), born between 1946 and 1964 and attending the cross-sectional phase of the Busselton Healthy Ageing Study (BHAS) between 2010 and 2015, were studied. Prevalence of 21 chronic conditions was estimated using clinical measurement, validated instrument scores and/or self-reported doctor-diagnosis. Non-random patterns of multimorbidity were explored using observed/expected (O/E) prevalence ratios and latent class analysis (LCA). Variables associated with numbers of conditions and class of multimorbidity were investigated. Results The individual prevalence of 21 chronic conditions ranged from 2 to 54% and multimorbidity was common with 73% of the cohort having 2 or more chronic conditions. (mean ± SD 2.75 ± 1.84, median = 2.00, range 0–13). The prevalence of multimorbidity increased with age, obesity, physical inactivity, tobacco smoking and family history of asthma, diabetes, myocardial infarct or cancer. There were 13 pairs and 27 triplets of conditions identified with a prevalence > 1.5% and O/E > 1.5. Of the triplets, arthritis (> 50%), bowel disease (> 33%) and depression-anxiety (> 33%) were observed most commonly. LCA modelling identified 4 statistically and clinically distinct classes of multimorbidity labelled as: 1) “Healthy” (70%) with average of 1.95 conditions; 2) “Respiratory and Atopy” (11%, 3.65 conditions); 3) “Non-cardiometabolic” (14%, 4.77 conditions), and 4) “Cardiometabolic” (5%, 6.32 conditions). Predictors of multimorbidity class membership differed between classes and differed from predictors of number of co-occurring conditions. Conclusion Multimorbidity is common among middle-aged adults from a general population. Some conditions associated with ageing such as arthritis, bowel disease and depression-anxiety co-occur in clinically distinct patterns and at higher prevalence than expected by chance. These findings may inform further studies into shared biological and environmental causes of co-occurring conditions of ageing. Recognition of distinct patterns of multimorbidity may aid in a holistic approach to care management in individuals presenting with multiple chronic conditions, while also guiding health resource allocation in ageing populations.

Abstract Background Osteoporosis is a complex disease with a strong genetic contribution. A recently published genome-wide association study (GWAS) for estimated bone mineral density (eBMD) identified 1103 independent genome-wide significant association signals. Most of these variants are non-coding, suggesting that regulatory effects may drive many of the associations. To identify genes with a role in osteoporosis, we integrate the eBMD GWAS association results with those from our previous osteoclast expression quantitative trait locus (eQTL) dataset. Results We identify sixty-nine significant cis-eQTL effects for eBMD GWAS variants after correction for multiple testing. We detect co-localisation of eBMD GWAS and osteoclast eQTL association signals for 21 of the 69 loci, implicating a number of genes including CCR5, ZBTB38, CPE, GNA12, RIPK3, IQGAP1 and FLCN. Summary-data-based Mendelian Randomisation analysis of the eBMD GWAS and osteoclast eQTL datasets identifies significant associations for 53 genes, with TULP4 presenting as a strong candidate for pleiotropic effects on eBMD and gene expression in osteoclasts. By performing analysis using the GARFIELD software, we demonstrate significant enrichment of osteoporosis risk variants among high-confidence osteoclast eQTL across multiple GWAS P value thresholds. Mice lacking one of the genes of interest, the apoptosis/necroptosis gene RIPK3, show disturbed bone micro-architecture and increased osteoclast number, highlighting a new biological pathway relevant to osteoporosis. Conclusion We utilise a unique osteoclast eQTL dataset to identify a number of potential effector genes for osteoporosis risk variants, which will help focus functional studies in this area.

BackgroundIn non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).MethodsFor the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.ResultsTen of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.ConclusionANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.

The LIM-domain containing protein Ajuba and the scaffold protein SQSTM1/p62 regulate signalling of NF-κB, a transcription factor involved in osteoclast differentiation and survival. The ubiquitin-associated domain of SQSTM1/p62 is frequently mutated in patients with Paget’s disease of bone. Here, we report that Ajuba activates NF-κB activity in HEK293 cells, and that co-expression with SQSTM1/p62 inhibits this activation in an UBA domain-dependent manner. SQSTM1/p62 regulates proteins by targeting them to the ubiquitin-proteasome system or the autophagy-lysosome pathway. We show that Ajuba is degraded by autophagy, however co-expression with SQSTM1/p62 (wild type or UBA-deficient) protects Ajuba levels both in cells undergoing autophagy and those exposed to proteasomal stress. Additionally, in unstressed cells co-expression of SQSTM1/p62 reduces the amount of Ajuba present in the nucleus. SQSTM1/p62 with an intact ubiquitin-associated domain forms holding complexes with Ajuba that are not destined for degradation yet inhibit signalling. Thus, in situations with altered levels and localization of SQSTM1/p62 expression, such as osteoclasts in Paget’s disease of bone and various cancers, SQSTM1/p62 may compartmentalize Ajuba and thereby impact its cellular functions and disease pathogenesis. In Paget’s, ubiquitin-associated domain mutations may lead to increased or prolonged Ajuba-induced NF-κB signalling leading to increased osteoclastogenesis. In cancer, Ajuba expression promotes cell survival. The increased levels of SQSTM1/p62 observed in cancer may enhance Ajuba-mediated cancer cell survival.

Clinical and epidemiological studies have identified male sex as an important risk factor for COVID-19 clinical outcomes and mortality. This raises the question as to how this risk factor can be addressed in the prognosis, clinical management, and the treatment of patients with Coronavirus disease 2019 (COVID-19). Currently, there are no guidelines or protocols to help alter the course of sex-specific COVID-19 prognosis, especially in severe disease presentations. This is partly due to the lack of research studies characterizing the differences in male vs. female host response to the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and a lack of a well-rounded understanding of the molecular mechanisms involved. Here, we discuss three distinct but interconnected molecular-level differences in males and females that likely play an essential role in the COVID-19 prognosis. We review interactions of SARS-CoV-2 with host cell angiotensin-converting enzyme 2 (ACE2) in the viral entry between males vs. females and discuss the differential regulation of the renin-angiotensin system (RAS) between the two sexes. Next, we present immune response disparities and how immune function and endocrine regulation may render males increasingly vulnerable to severe COVID-19. We describe the interconnected roles of these three regulatory systems in males and females in response to SARS-CoV-2 infection. Finally, we highlight the clinical implications of these mechanisms to patients with COVID-19 and propose putative targeted therapies that can help reduce COVID-19 severity in those critically ill.

Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD.

Transtendinous abductor tendon repair is a technique the authors described previously to diagnose and treat undersurface tears of the abductor tendons. In this surgical technique article, the authors describe a technique for knotless repair of undersurface tears of the abductor tendons that does not require a transtendinous split or suture passage through the abductor tendon. Because there is no suture passage through the abductor tendon or knot tying, the potential advantages include expeditious technique, compression of tendon against bony footprint, anatomic repair, and avoidance of knots facing the undersurface of the iliotibial band, which may lead to bursal irritation.

Pathology of the iliopsoas may cause painful internal snapping of the hip or labral damage from soft impingement. Favorable outcomes have been reported after arthroscopic release or fractional lengthening of the iliopsoas. In patients with risk factors for instability, restoration of other soft-tissue constraints such as the labrum and capsule should be performed if iliopsoas fractional lengthening is undertaken. The purpose of this article is to detail the step-by-step surgical technique of arthroscopic iliopsoas fractional lengthening, in addition to the indications, pearls, and pitfalls of the technique.

This article presents the authors' technique for evaluation of possible abductor tears with magnetic resonance imaging (MRI). By using T2 fat-saturated coronal and axial slices of the hip and T1 coronal images of the pelvis, the authors show how to visualize all tears of the abductor tendons and signs of chronic abductor deficiency. After diagnosis has been made, signs that may help the surgeon determine if open or arthroscopic surgery would be best used are reviewed. Finally, the author reviews indications for a gluteus medius repair with concomitant gluteus maximus reconstruction.

Excessive femoral anteversion may lead to increasing stress placed on the anterior acetabulum and soft tissues, which can predispose to intra-articular hip pathology. By addressing the excessive femoral anteversion in combination with intra-articular hip pathology, the results will be durable over time. This technique details how to perform a femoral derotation osteotomy for excessive femoral anteversion after addressing intra-articular pathology with hip arthroscopy in one surgical intervention. This allows the surgeon to address both the underlying pathoanatomy and the resultant intra-articular sequelae.

This article describes the arthroscopic approach and management of a “reverse contre-coup” injury to the hip labrum. The injury occurs in the setting of posterolateral acetabular rim over-coverage impinging on the distal femoral neck in extension causing the femoral head to lever out anteriorly against the labrum. Ligamentous laxity and associated loss of anterior capsular restraint allow increased femoral head translation, adding further insult to the anterior labrum. The arthroscopic approach entails not only a labral repair with correction of the osseous conflict but also restoration of soft-tissue stability to minimize anterior femoral translation.

Arthroscopic labral reconstruction is an alternative procedure for an irreparable hip labrum in the nonarthritic hip population. Although labral reconstruction is a relatively new procedure, data in the literature show favorable outcomes. Patients have shown beneficial outcomes from labral reconstructive surgery as well as when compared with labral repair and debridement patients. However, one of the challenges in performing labral reconstruction has been correctly measuring the graft to perfectly fit the area of labral deficiency. We propose a labral reconstruction technique that will eliminate inaccuracies in graft measurement while incorporating beneficial characteristics of the knotless suture. The advantages of this technique will increase procedural accuracy and brevity.

Exercise has been shown to be beneficial for Parkinson's disease (PD). A major interest in our lab has been to investigate how exercise modulates basal ganglia function and modifies disease progression. Dopamine (DA) depletion leads to loss of dendritic spines within the caudate nucleus and putamen (striatum) in PD and its animal models and contributes to motor impairments. Striatal medium spiny neurons (MSNs) can be delineated into two populations, the dopamine D1 receptor (DA-D1R)-containing MSNs of the direct pathway and dopamine D2 receptor (DA-D2R)-containing MSNs of the indirect pathway. There is evidence to suggest that the DA-D2R-indirect pathway MSNs may be preferentially affected after DA-depletion with a predominate loss of dendritic spine density when compared to MSNs of the DA-D1R-direct pathway in rodents; however, others have reported that both pathways may be affected in primates. The purpose of this study was to investigate the effects of intensive exercise on dendritic spine density and arborization in MSNs of these two pathways in the MPTP mouse model of PD. We found that MPTP led to a decrease in dendritic spine density in both DA-D1R- and DA-D2R-containing MSNs and 30 days of intensive treadmill exercise led to increased dendritic spine density and arborization in MSNs of both pathways. In addition, exercise increased the expression of synaptic proteins PSD-95 and synaptophysin. Taken together these findings support the potential effect of exercise in modifying synaptic connectivity within the DA-depleted striatum and in modifying disease progression in individuals with PD.

Atraumatic instability of the hip has become an increasingly studied occurrence in recent years. There are several established surgical techniques that help restore stability of the native hip joint. In some cases, these procedures are not an option. As the phenomenon has become recognized more frequently, a greater number of revision surgeries are warranted in patients with ligamentous laxity. A durable solution for irreparable microinstability needs to be formulated to address this vulnerable patient demographic. We describe the surgical technique for capsular reconstruction with acellular dermal extracellular matrix.

To perform a proper labral repair, most surgeons use anchors to secure the labrum to the acetabular bone. We aim to describe a technique for labral repair with a knotless tensionable suture anchor. This technique uses a looped suture configuration, allowing selective tensioning of the repair to maintain the anatomic suction seal of the hip. The use of this technique is easily reproducible and reduces the surgical time compared with previous techniques.

We report the first case of an anaphylactic reaction to Reandron 1000 (depot testosterone undecanoate with a castor oil and benzyl benzoate vehicle). While considered to have a favourable safety profile, serious complications such as oil embolism and anaphylaxis can occur. In our patient, skin testing identified benzyl benzoate to be the trigger, with no reaction to castor oil or testosterone undecanoate components. As benzyl benzoate exists in multiple pharmaceuticals, foods, and cosmetics, individual components of pharmaceuticals should be tested when investigating drug allergies. Doctors should be alert to the potential for serious reactions to any of the components of Reandron 1000.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain.

The declining birth rate throughout Asia has serious consequences that require sound strategies in the business of education. This study explores ways in which Taiwanese and Chinese institutions may expand their offer abroad. The analysis of a sample of experiences in Myanmar, Vietnam and Cambodia suggests that successful market entry results from educational regulatory constraints of the host countries, as well as socio-cultural preferences influencing student choices. Taiwanese and Chinese private universities must plan carefully for a successful expansion of their graduate programs towards Southeast Asian populations.

The design, implementation and evaluation of a year 1 pharmacy-integrated learning component, using the World Health Organisation’s (WHO) analgesic ladder as a scaffold for case-based learning, is described. A novel aspect of the integrated component is the mapping of the cases to the national Core Competency Framework (CCF) for Pharmacists in Ireland and to the school’s own cross-cutting curricular integration themes. The integrated cases were student led and delivered through peer-to-peer teaching for 68 first-year pharmacy students. The integrated cases mapped strongly to three of the CCF’s domains, namely, personal skills, organisation and management skills and supply of medicines. With regard to the school’s curricular integrative themes, the cases mapped strongly to the curricular integration themes of professionalism and communications; medicines sourcing, production and use; and safe and rational use of medicines. Highlights from an anonymous online student survey were the recognition by students of the importance of core science knowledge for practice, the enabling of integrated learning and the suitability of the integrated component for entry-level. While a majority of students were found to favour individual work over group work, future iterations will need to consider a greater degree of group work with a view to reducing the volume of content and time required to complete the cases.

This paper describes the design and implementation of elements of an integrated competency-focused pharmacy programme in the School of Pharmacy and Pharmaceutical Sciences (SoPPS), Trinity College Dublin (TCD), Ireland. Following a national review of pharmacy education and training in Ireland in 2010, and subsequent publication of legislation in 2014, the School has implemented a five-year integrated programme of pharmacy education and training, leading to the award of a Master’s degree in Pharmacy (M. Pharm.). Curricular integration has been achieved by underpinning the new programme with a national competency framework for pharmacists and through the utilisation of curricular integration themes. Programme integration also encompasses embedded experiential learning placements in Years 2, 4 and 5 of the five-year programme. The new five-year integrated pharmacy programme, which commenced in 2015, replaced the 4 + 1 model of education and training where a four-year Bachelor’s degree was followed by a one-year internship, which was a distinct and separate element of the students’ training.

Sea ice has emerged as the canary in the coal mine of climate change. Its summer extent in the Arctic has decreased by about 50% over the past decade, and the Arctic Ocean has undergone a regime shift from a cover of thick multiyear ice to a largely seasonal and much thinner ice cover. The recent loss is unprecedented in the periods of satellite and historical records of sea ice, and it also appears to be unique in paleo reconstructions spanning more than a thousand years. A "perfect storm" of warmer atmospheric and oceanic forcing, together with a boost from natural variability of wind forcing in some years, drove the change. However, the reduction of ice coverage is not apparent in some sub-Arctic regions during the winter, nor has it occurred in the Antarctic region.Signals of a response to the loss of sea ice are emerging in the ocean and the atmosphere. Ocean heat storage during the ice-free season not only contributes to a later freeze-up than in the past, but it also reduces the thickness to which first-year ice can grow. The vulnerability of this thinner ice to rapid spring melt is a manifestation of the ice-albedo-temperature feedback that has long been postulated as a contributor to polar amplification of climate change. More notably for middle latitudes, the loss of sea ice appears to be triggering a reduction of the large-scale westerlies that characterize atmospheric circulation in middle and subpolar latitudes. This response is consistent with increased persistence of departures from normal temperature, precipitation, and extreme weather during autumn and winter in heavily populated areas of the Northern Hemisphere.