Discovery Elbow System arthroplasty polyethylene bearing exchange: outcomes and experience.

BACKGROUND: The Discovery Elbow System (DES) utilizes a polyethylene bearing within the ulnar component. An exchange bearing requires preoperative freezing and implantation within 2 minutes of freezer removal to allow insertion. We report our outcomes and experience using this technique. METHODS: This was an analysis of a two-surgeon consecutive series of DES bearing exchange. Inclusion criteria included patients in which exchange was attempted with a minimum 1-year follow-up. Clinical and radiographic review was performed 1, 2, 3, 5, 8 and 10 years postoperative. Outcome measures included range of movement, Oxford Elbow Score (OES), Mayo Elbow Performance Score (MEPS), complications and requirement for revision surgery. RESULTS: Eleven DESs in 10 patients were included. Indications were bearing wear encountered during humeral component revision (n=5); bearing failure (n=4); and infection treated with debridement, antibiotics and implant retention (DAIR; n=2). Bearing exchange was conducted on the first attempt in 10 cases. One case required a second attempt. One patient developed infection postoperatively managed with two-stage revision. Mean follow-up of the bearing exchange DES was 3 years. No further surgery was required, with no infection recurrence in DAIR cases. Mean elbow flexion-extension and pronosupination arcs were 107° (±22°) and 140° (±26°). Mean OES was 36/48 (±12) and MEPS was 83/100 (±19). CONCLUSIONS: Our results support the use of DES bearing exchange in cases of bearing wear with well-fixed stems or acute infection. This series provides surgeons managing DES arthroplasty with management principles, successful and reproducible surgical techniques and expected clinical outcomes in performing DES polyethylene bearing exchange. Level of evidence: IV.

Antibodies targeting the fusion peptide on the HIV envelope provide protection to rhesus macaques against mucosal SHIV challenge.

The fusion peptide (FP) on the HIV-1 envelope (Env) trimer can be targeted by broadly neutralizing antibodies (bNAbs). Here, we evaluated the ability of a human FP-directed bNAb, VRC34.01, along with two vaccine-elicited anti-FP rhesus macaque mAbs, DFPH-a.15 and DF1W-a.01, to protect against simian-HIV (SHIV)BG505 challenge. VRC34.01 neutralized SHIVBG505 with a 50% inhibitory concentration (IC50) of 0.58 µg/ml, whereas DF1W-a.01 and DFPH-a.15 were 4- or 30-fold less potent, respectively. VRC34.01 was infused into four rhesus macaques at a dose of 10 mg/kg and four rhesus macaques at a dose of 2.5 mg/kg. The animals were intrarectally challenged 5 days later with SHIVBG505. In comparison with all 12 control animals that became infected, all four animals infused with VRC34.01 (10 mg/kg) and three out of four animals infused with VRC34.01 (2.5 mg/kg) remained uninfected. Because of the lower potency of DF1W-a.01 and DFPH-a.15 against SHIVBG505, we infused both Abs at a higher dose of 100 mg/kg into four rhesus macaques each, followed by SHIVBG505 challenge 5 days later. Three of four animals that received DF1W-a.01 were protected against infection, whereas all animals that received DFPH-a.15 were protected. Overall, the protective serum neutralization titers observed in these animals were similar to what has been observed for other bNAbs in similar SHIV infection models and in human clinical trials. In conclusion, FP-directed mAbs can thus provide dose-dependent in vivo protection against mucosal SHIV challenges, supporting the development of prophylactic vaccines targeting the HIV-1 Env FP.

Does long-term follow-up and monitoring of primary shoulder arthroplasty identify failing implants requiring revision?

BACKGROUND: Published scoping review has identified evidence paucity related to long-term follow-up of shoulder arthroplasty. We aim to report effectiveness of elective primary shoulder arthroplasty surveillance in identifying failing implants requiring revision. METHODS: A prospective database recording shoulder arthroplasty and subsequent follow-up surveillance in a shoulder unit was analyzed. Shoulder arthroplasty was performed by 4 fellowship-trained shoulder surgeons for accepted elective indications including the use of anatomic arthroplasty in arthritic shoulders with intact rotator cuff and a reverse prosthesis being used in rotator cuff-deficient shoulders and rotator cuff-competent arthritic shoulders when deemed preferable by the treating surgeon. All shoulder arthroplasty implants used had achieved a minimum 7A Orthopaedic Data Evaluation Panel (ODEP) rating. The included shoulder arthroplasties were performed between May 1, 2004, and December 31, 2021, with minimum 1-year follow-up. Surveillance program involves specialist physiotherapist review at 1, 2, 3, 5, 8, 10, and 15 years postoperatively, including clinical examination, outcome scoring, and radiographs. Patient-initiated review occurred between time points if a patient requested assessment because of symptoms. Outcome measures include ratio of failing implants identified by surveillance and patient-initiated review, with number of surveillance reviews offered and proportion that identified a failing implant requiring revision calculated. RESULTS: A total of 1002 elective primary shoulder arthroplasty with minimum 1-year follow-up were performed (547 reverse total shoulder arthroplasty [rTSA], 234 anatomic total shoulder arthroplasty [aTSA], and 221 hemiarthroplasty [HA]). A total of 238 patients died prior to December 31, 2022, resulting in 4019 surveillance appointments offered. Thirty-eight prostheses required revision ≥1 year postoperatively (6 rTSA, 9 aTSA, and 23 HA), with surveillance identifying requirement in 53% (33% rTSA, 56% aTSA, and 57% HA) and patient-initiated review in 47%. Mean years from implantation to revision was 5.2 (2.7 rTSA, 3.6 aTSA, and 6.6 HA). Revision indications included rotator cuff failure (56% aTSR and 43% HA) and glenoid erosion (57% HA). CONCLUSION: This is the first series reporting effectiveness of shoulder arthroplasty surveillance in identifying implants requiring revision. Surveillance identified more than half of implants requiring revision, although only 0.5% of appointments identified revision requirement. Surveillance enrolment may influence patient-initiated review utilization; therefore, similar studies using only patient-initiated follow-up would help inform recommendations.

Observation of pH-Dependent Residual Structure in the Pmel17 Repeat Domain and the Implication for Its Amyloid Formation.

The varying conformational states of amyloid-forming protein monomers can determine their fibrillation outcome. In this study, we utilize solution NMR and the paramagnetic relaxation enhancement (PRE) effect to observe monomer properties of the repeat domain (RPT) from a human functional amyloid, premelanosomal protein, Pmel17. After excision from the full-length protein, RPT can self-assemble into amyloid fibrils, functioning as a scaffold for melanin deposition. Here, we report possible conformational states of the short RPT (sRPT) isoform, which has been demonstrated to be a fibrillation nucleator. NMR experiments were performed to determine conformational differences in sRPT by comparing aggregation-prone vs nonaggregating solution conditions. We observed significant chemical shift perturbations localized to residues near the C-terminus, demonstrating that the local chemical environment of the amyloid core region is highly sensitive to changes in pH. Next, we introduced cysteine point mutations for the covalent attachment of PRE ligands to sRPT to facilitate the observation of intramolecular interactions. We also utilized solvent PRE molecules with opposing charges to measure changes in the electrostatic potential of sRPT in different pH environments. These observed PRE effects offer insight into initial molecular events that might promote intermolecular interactions, which can trigger fibrillation. Taken together, our results show that sRPT monomers adopt a conformation inconsistent with a fully random coil at neutral pH and undergo conformational changes at lower pH values. These observations highlight regulatory mechanisms via organelle-associated pH conditions that can affect the fibrillation activity of proteins like RPT.

Evidence of natural selection in the mitochondrial-derived peptides humanin and SHLP6.

Mitochondrial-derived peptides are encoded by mitochondrial DNA but have biological activity outside mitochondria. Eight of these are encoded by sequences within the mitochondrial 12S and 16S ribosomal genes: humanin, MOTS-c, and the six SHLP peptides, SHLP1-SHLP6. These peptides have various effects in cell culture and animal models, affecting neuroprotection, insulin sensitivity, and apoptosis, and some are secreted, potentially having extracellular signaling roles. However, except for humanin, their importance in normal cell function is unknown. To gauge their importance, their coding sequences in vertebrates have been analyzed for synonymous codon bias. Because they lie in RNA genes, such bias should only occur if their amino acids have been conserved to maintain biological function. Humanin and SHLP6 show strong synonymous codon bias and sequence conservation. In contrast, SHLP1, SHLP2, SHLP3, and SHLP5 show no significant bias and are poorly conserved. MOTS-c and SHLP4 also lack significant bias, but contain highly conserved N-terminal regions, and their biological importance cannot be ruled out. An additional potential mitochondrial-derived peptide sequence was discovered preceding SHLP2, named SHLP2b, which also contains a highly conserved N-terminal region with synonymous codon bias.

A review of cutaneous hypersensitivity reactions in dogs: A diagnostician's guide to allergy.

Allergic dermatoses are common in people and domestic animals. Resultant lesions are routinely biopsied and submitted for histological examination to confirm a diagnosis or rule out diseases with overlapping or atypical clinical features. Diagnostic pathologists and clinicians are often faced with the difficult task of determining whether an allergic reaction pattern is present on both the microscopic and macroscopic levels and correlating histopathologic findings with clinical and historical data to achieve a precise clinical diagnosis. The bulk of the current veterinary literature on allergic dermatoses focuses on atopic dermatitis in dogs, distantly followed by cats, horses, and other animals. The objectives of this review are to demonstrate the key histopathologic and clinical diagnostic features of the various allergy-mediated reaction patterns, and to provide diagnosticians with a practical guide for clinicopathological correlations. Current concepts in the pathophysiology of immediate hypersensitivity reactions, with a focus on atopic dermatitis, are discussed. Points of potential histopathologic overlap between the "classic" allergic reaction pattern and less common inflammatory, predominately eosinophilic, conditions that may mimic this pattern will be discussed with the goal of highlighting the critical need for collaboration between pathologists and clinicians in furthering patient care.

Combined ARFI and Shear Wave Imaging of Prostate Cancer: Optimizing Beam Sequences and Parameter Reconstruction Approaches.

This study demonstrates the implementation of a shear wave reconstruction algorithm that enables concurrent acoustic radiation force impulse (ARFI) imaging and shear wave elasticity imaging (SWEI) of prostate cancer and zonal anatomy. The combined ARFI/SWEI sequence uses closely spaced push beams across the lateral field of view and simultaneously tracks both on-axis (within the region of excitation) and off-axis (laterally offset from the excitation) after each push beam. Using a large number of push beams across the lateral field of view enables the collection of higher signal-to-noise ratio (SNR) shear wave data to reconstruct the SWEI volume than is typically acquired. The shear wave arrival times were determined with cross-correlation of shear wave velocity signals in two dimensions after 3-D directional filtering to remove reflection artifacts. To combine data from serially interrogated lateral push locations, arrival times from different pushes were aligned by estimating the shear wave propagation time between push locations. Shear wave data acquired in an elasticity lesion phantom and reconstructed using this algorithm demonstrate benefits to contrast-to-noise ratio (CNR) with increased push beam density and 3-D directional filtering. Increasing the push beam spacing from 0.3 to 11.6 mm (typical for commercial SWEI systems) resulted in a 53% decrease in CNR. In human in vivo data, this imaging approach enabled high CNR (1.61-1.86) imaging of histologically-confirmed prostate cancer. The in vivo images had improved spatial resolution and CNR and fewer reflection artifacts as a result of the high push beam density, the high shear wave SNR, the use of multidimensional directional filtering, and the combination of shear wave data from different push beams.

Greener Operations: a James Lind Alliance Priority Setting Partnership to define research priorities in environmentally sustainable perioperative practice through a structured consensus approach.

OBJECTIVES: To agree on the 'top 10' research priorities for environmentally sustainable perioperative practice. DESIGN: Surveys and literature review; final consensus workshop using a nominal group technique. SETTING: UK-based setting. PARTICIPANTS: Healthcare professionals, patients, carers and the public. OUTCOME MEASURES: Initial survey-suggested research questions; interim survey-shortlist of 'indicative' questions (the 20 most frequently nominated by patients, carers and the public, and healthcare professionals); final workshop-ranked research priorities. RESULTS: Initial survey-1926 suggestions by 296 respondents, refined into 60 indicative questions. Interim survey-325 respondents. Final workshop-21 participants agreed the 'top 10': (1) How can more sustainable reusable equipment safely be used during and around the time of an operation? (2) How can healthcare organisations more sustainably procure (obtain) medicines, equipment and items used during and around the time of an operation? (3) How can healthcare professionals who deliver care during and around the time of an operation be encouraged to adopt sustainable actions in practice? (4) Can more efficient use of operating theatres and associated practices reduce the environmental impact of operations? (5) How can the amount of waste generated during and around the time of an operation be minimised? (6) How do we measure and compare the short-term and long-term environmental impacts of surgical and non-surgical treatments for the same condition? (7) What is the environmental impact of different anaesthetic techniques (eg, different types of general, regional and local anaesthesia) used for the same operation? (8) How should the environmental impact of an operation be weighed against its clinical outcomes and financial costs? (9) How can environmental sustainability be incorporated into the organisational management of operating theatres? (10) What are the most sustainable forms of effective infection prevention and control used around the time of an operation (eg, personal protective equipment, drapes, clean air ventilation)? CONCLUSIONS: A broad range of 'end-users' have identified research priorities for sustainable perioperative care.

Temporal artery biopsy: time for a rethink on training?

BACKGROUND: Temporal artery biopsy (TAB) is often performed by ophthalmology trainees without direct supervision. The traditional model of 'see one, do one, teach one' still prevails in most units. Whilst it is generally a safe procedure, damage to the temporal branch of the facial nerve has been reported when harvesting the frontal branch of the superficial temporal artery. METHODS: A survey of trainees from Wessex, Wales, London and Severn deaneries was performed to look at current training techniques, anatomical knowledge and practice. RESULTS: 38 trainees responded to the survey, with complete responses from 28 participants. Formal teaching of the anatomical considerations in TAB was not reported by any trainee, with informal teaching being standard practice. Whilst 61% of respondents reported having learnt about the anatomical 'danger zone' for facial nerve damage, 97% of trainees chose an incision that fell within this zone when given a choice between potential incision sites. CONCLUSION: TAB remains a largely trainee-taught, trainee-performed procedure. Most trainees are not aware of how to avoid the risk of damage to the temporal branch of the facial nerve. We suggest harvesting the parietal branch of the temporal artery via an incision outside the anatomical 'danger zone'. In our experience, this is an easily taught technique that minimises the potential risk of damage to the frontal branch of the facial nerve.

Innovations towards achieving environmentally sustainable operating theatres: A systematic review.

INTRODUCTION: The NHS accounts for 5.4% of the UK's total carbon footprint, with the perioperative environment being the most resource hungry aspect of the hospital. The aim of this systematic review was to assimilate the published studies concerning the sustainability of the perioperative environment, focussing on the impact of implemented interventions. METHODS: A systematic review was performed using Pubmed, OVID, Embase, Cochrane database of systematic reviews and Medline. Original manuscripts describing interventions aimed at improving operating theatre environmental sustainability were included. RESULTS: 675 abstracts were screened with 34 manuscripts included. Studies were divided into broad themes; recycling and waste management, waste reduction, reuse, reprocessing or life cycle analysis, energy and resource reduction and anaesthetic gases. This review summarises the interventions identified and their resulting effects on theatre sustainability. DISCUSSION: This systematic review has identified simple, yet highly effective interventions across a variety of themes that can lead to improved environmental sustainability of surgical operating theatres. Combining these interventions will likely result in a synergistic improvement to the environmental impact of surgery.

Efficient Synthesis for Altering Side Chain Length on Cannabinoid Molecules and Their Effects in Chemotherapy and Chemotherapeutic Induced Neuropathic Pain.

(1) Background: Recently, a number of side chain length variants for tetrahydrocannabinol and cannabidiol have been identified in cannabis; however, the precursor to these molecules would be based upon cannabigerol (CBG). Because CBG, and its side chain variants, are rapidly converted to other cannabinoids in the plant, there are typically only small amounts in plant extracts, thus prohibiting investigations related to CBG and CBG variant therapeutic effects. (2) Methods: To overcome this, we developed an efficient synthesis of corresponding resorcinol fragments using the Wittig reaction which, under acid catalyzed coupling with geraniol, produced the desired side chain variants of CBG. These compounds were then tested in an animal model of chemotherapeutic-induced neuropathic pain and to reduce colorectal cancer cell viability. (3) Results: We found that all side-chain variants were similarly capable of reducing neuropathic pain in mice at a dose of 10 mg/kg. However, the molecules with shorter side chains (i.e., CBGV and CBGB) were better at reducing colorectal cancer cell viability. (4) Conclusions: The novel synthesis method developed here will be of utility for studying other side chain derivatives of minor cannabinoids such as cannabichromene, cannabinol, and cannabielsoin.

Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy-induced peripheral neuropathy.

BACKGROUND: Cannabigerol (CBG) is a non-psychoactive phytocannabinoid produced by the plant Cannabis sativa with affinity to various receptors involved in nociception. As a result, CBG is marketed as an over-the-counter treatment for many forms of pain. However, there is very little research-based evidence for the efficacy of CBG as an anti-nociceptive agent. METHODS: To begin to fill this knowledge gap, we assessed the anti-nociceptive effects of CBG in C57BL/6 mice using three different models of pain; cisplatin-induced peripheral neuropathy, the formalin test, and the tail-flick assay. RESULTS: Using the von Frey test, we found that CBG-attenuated mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy in both male and female mice. Additionally, we observed that this CBG-induced reduction in mechanical hypersensitivity was attenuated by the α2 -adrenergic receptor antagonist atipamezole (3 mg/kg, i.p.) and the CB1 R antagonist, AM4113 (3 mg/kg, i.p.), and blocked by the CB2 R antagonist/inverse agonist, SR144528 (10 mg/kg, i.p.). We found that the TRPV1 antagonist, SB705498 (20 mg/kg, i.p.) was unable to prevent CBG actions. Furthermore, we show that CBG:CBD oil (10 mg/kg, i.p.) was more effective than pure CBG (10 mg/kg) at reducing mechanical hypersensitivity in neuropathic mice. Lastly, we show that pure CBG and CBG:CBD oil were ineffective at reducing nociception in other models of pain, including the formalin and tail flick assays. CONCLUSIONS: Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain. SIGNIFICANCE: There are few effective treatments for neuropathic pain and neuropathic pain is projected to increase with the aging population. We demonstrate that CBG (cannabigerol) and CBG:CBD oil attenuate neuropathy-induced mechanical hypersensitivity mice. Second, we identify receptor targets that mediate CBG-induced reduction in mechanical hypersensitivity in neuropathic mice. Third, we demonstrate that an acute injection of CBG is anti-nociceptive specifically for neuropathic pain rather than other forms of pain, including persistent pain and thermal pain.

Peak O2 -pulse predicts exercise training-induced changes in peak V̇O2 in heart failure with preserved ejection fraction.

AIMS: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O2 ) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter-individual responses vary significantly. Because it is unlikely that ET-induced improvements in peak V̇O2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O2 -pulse (V̇O2  × HR-1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O2 , is inversely associated with the change in peak V̇O2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF. METHODS AND RESULTS: This was a secondary analysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇O2 (%) was analysed as a function of baseline peak V̇O2 and its determinants (absolute peak V̇O2 , peak O2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O2 through changes in peak O2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O2 -pulse explained approximately 72% of the difference in changes in peak V̇O2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O2 -pulse on change in peak V̇O2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O2 -pulse was associated with a decreased mean change in peak V̇O2 of -1.45% (95% CI, -2.30 to -0.60, P = 0.001) compared with a mean change of -0.08% (95% CI, -1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O2 (P > 0.05). Change in V̇O2 at VT1 was not associated with any of the investigated factors (P > 0.05). CONCLUSIONS: In patients with HFpEF, the easily measurable peak O2 -pulse seems to be a good indicator of the potential for improving peak V̇O2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O2 -pulse, patients with high O2 -pulse may need to use additional therapies to significantly increase peak V̇O2 .

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention.

INTRODUCTION: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. RESULTS: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3-12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. CONCLUSION: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.

Left atrial strain predicts exercise capacity in heart failure independently of left ventricular ejection fraction.

AIMS: We hypothesized that left atrial (LA) remodelling and function are associated with poor exercise capacity as prognostic marker in chronic heart failure (CHF) across a broad range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: One hundred seventy-one patients with CHF were analysed [age 65 ± 11 years, 136 males (80%); 86 heart failure with reduced ejection fraction (HFrEF), 27 heart failure with mid-range ejection fraction (HFmrEF), 58 heart failure with preserved ejection fraction (HFpEF)]. All patients underwent echocardiography and maximal cardiopulmonary exercise testing and were classified according to a prognostic cut-off of peak VO2 (pVO2 ; 14 mL/kg/min). Seventy-seven (45%) patients reached pVO2  < 14 and 94 (55%) pVO2  ≥ 14 mL/kg/min. Between the two groups, there was a considerable difference in both left atrial volume (LAVi, 53 ± 24 vs. 44 ± 18 mL/m2 , P = 0.005) and function (LA reservoir strain 12 ± 5 vs. 20 ± 10%, P < 0.0001). Receiver-operating characteristic curves identified LA reservoir strain (area under the curve: 0.73 [0.65-0.80], P < 0.0001) as strong predictor for impaired pVO2 among all echocardiographic variables; LA reservoir strain < 23% had 37% specificity but a very high sensitivity (96%) in identifying a severely reduced pVO2 . In logistic regression analysis, LA reservoir strain < 23% was associated with a highly increased risk of pVO2  < 14 mL/kg/min (odds ratio 16.0 [4.7-54.6]; P < 0.0001). The multivariate analysis showed that a reduced LA reservoir strain was associated with pVO2  < 14 mL/kg/min after adjustment for age, body mass index (BMI), and clinical variables, that is, New York Heart Association class, atrial fibrillation, haemoglobin, and creatinine (b 0.22 [95% confidence interval, CI, 0.12-0.31]; P < 0.0001), and after adjustment for echocardiographic variables, that is, LVEF or left ventricular global longitudinal strain (LVGLS) and tricuspid annular plane systolic excursion (TAPSE) (b 0.16 [95% CI 0.08-0.24]; P < 0.0001). Patients with HFrEF, HFmrEF, and HFpEF were separately analysed. Among LA reservoir strain, LAVi, LVEF, LVGLS, and TAPSE, LA reservoir strain was the only one significantly associated with pVO2 in all subgroups (after adjustment for sex and BMI, P = 0.003, 0.04, and 0.01, respectively). CONCLUSIONS: In patients with CHF, an impaired LA reservoir function is independently associated with a severely reduced pVO2 . LA dysfunction represents a marker of poor prognosis across LVEF borders in the CHF population.

Relation of left atrial function with exercise capacity and muscle endurance in patients with heart failure.

AIMS: Both left atrial strain (LAS) and skeletal muscle endurance demonstrate a linear relationship to peak VO2 . Less is known about the relationship between central (cardiac) and peripheral (muscle endurance) limitations of exercise capacity in patients with heart failure (HF). We investigated this relationship using novel cardiac markers such as LAS and left atrial emptying fraction (LAEF). METHODS AND RESULTS: We analysed echocardiographic measurements, cardiopulmonary exercise testing (CPET), and isokinetic muscle function in 55 subjects with HF and controls [17 heart failure with preserved ejection fraction (HFpEF), 18 heart failure with reduced ejection fraction (HFrEF), and 20 healthy controls]. Patients with reduced LAEF showed reduced peak VO2 : 14.3 ± 3.5 vs. 18.5 ± 3.5 mL/min/kg, P = 0.003, and reduced muscle endurance (RME): 64.3 ± 23.9 vs. 88.5 ± 32.3 Nm/kg, P = 0.028. Patients with reduced LAS showed similar results. Neither left ventricular global longitudinal strain (LVGLS) nor left atrial volume index (LAVI) was associated with RME. The area under the curve of LAS and LAEF in patients with HF in association with RME were (0.76 vs. 0.80) with 95% confidence interval (CI) (0.59-0.96, P = 0.012 vs. 0.63-0.98, P = 0.006, respectively). In a multiple linear regression, LAEF and working load measured during CPET (watt) were independent factors for RME after adjusting for age, LVGLS, and 6 min walk test (6MWT) [LAEF (B: 0.09, 95% CI: 1.01; 1.18, P = 0.024), working load (B: 0.05, 95% CI: 1.01; 1.08, P = 0.006)]. Peak torque of the left leg was associated with E/LAS (E: early diastolic) in patients with HFpEF (r = -0.6, P = 0.020). Endurance of the left leg was associated with LAEF (r = 0.79, P = 0.001) in patients with HFrEF. CONCLUSIONS: LAS/LAEF are potential cardiac markers in demonstrating the link between cardiac and peripheral limitations of exercise capacity. Thus, integrating LAS/LAEF in the evaluation of exercise intolerance in patients with HF could be useful.

The Role of Mitochondria-Linked Fatty-Acid Uptake-Driven Adipogenesis in Graves Orbitopathy.

CONTEXT: Depot-specific expansion of orbital adipose tissue (OAT) in Graves orbitopathy (GO; an autoimmune condition producing proptosis, visual impairment and reduced quality of life) is associated with fatty acid (FA)-uptake-driven adipogenesis in preadipocytes/fibroblasts (PFs). OBJECTIVE: This work sought a role for mitochondria in OAT adipogenesis in GO. METHODS: Confluent PFs from healthy OAT (OAT-H), OAT from GO (OAT-GO) and white adipose tissue in culture medium compared with culture medium containing a mixed hormonal cocktail as adipogenic medium (ADM), or culture-medium containing FA-supplementation, oleate:palmitate:linoleate (45:30:25%) with/without different concentration of mitochondrial biosubstrate adenosine 5'-diphosphate/guanosine 5'-diphosphate (ADP/GDP), AICAR (adenosine analogue), or inhibitor oligomycin-A for 17 days. Main outcome measures included oil-red-O staining and foci count of differentiated adipocytes for in vitro adipogenesis, flow cytometry, relative quantitative polymerase chain reaction, MTS-assay/106 cells, total cellular-ATP detection kit, and Seahorse-XFe96-Analyzer for mitochondria and oxidative-phosphorylation (OXPHOS)/glycolysis-ATP production analysis. RESULTS: During early adipogenesis before adipocyte formation (days 0, 4, and7), we observed OAT-specific cellular ATP production via mitochondrial OXPHOS in PFs both from OAT-H and OAT-GO, and substantially disrupted OXPHOS-ATP/glycolysis-ATP production in PFs from OAT-GO, for example, a 40% reduction in OXPHOS-ATP and trend-increased glycolysis-ATP production on days 4 and 7 compared with day 0, which contrasted with the stable levels in OAT-H. FA supplementation in culture-medium triggered adipogenesis in PFs both from OAT-H and OAT-GO, which was substantially enhanced by 1-mM GDP reaching 7% to 18% of ADM adipogenesis. The FA-uptake-driven adipogenesis was diminished by oligomycin-A but unaffected by treatment with ADP or AICAR. Furthermore, we observed a significant positive correlation between FA-uptake-driven adipogenesis by GDP and the ratios of OXPHOS-ATP/glycolysis-ATP through adipogenesis of PFs from OAT-GO. CONCLUSION: Our study confirmed that FA uptake can drive OAT adipogenesis and revealed a fundamental role for mitochondria-OXPHOS in GO development, which provides potential for therapeutic interventions.

Inducible fold-switching as a mechanism to fibrillate pro-apoptotic BCL-2 proteins.

Neurodegenerative diseases often are associated with cellular dysregulation that results in premature cell death or apoptosis. A common example is the accumulation of amyloid plaques that promotes the excessive expression of p38 mitogen-activated protein kinase. The increased abundance of this enzyme leads to mass phosphorylation and activation of a protein from the B-cell lymphoma 2 (BCL-2) family, BAX. BAX is the central regulatory protein for mitochondrial outer membrane permeabilization (MOMP), a poration process that commits cells to apoptosis by releasing death-propagating factors from the mitochondria. Recent reports identify a naturally occurring peptide, Humanin (HN), that could block amyloid-beta-associated neuronal apoptosis by interacting with BCL-2 proteins. We recently showed humanin interaction leads to the amyloid-like fibrillation of BAX and a second BCL-2 family member, BID. We proposed this as a novel anti-apoptotic mechanism that inhibits pro-apoptotic BCL-2 proteins from initiating MOMP by sequestering them into fibrils, a heretofore unprecedented phenomenon that involves refolding globular BCL-2 proteins rapidly into fibrils where they undergo significant alpha-helix to beta-sheet fold-switching. Here we seek to further characterize the fibrillation and fold-switch in conditions that are known to induce amyloid fibrillation.

Primary open elbow arthrolysis in post-traumatic elbow stiffness - A comparison of outcomes in severity of elbow injury.

PURPOSE: Stiffness is a sequelae of elbow trauma. Arthrolysis may be considered to increase range of movement (ROM). Little is published on the outcomes/complications of elbow arthrolysis. We present our series of primary open arthrolysis in posttraumatic elbow stiffness. METHODS: A consecutive series of patients that underwent primary open arthrolysis for posttraumatic elbow stiffness in our unit (2011-2018) were analysed. All procedures were performed by an elbow surgeon. Postoperative rehabilitation followed protocol with early motion; continuous passive motion (CPM) was utilised if requested. Data collected included patient demographics, traumatic injury type, arthrolysis technique, preoperative, intraoperative and postoperative elbow ROM, complications and postoperative Oxford Elbow Score (OES). RESULTS: 41 patients were included. 59% were male. Mean age at time of arthrolysis was 43 years (range 12-79 years). Mean duration of follow-up was 53 months (range 8-100 months). Median duration from time of injury to arthrolysis was 11 months (range 2-553 months). Mean preoperative flexion-extension arc (FEA) was 70°, improving to 104° postoperatively (p < 0.001). Mean preoperative pronosupination arc (PSA) was 125°, improving to 165° postoperatively (p < 0.001). Mean postoperative OES was 37 (n = 28). Complication rate was 24% with 7 recurrence requiring surgery, 2 nerve injuries and 1 infection. CPM, 10 patients, saw mean FEA improvement of 56°. Mean PSA improvement was 36°. Complication rate for these patients was 40%. Severe traumatic injury was associated with increased preoperative stiffness (FEA 61° vs 84°, PSA 111° vs 149°) but larger improvements in ROM (postoperative FEA 98° [p < 0.001], PSA 165° [p < 0.001]). CONCLUSION: This series demonstrates improvement in elbow ROM following open arthrolysis with significantly higher gain in pronosupination for those withsevere injury. Moderate results were seen in a patient reported outcome measure. Patients considering arthrolysis should be counselled regarding expectations/complication rate.