Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.

Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.

Characterization of a novel deep-intronic variant in DYNC2H1 identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III.

Biallelic pathogenic variants in DYNC2H1 are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the DYNC2H1 gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in DYNC2H1 was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited DYNC2H1 deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of DYNCH2H1 mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.

Anticipatory care planning for community-dwelling older adults at risk of functional decline: a feasibility cluster randomized controlled trial.

OBJECTIVES: To determine the feasibility, implementation and outcomes of an Anticipatory Care Planning (ACP) intervention in primary care to assist older adults at risk of functional decline by developing a personalized support plan. DESIGN: Feasibility cluster randomized control trial. SETTING AND PARTICIPANTS: Eight primary care practices (four in Northern Ireland, United Kingdom and four in the Republic of Ireland) were randomly assigned to either intervention or control arm. Eligible patients were those identified in each practice as 70 years of age or older and assessed as at risk of functional decline. Study participants (intervention n = 34, control n = 31) and research staff were not blinded to group assignment. ANTICIPATORY CARE INTERVENTION: The intervention delivered by a registered nurse including: a) a home-based patient assessment; b) care planning on the basis of a holistic patient assessment, and c) documentation of a support plan. OUTCOME MEASURES: A conceptual framework (RE-AIM) guided the assessment on the potential impact of the ACP intervention on patient quality of life, mental health, healthcare utilisation, costs, perception of person-centred care, and reduction of potentially inappropriate prescribing. Data were collected at baseline and at 10 weeks and six months following delivery of the intervention. RESULTS: All pre-specified feasibility indicators were met. Patients were unanimous in the acceptance of the ACP intervention. Health care providers viewed the ACP intervention as feasible to implement in routine clinical practice with attending community supports. While there were no significant differences on the primary outcomes (EQ-5D-5L: -0.07 (-0.17, 0.04) p = .180; CES-D: 1.2 (-2.5, 4.8) p = .468) and most secondary measures, ancillary analysis on social support showed responsiveness to the intervention. Incremental cost analysis revealed a mean reduction in costs of €320 per patient (95% CI -31 to 25; p = 0.82) for intervention relative to the control. CONCLUSIONS: We successfully tested the ACP intervention in primary care settings and have shown that it is feasible to implement. The ACP intervention deserves further testing in a definitive trial to determine whether its implementation would lead to better outcomes or reduced costs. TRIAL REGISTRATION: Clinicaltrials.gov, ID: NCT03902743 . Registered on 4 April 2019.

Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver-Brain Axis for Lipid Homeostasis.

Though biallelic variants in SLC13A5 are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs of these perturbations are inconsistent across SLC13A5 deficiency patients. To investigate SLC13A5-related disorders, we performed untargeted metabolic analyses on the liver, brain, and serum from a Slc13a5-deficient mouse model. Metabolomic data were analyzed using the connect-the-dots (CTD) methodology and were compared to plasma and CSF metabolomics from SLC13A5-deficient patients. Mice homozygous for the Slc13a5tm1b/tm1b null allele had perturbations in fatty acids, bile acids, and energy metabolites in all tissues examined. Further analyses demonstrated that for several of these molecules, the ratio of their relative tissue concentrations differed widely in the knockout mouse, suggesting that deficiency of Slc13a5 impacts the biosynthesis and flux of metabolites between tissues. Similar findings were observed in patient biofluids, indicating altered transport and/or flux of molecules involved in energy, fatty acid, nucleotide, and bile acid metabolism. Deficiency of SLC13A5 likely causes a broader state of metabolic dysregulation than previously recognized, particularly regarding lipid synthesis, storage, and metabolism, supporting SLC13A5 deficiency as a lipid disorder.

Estimating and examining the costs of inpatient diabetes care in an Irish Public Hospital.

AIM: To estimate and examine hospitalisation costs of Type 1 and Type 2 diabetes in an Irish public hospital. METHODS: A retrospective audit of hospital inpatient admissions over a 5-year period was undertaken, and a wide range of admission-related data were collected for a sample of 7,548 admissions. Hospitalisations were costed using the diagnosis-related group methodology. A series of descriptive, univariate and multivariate regression analyses were undertaken. RESULTS: The mean hospitalisation cost for Type 1 diabetes was €4,027 and for Type 2 diabetes was €5,026 per admission. Sex, admission type and length of stay were significantly associated with hospitalisation costs for admissions with a primary diagnosis of Type 1 diabetes. Age, admission type, diagnosis status, complications status, discharge destination, length of stay and year were significantly associated with hospitalisation costs for admissions with a primary diagnosis of Type 2 diabetes. Length of stay was associated with higher mean costs, with each additional day increasing Type 1 diabetes costs by €260 (p = 0.001) and Type 2 diabetes by €216 (p < 0.001). Unscheduled admissions were associated with significantly lower costs than elective admissions; €1,578 (p = 0.035) lower for Type 1 diabetes and €2,108 (p < 0.001) lower for Type 2 diabetes. CONCLUSIONS: This study presents estimates of the costs of diabetes care in the Irish public hospital system and identifies the factors which influence costs for Type 1 and Type 2 diabetes. These findings may be of interest to patients, the public, researchers and those with influence over diabetes policy and practice in Ireland and internationally.

Successful implementation of a trans-jurisdictional, primary care, anticipatory care planning intervention for older adults at risk of functional decline: interviews with key health professionals.

BACKGROUND: Aging populations present a challenge to health systems internationally, due to the increasing complexity of care for older adults living with functional decline. This study aimed to elicit expert views of key health professionals on effective and sustainable implementation of a nurse-led, person-centred anticipatory care planning (ACP) intervention for older adults at risk of functional decline in a primary care setting. METHODS: We examined the feasibility of an ACP intervention in a trans-jurisdictional feasibility cluster randomized controlled trial consisting of home visits by research nurses who assessed participants' health, discussed their health goals and devised an anticipatory care plan following consultation with participants' GPs and adjunct clinical pharmacist. As part of the project, we elicited the views and recommendations of experienced key health professionals working with the target population who were recruited using a 'snowballing technique' in cooperation with older people health networks in the Republic of Ireland (ROI) and Northern Ireland (NI), United Kingdom [n = 16: 7 ROI, 9 NI]. Following receipt of written information about the intervention and the provision of informed consent, the health professionals were interviewed to determine their expert views on the feasibility of the ACP intervention and recommendations for successful implementation. Data were analyzed using thematic analysis. RESULTS: The ACP intervention was perceived to be beneficial for most older patients with multimorbidity. Effective and sustainable implementation was said to be facilitated by accurate and timely patient selection, GP buy-in, use of existing structures within health systems, multidisciplinary and integrated working, ACP nurse training, as well as patient health literacy. Barriers emerged as significant work already undertaken, increasing workload, lack of time, funding and resources, fragmented services, and geographical inequalities. CONCLUSIONS: The key health professionals perceived the ACP intervention to be highly beneficial to patients, with significant potential to prevent or avoid functional decline and hospital admissions. They suggested that successful implementation of this primary care based, whole-person approach would involve integrated and multi-disciplinary working, GP buy in, patient health education, and ACP nurse training. The findings have potential implications for a full trial, and patient care and health policy. TRIAL REGISTRATION: Clinicaltrials.gov, ID: NCT03902743 . Registered on 4 April 2019.

Anticipatory care planning intervention for older adults at risk of functional decline: study protocol for a primary care cluster feasibility randomised trial.

BACKGROUND: The treatment and management of long-term health conditions is the greatest challenge facing health systems around the world today. Innovative approaches to patient care in the community such as Anticipatory Care Planning (ACP), which seek to help with the provision of high-quality comprehensive care to older adults at risk of functional decline, require evaluation. This study will evaluate one approach that will include primary care as the setting for ACP. METHODS/DESIGN: This study will help to determine the feasibility for a definitive randomised trial to evaluate the implementation and outcomes of an ACP intervention. The intervention will be delivered by specially trained registered nurses in a primary care setting with older adults identified as at risk of functional decline. The intervention will comprise: (a) information collection via patient assessment; (b) facilitated informed dialogue between the patient, family carer, general practitioner and other healthcare practitioners; and, (c) documentation of the agreed support plan and follow-up review dates. Through a structured consultation with patients and their family carers, the nurses will complete a mutually agreed personalised support plan. DISCUSSION: This study will determine the feasibility for a full trial protocol to evaluate the implementation and outcomes of an (ACP) intervention in primary care to assist older adults aged 70 years of age or older and assessed as being at risk of functional decline. The study will be implemented in two jurisdictions on the island of Ireland which employ different health systems but which face similar health challenges. This study will allow us to examine important issues, such as the impact of two different healthcare systems on the health of older people and the influence of different legislative interpretations on undertaking cross jurisdictional research in Ireland. PROTOCOL VERSION: Version 1, 17 September 2019. TRIAL REGISTRATION: Clinicaltrials.gov, ID: NCT03902743. Registered on 4 April 2019.

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice.

AIMS/HYPOTHESIS: Islet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-ß deposits in the brain, also allows identification of islet amyloid in the pancreas. METHODS: Saturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro. Islet amyloid-prone transgenic mice that express hIAPP in their beta cells and amyloid-free non-transgenic control mice were used to examine the ability of florbetapir to detect islet amyloid deposits in vitro, in vivo and ex vivo. Mice or mouse pancreases were subjected to autoradiographic, histochemical and/or positron emission tomography (PET) analyses to assess the utility of florbetapir in identifying islet amyloid. RESULTS: In vitro, florbetapir bound synthetic hIAPP fibrils with a dissociation constant of 7.9 nmol/l. Additionally, florbetapir bound preferentially to amyloid-containing hIAPP transgenic vs amyloid-free non-transgenic mouse pancreas sections in vitro, as determined by autoradiography (16,475 ± 5581 vs 5762 ± 575 density/unit area, p < 0.05). In hIAPP transgenic and non-transgenic mice fed a high-fat diet for 1 year, intravenous administration of florbetapir followed by PET scanning showed that the florbetapir signal was significantly higher in amyloid-laden hIAPP transgenic vs amyloid-free non-transgenic pancreases in vivo during the first 5 min of the scan (36.83 ± 2.22 vs 29.34 ± 2.03 standardised uptake value × min, p < 0.05). Following PET, pancreases were excised and florbetapir uptake was determined ex vivo by γ counting. Pancreatic uptake of florbetapir was significantly correlated with the degree of islet amyloid deposition, the latter assessed by histochemistry (r = 0.74, p < 0.001). CONCLUSIONS/INTERPRETATION: Florbetapir binds to islet amyloid deposits in a specific and quantitative manner. In the future, florbetapir may be useful as a non-invasive tool to identify islet amyloid deposits in humans.

MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques.

Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques (Macaca mulatta) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoroacetate ([18F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [18F]fluorothymidine ([18F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single-nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1-rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans.

Kirschner Wire Breakage during Removal Requiring Retrieval.

Kirschner wires (K-wires) are widely used for fixation of fractures and dislocations in the hand as they are readily available, reliable, and cost-effective. Complication rates of up to 18% have been reported. However, K-wire breakage during removal is rare. We present one such case illustrating a simple technique for retrieval. A 35-year-old male presented with a distal phalanx fracture of his right middle finger. This open fracture was treated with K-wire fixation. Postoperatively, he developed a pin site infection with associated finger swelling. The K-wire broke during removal with the proximal piece completely retained in his middle phalanx. To minimise risk of osteomyelitis, the K-wire was removed with a novel surgical technique. He had full return of hand function. Intraoperative K-wire breakage has a reported rate of 0.1%. In our case, there was no obvious cause of breakage and the patient denied postoperative trauma. On the other hand, pin site infections are much more common with reported rates of up to 7% in the hand or wrist. K-wire fixation is a simple method for bony stabilisation but can be a demanding procedure with complications often overlooked. It is important to be aware of the potential sequelae.

Bilateral closed flexor pollicis longus musculotendinous junction ruptures.

We present a case of bilateral closed flexor pollicis longus musculotendinous junction ruptures. Our case suggests multifactorial aetiology and provides further evidence for genetic influences in musculotendinous junction injuries.

Reconstruction of complex orbital exenteration defects: a single center's experience with a five-year follow-up.

BACKGROUND: Orbital exenteration presents a challenge to the reconstructive surgeon. Defects may be treated with split skin grafts, local advancement flaps, or free flap coverage. There are few published series showing the long-term outcomes of reconstruction. Our results, with at least a 5-year follow-up, are presented. METHODS: A retrospective review of 15 immediate reconstructions after orbital exenterations for malignancies in 12 patients at a tertiary referral center over a 5-year period, was done. All flaps were followed up for at least 5 years (mean, 75 months; range, 3-118 months). RESULTS: Malignancies included squamous cell carcinoma, basal cell carcinoma, meningioma, sebaceous gland carcinoma, and rhabdomyosarcoma. Eight cervicofacial rotation-advancement flaps and 4 anterolateral thigh, 1 rectus abdominis, and 1 radial forearm free tissue transfers were used. Aggressive postoperative radiotherapy (9/15) was well tolerated by both regional and free flaps. Both cervicofacial flaps in previously irradiated patients had wound dehiscence or fistula formation. Six (50%) patients died during follow-up, 4 of whom (33%) died of tumor recurrence. CONCLUSIONS: Flap reconstruction after complex orbital exenteration is associated with low morbidity. Cervicofacial rotation-advancement flaps offer reliable, single-stage, aesthetically pleasing reconstructions. They should be avoided in the previously irradiated. Free tissue transfer is indicated for volume replacement, after previous radiotherapy, after tumor recurrence and previous use of locoregional flaps. Reconstruction of complex orbital exenteration defects for malignancies should be undertaken in centers with experience in the management of these procedures.

Skin graft meshing, over-meshing and cross-meshing.

INTRODUCTION: Split skin grafts (SSGs) are often meshed to increase their size and allow exudate to escape. We investigated the expansion obtained with meshing, and the possibility of re-meshing skin that has already been meshed ("overmeshing"). Both useful and inadvisable permutations are illustrated. MATERIAL AND METHODS: Thin porcine SSGs were sideways meshed, or meshed with ratios of 1.5:1 and 3:1. Subsequently samples were over-meshed in a variety of ratios and directions. All grafts were maximally expanded and their areas calculated. RESULTS: Meshed skin did not expand as much as suggested by the ratios displayed on dermacarriers. A 1:1.5 dermacarrier produced an area expansion of 1.36×, and a 1:3 meshing apparatus produced only a 1.80×area expansion. Several combinations of twice-meshed SSGs maintained integrity as long as over-meshing was done in the axis of initial meshing. Up to 2.3×expansion was obtained, by following a 1:1.5 mesh with a 1:3 mesh. We term this procedure as "overmeshing". Re-meshing in a direction orthogonal to initial meshing (cross meshing) cut the skin into small pieces. CONCLUSION: Over-meshing a SSG can allow considerable further expansion, facilitating overgrafting of donor sites or simply increasing the area that can be covered with the existing harvested skin.

Observed characteristics of suicidal hangings: an 11-year retrospective review.

Many studies have been published regarding suicidal hanging deaths, and most forensic pathologists and coroners are very familiar with such causes of death. Forensic pathologists are challenged over their rulings regarding manner of death in part because the general public has a limited scope of knowledge. One such challenge centers on the question of whether a hanging can be a suicide if the individual is not fully suspended. The authors designed a retrospective study to review suspension in hangings and to analyze other criteria used to help in deciding manner of death. We examined 229 suicidal hanging deaths over an 11-year period (1997 through early 2009) using the data from two separate jurisdictions in Ohio. In conclusion, we found that the vast majority (83.4%) of people who hanged themselves were found partially suspended. Among other criteria analyzed, only the presence of petechial hemorrhages and acute neck injury was statistically significant.

Epitendinous suture techniques in extensor tendon repairs--an experimental evaluation.

PURPOSE: The tension-band principle might be relevant to extensor tendon repairs, and a dorsal-only Silfverskiöld epitendinous repair is stronger and stiffer than more conventional techniques in vitro. We aimed to evaluate the strength and stiffness of the strongest epitendinous sutures described, using an in vitro model that subjects the repair to angular force over a pulley, thereby creating a tension-band model. METHODS: Silfverskiöld dorsal-only epitendinous extensor tendon repairs in porcine foot tendons (n = 8) were compared to reverse (buried) Silfverskiöld (n = 8), Halsted (n = 8), and interrupted horizontal mattress (IHM) repairs (n = 6) in vitro with a tensiometer around a 45° pulley. Thirty tendons total were tested to assess the force required for 2-mm gapping and ultimate tensile strength. RESULTS: The IHM repair had a significantly higher ultimate tensile strength (43 N; SD, 10 N) than the other repairs, which had strengths between 27 N (SD, 4 N) and 31 N (SD, 7 N). The IHM was also significantly more resistant to gapping than the Silfverskiöld and Halsted repairs. CONCLUSIONS: Interlocking horizontal mattress, dorsal-only extensor tendon repairs were significantly stronger and more resistant to gapping than Silfverskiöld and Halsted repairs. Other repairs were still strong and resistant to gapping in comparison to previously published data for conventional repairs. CLINICAL RELEVANCE: The IHM is a relatively difficult technique to perform, and it remains to be seen whether the additional strength translates to clinical benefits over the easier Silfverskiöld technique.

Inflammatory posterior interosseous nerve palsy in a patient with psoriatic arthropathy.

Psoriasis is a chronic, relapsing, inflammatory skin disorder with a strong genetic basis. Five patterns of psoriatic arthritis have been identified: asymmetrical oligoarticular arthritis, symmetrical polyarthritis, distal interphalangeal arthropathy, arthritis mutilans and spondylitis with or without sacroiliitis. Extra-articular disease is uncommon. We report a rare case of an inflammatory posterior interosseus nerve palsy in a patient with known psoriatic arthropathy, where investigation warranted medical treatment over a surgical approach. The commonest cause of posterior interosseus nerve palsy is entrapment at the proximal forearm. Other possible aetiologies include extension of elbow synovitis as described in rheumatoid arthritis, trauma eg. Monteggia fractures, tumours and iatrogenic injuries. We discuss the diagnostic dilemma and the management issues for upper limb surgeons.

The prevalence of multimorbidity in primary care and its effect on health care utilization and cost.

INTRODUCTION: Multimorbidity is common among the heterogeneous primary care population, but little data exist on its association with health care utilization or cost. OBJECTIVE: The aim of this observational study was to examine the prevalence and associated health care utilization and cost of patients with multimorbidity. METHODS: All patients >50 years of age were eligible for the study which took place in three primary care practices in the West of Ireland. Chronic medical conditions and associated health care utilization in primary and secondary care were identified through patient record review. RESULTS: In a sample of 3309 patients in the community, the prevalence of multimorbidity was 66.2% (95% CI: 64.5-67.8) in those >50 years of age. Health care utilization and cost was significantly increased among patients with multimorbidity (P < 0.001). After multivariate adjustment for age, gender and free medical care eligibility, the addition of each chronic condition led to an associated increase in primary care consultations (P = 0.001) (11.9 versus 3.7 for >4 conditions versus 0 conditions); hospital out-patient visits (P = 0.001) (3.6 versus 0.6 for >4 conditions versus 0 conditions); hospital admissions (P = 0.01) [adjusted odds ratio (OR) of 4.51 for >4 conditions versus 0 conditions] and total health care costs (P < 0.001) (€4,096.86 versus €760.20 for >4 conditions versus 0 conditions) over the previous 12 months. CONCLUSIONS: Multimorbidity is very common in primary care and in a system with strong gatekeeping is associated with high health care utilization and cost across the health care system. Interventions to address quality and cost associated with multimorbidity must focus on primary as well as secondary care.