Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real-world evidence from the MSGo digital support programme.

Background: Siponimod is approved for use in people with secondary progressive multiple sclerosis (pwSPMS). An integrated digital platform, MSGo, was developed for pwSPMS and clinicians to help navigate the multiple steps of the pre-siponimod work-up. Objective: To explore real-world onboarding experiences of siponimod amongst pwSPMS in Australia. Methods: Retrospective, non-interventional, longitudinal, secondary analysis of data extracted from MSGo (20 April 2022). The primary endpoint was the average time for siponimod onboarding; secondary endpoints were adherence and sub-group analyses of variables influencing onboarding. Results: Mixed-cure modelling estimated that 58% of participants (N = 368, females 71%, median age of 59 years) registered in MSGo would ever initiate siponimod. The median time to initiation was 56 days (95% CI [47-59] days). Half of the participants cited 'waiting for vaccination' as the reason for initiation delay. Cox regression analyses found participants with a nominated care partner had faster onboarding (HR 2.1, 95% CI [1.5-3.0]) and were more likely to continue self-reporting daily siponimod dosing than were those without a care partner (HR 2.2, 95% CI [1.3-3.7]). Conclusions: Despite the limitations of self-reported data and the challenges of the COVID-19 pandemic, this study provides insights into siponimod onboarding in Australia and demonstrates the positive impact of care partner support.

The surgical care of diabetic feet: a survey about clinics, acute care, and the surgical specialists involved.

INTRODUCTION: Diabetic foot problems are becoming increasingly common. Diabetic foot care services are fundamental in managing them, and there is the further issue of acute surgery for foot sepsis. The involvement of different surgical specialists has been variable; this survey aimed to provide information about current service provision. METHODS: Questionnaires were emailed to Vascular Society members, and targeted approaches were then undertaken. RESULTS: We aimed to obtain information from 61 localities identified as providing shared services, and received informative responses from 46 (75%). These described diabetic foot clinics each day (11%), or once (50%), twice (13%) or three times (17%) weekly - attended regularly by vascular surgeons, and less frequently by orthopaedic surgeons. The frequency of clinics was considered inadequate by 30% of respondents, and only 75% reported written policies for diabetic foot care pathways. Operations for acute foot sepsis are done by vascular surgeons in 98% of localities and by orthopaedic surgeons in 22% (in some localities by both): the latter are orthopaedic foot specialists in all localities but two. Both specialties perform a range of foot procedures, including toe/foot-preserving operations. Major amputations are done by vascular surgeons in 98% of localities and by orthopaedic surgeons in only 9%. All deformity correction procedures are performed by orthopaedic surgeons. CONCLUSION: This survey shows that diabetic foot clinics are now held frequently in most localities. There is variation in the involvement of vascular and orthopaedic surgeons. Some localities need to consider increased provision of clinics and better defined pathways of care.

Influence of fibroids on cell-free DNA screening accuracy.

OBJECTIVE: Cell-free DNA (cfDNA) screening assesses both maternal and placental cfDNA. Fibroids are common and release cfDNA into maternal serum. Genetic abnormality is seen in 50% of fibroids. We aimed to assess the impact of fibroids on the accuracy of genome-wide cfDNA screening. METHODS: This was a prospective cohort study of singleton pregnancies examined at one of two centers in Melbourne and Sydney, Australia, between 1 November 2019 and 31 December 2020. All cases underwent pretest ultrasound examination to confirm an ongoing pregnancy of at least 10 weeks' gestation, and, at this stage, the number and volume of any uterine fibroid were documented. Genome-wide cfDNA screening was performed to detect all copy-number variants (CNV) > 7 megabases. The incidence of a false-positive result was compared between cases with and those without fibroids. RESULTS: Over the 14-month study period, 13 184 patients underwent cfDNA screening, of whom 1017 (7.7%) had fibroids. Fibroids were not identified in any of the 17 participants who had a false-positive result for chromosomes 13, 18, 21, X or Y. Ninety-five (0.7%) cases were screen-positive for subchromosomal aberration (SA), rare autosomal trisomy (RAT) or multiple abnormalities (MA), with 10 of these cases having a fetal genetic abnormality. The incidence of a false-positive RAT, MA or SA result was significantly higher in participants with fibroids (20/1017 (2.0%)) than in those without fibroids (64/12 167 (0.5%)). Women with fibroids were approximately six times as likely to have a false-positive result for SA, and this was associated positively with both fibroid number and volume. CONCLUSIONS: Most women with fibroids do not have an abnormal result on genome-wide cfDNA screening. However, CNVs due to fibroids are associated with false-positive SA findings, although fibroids do not appear to influence cfDNA screening accuracy for the common autosomal trisomies or sex-chromosomal abnormalities. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Clinico-radiological findings of neuroendocrine tumour metastases to the orbit.

PURPOSE: We present the clinico-radiological findings of neuroendocrine tumour metastases to the orbit. METHODS: This was a multicentre, retrospective study of patients with neuroendocrine tumour metastases to the orbit. Data was collected from medical records across five different sites within Australia and the United Kingdom. RESULTS: Nine patients (eleven lesions) were identified. The most common presenting complaint was diplopia (5/9, 56%). Disease occurred bilaterally in two patients. Seven patients (78%) had extraocular muscle involvement. The lateral recti (4/9, 44%) and superior recti (2/9, 22%) were the most commonly affected. Ocular presentation preceded primary tumour diagnosis in three patients (33%). On orbital imaging, metastases were most commonly reported as well circumscribed, ovoid or round, heterogeneous, contrast-enhancing masses. Features of intralesional haemorrhage and bony invasion are uncommonly reported. CONCLUSIONS: Neuroendocrine tumour metastasis to the orbit is uncommon. Metastases have a propensity for the extraocular muscles, commonly presenting as heterogeneous, well circumscribed, contrast-enhancing lesions on neuroimaging. New ocular symptoms, a history of neuroendocrine tumours, and these radiological findings, should lead to high clinical suspicion of metastatic disease. Atypical findings warrant biopsy to exclude other causes of orbital lesions.

Hemiarthroplasty for Femoral Neck Fractures: Does Surgeon Subspecialty Affect Perioperative Outcomes?

OBJECTIVES: To determine if surgeon subspecialty training affects perioperative outcomes for displaced femoral neck fractures treated with hemiarthroplasty. DESIGN: Retrospective comparative study. SETTING: One health system with 2 hospitals (Level I and Level III trauma centers). PATIENT AND PARTICIPANTS: Patients who were treated with hemiarthroplasty for displaced femoral neck fractures between October 2012 and September 2017. OUTCOME MEASURES: Leg length discrepancy, femoral offset, estimated blood loss (EBL), incidence of blood transfusion, time to surgery, operative time, and length of stay. Data were analyzed based on the treating surgeon's subspecialty training [arthroplasty (A), trauma (T), other (O)]. Hierarchical regression was used to compare the groups and control for confounding variables. RESULTS: A total of 292 patients who received hemiarthroplasty for displaced femoral neck fractures were included (A = 158; T = 73; O = 61). Surgeon subspecialty had a statistically significant effect on operative time, with arthroplasty surgeons completing the procedure 9.6 minutes faster than trauma surgeons and 17.7 minutes faster than other surgeons (P < 0.01; ΔR = 0.03). Surgeon subspecialty did not significantly affect other outcomes, including leg length discrepancy (P = 0.26), femoral offset (P = 0.37), EBL (P = 0.10), incidence of transfusion (P = 0.67), time to surgery (P = 0.10), or length of stay (P = 0.67). CONCLUSIONS: This study demonstrates that arthroplasty-trained surgeons perform hemiarthroplasty slightly faster than other subspecialists, but subspecialty training does not affect other perioperative outcomes, including leg length discrepancy, femoral offset, EBL, transfusion rate, time to surgery, or length of stay. This suggests that hemiarthroplasty can be adequately performed by various subspecialists, and deferring treatment to an arthroplasty surgeon might not have a clinically significant benefit in the perioperative period. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A Japanese Bioventure Company's Application of Stem Cell Technology in Regenerative Medicine.

Regenerative medicine mediated by the transplantation of somatic stem cells and functional cells derived from induced pluripotent stem cells has great potential in the treatment of currently incurable diseases and thus has attracted significant public attention. To put this into practice, several functional cell lines were developed and laws regarding regenerative medicine were put in force in Japan. In this report, we introduce recent efforts of a bioventure company with special attention to the case of Healios K.K.

The evolution of "No Evidence of Disease Activity" in multiple sclerosis.

The availability of effective therapies for patients with relapsing-remitting multiple sclerosis (RRMS) has prompted a re-evaluation of the most appropriate way to measure treatment response, both in clinical trials and clinical practice. Traditional parameters of treatment efficacy such as annualized relapse rate, magnetic resonance imaging (MRI) activity, and disability progression have an important place, but their relative merit is uncertain, and the role of other factors such as brain atrophy is still under study. More recently, composite measures such as "no evidence of disease activity" (NEDA) have emerged as new potential treatment targets, but NEDA itself has variable definitions, is not well validated, and may be hard to implement as a treatment goal in a clinical setting. We describe the development of NEDA as an outcome measure in MS, discuss definitions including NEDA-3 and NEDA-4, and review the strengths and limitations of NEDA, indicating where further research is needed.

Expansion of the Mexican Rice Borer (Lepidoptera: Crambidae) into Rice and Sugarcane in Louisiana.

The Mexican rice borer, Eoreuma loftini (Dyar) (Lepidoptera: Crambidae), is an invasive pest of sugarcane, Saccharum spp., rice, Oryza sativa L., and other graminaceous crops in the Gulf Coast region of the United States. Traps baited with E. loftini female sex pheromones were used to document establishment and distribution of E. loftini near sugarcane, rice, and noncrop hosts in seven southwest Louisiana parishes from 2009 to 2013. Additional field surveys documented larval infestations in commercial sugarcane and rice. After its initial detection in 2008, no E. loftini were detected in Louisiana in 2009 and only two adults were captured in 2010. Trapping documented range expansion into Cameron, Beauregard, and Jefferson Davis parishes in 2011 and Allen, Acadia, and Vermilion parishes in 2013. During the course of this study, E. loftini expanded its range eastward into Louisiana 120 km from the Texas border (≈22 km/yr). Surveys of larval infestations provided the first record of E. loftini attacking rice and sugarcane in Louisiana. Infestations of E. loftini in rice planted without insecticidal seed treatments in Calcasieu Parish reached damaging levels.

Incidental non-inguinals hernias in totally extra-peritoneal hernia repair.

INTRODUCTION: Totally extra-peritoneal (TEP) inguinal hernia repair allows identification and repair of incidental non-inguinal groin hernias. We assessed the prevalence of incidental hernias during TEP inguinal hernia repair and identified the risk factors for incidental hernias. MATERIALS AND METHODS: Consecutive patients undergoing TEP repair from May 2005 to November 2012 were the study cohort. Inspection for ipsilateral femoral, obturator and rarer varieties of hernia was undertaken during TEP repair. Patient characteristics and operative findings were recorded on a prospectively collected database. RESULTS: A total of 1,532 TEP repairs were undertaken in 1,196 patients. Ninety-three patients were excluded due to incomplete data, leaving 1,103 patients and 1,404 hernias for analyses (1,380 male; 802 unilateral and 301 bilateral repairs; median age, 59 years). Among the 37 incidental hernias identified (2.6% of cases), the most common type of incidental hernia was femoral (n=32, 2.3%) followed by obturator (n=2, 0.1%). Increasing age was associated with an increased risk of incidental hernia, with a significant linear trend (p<0.01). The risk for patients >60 years of age was 4.0% vs 1.4% for those aged <60 years (p<0.01). Incidental hernias were found in 29.2% of females vs 2.2% of males, (p<0.0001). Risk of incidental hernia in those with a recurrent inguinal hernia was 3.0% vs 2.6% for primary repair (p=0.79). CONCLUSIONS: Incidental hernias during TEP inguinal hernia repair were found in 2.6% of cases and, though infrequent, could cause complications if left untreated. The risk of incidental hernia increased with age and was significantly higher in patients aged >60 years and in females.

Medicinal chemistry of the epigenetic diet and caloric restriction.

The pronounced effects of the epigenetic diet (ED) and caloric restriction (CR) have on epigenetic gene regulation have been documented in many pre-clinical and clinical studies. Understanding epigenetics is of high importance because of the concept that external factors such as nutrition and diet may possess the ability to alter gene expression without modifying the DNA sequence. The ED introduces bioactive medicinal chemistry compounds such as sulforaphane (SFN), curcumin (CCM), epigallocatechin gallate (EGCG) and resveratrol (RSV) that are thought to aid in extending the human lifespan. CR, although similar to ED in the target of longevity, mildly reduces the total daily calorie intake while concurrently providing all beneficial nutrients. Both CR and ED may act as epigenetic modifiers to slow the aging process through histone modification, DNA methylation, and by modulating microRNA expression. CR and ED have been proposed as two important mechanisms that modulate and potentially slow the progression of age-related diseases such as cardiovascular disease (CVD), cancer, obesity, Alzheimer's and osteoporosis to name a few. While many investigators have examined CR and ED as separate entities, this review will primarily focus on both as they relate to age-related diseases, their epigenetic effects and their medicinal chemistry.

Impact of olanzapine or risperidone treatment on insulin sensitivity in schizophrenia or schizoaffective disorder.

AIM: To assess changes in insulin sensitivity in non-diabetic adults with schizophrenia or schizoaffective disorder treated with olanzapine or risperidone. METHODS: One hundred and thirty patients were randomly assigned to 12 weeks double-blind treatment with olanzapine or risperidone. Insulin sensitivity was measured using a two-step euglycaemic, hyperinsulinaemic clamp procedure. Whole-body adiposity was measured using dual-energy X-ray absorptiometry. The primary endpoint was the within-group change from baseline in insulin sensitivity normalized to fat-free mass (M(ffm) /I) during the clamp procedure's low-insulin phase, using an analysis of covariance model including the covariate weight change. RESULTS: Forty-one olanzapine-treated and 33 risperidone-treated patients completed baseline and endpoint clamp measurements. Mean M(ffm) /I during the low-insulin phase declined 9.0% (p = 0.226) in olanzapine-treated patients and 13.2% (p = 0.047) in risperidone-treated patients (between-group difference p = 0.354). During the high-insulin phase, M(ffm) /I declined 10.4% (p = 0.036) in olanzapine-treated patients and 2.1% (p = 0.698) in risperidone-treated patients (between-group difference p = 0.664). Changes in M(ffm) /I correlated inversely with changes in body weight and adiposity, which were generally higher in olanzapine-treated patients. Significant within-group increases in fasting glucose, but not haemoglobin A1c (HbA1c), were observed during olanzapine treatment. The fasting glucose change was not correlated with M(ffm) /I changes. CONCLUSIONS: Small, but statistically significant, decrements in insulin sensitivity were observed in olanzapine- and risperidone-treated patients at 1 of 2 insulin doses tested. Significant increases in fasting glucose and insulin and total fat mass were observed only in olanzapine-treated patients. Changes in insulin sensitivity correlated significantly with changes in weight or adiposity, but not with changes in glucose.

A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes.

AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 (LY), a novel, long-acting glucagen-like peptide-1 analogue, administered once weekly to subjects with type 2 diabetes. METHODS: This was a placebo-controlled, parallel-group, subject- and investigator-blind study of LY in subjects (N = 43) with type 2 diabetes mellitus controlled with diet and exercise alone or with a single oral antidiabetic medication. Subjects taking metformin or thiazolidinediones continued on their therapy. Subjects receiving sulfonylurea, acarbose, repaglinide or nateglinide were switched to metformin prior to enrollment. Subjects received five once-weekly doses of 0.05, 0.3, 1, 3, 5 or 8 mg. Effects on glucose, insulin and C-peptide concentrations were determined during fasting and following standard test meals. The pharmacokinetics of LY and its effects on HBA1c, glucagon, body weight, gastric emptying and safety parameters were assessed. RESULTS: Once-weekly administration of LY significantly reduced (p < 0.01) fasting plasma glucose, 2-h post-test meal postprandial glucose and area under the curve (AUC) of glucose after test meals at doses ≥1 mg. These effects were seen after the first dose and were sustained through the weekly dosing cycle. Most doses produced statistically significant increases in insulin and C-peptide AUC when normalized for glucose AUC. Statistically significant reductions in HBA1c were observed for all dose groups except 0.3 mg. The most commonly reported adverse effects (AEs) were nausea (35 events), headache (20 events), vomiting (18 events) and diarrhoea (8 events). CONCLUSIONS: LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent.

Tumour necrosis factor (TNF) inhibitor therapy in Susac's syndrome.

Susac's syndrome is the clinical triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss (Susac 1994) [1]. It occurs predominantly in young females and is believed to be an immune-mediated endotheliopathy of small vessels of the brain, retina and cochlea (Neumayer et al. 2009) [2]. Early, aggressive, and sustained immunosuppressive therapy has been recommended for Susac's syndrome and anecdotal evidence has suggested a therapeutic role for monoclonal antibodies (Rennebohm et al. 2008, Lee and Amezcua 2009) [3,4]. We report a case of Susac's syndrome in which the patient improved immediately after tumour necrosis factor (TNF) inhibition with the monoclonal antibody, infliximab.

Use of the orbicularis retaining ligament in lower eyelid reconstruction.

INTRODUCTION: The orbicularis retaining ligament (ORL) is a distinct anatomical structure that has only been recently characterised. A variety of techniques, based on Hamra's concepts, now divide this ligament during lower lid blepharoplasty. This often produces a substantial skin excess which is discarded. We set out to investigate the validity of this surgical manoeuvre as a means of recruiting anterior lamella for the purposes of lower lid reconstruction. MATERIALS AND METHODS: Between September 2002 and August 2004, 23 patients underwent reconstruction of the anterior lamella of their lower eyelid using this technique. The mean age of the patients was 56 years (range 26-86 years). The mean follow-up time was 20 months (range 12-36 months). Clinical evaluation was carried out preoperatively and postoperatively to assess the presence of palpebral non occlusion, epiphora, the sensation of a dry eye, ectropion, conjunctivitis and keratitis. Assessment of the tissue deficit was made clinically and with standardised digital photographs. RESULTS: Satisfactory reconstruction of the anterior lamella of the lower eyelid was achieved in 19/23 patients. Preoperative symptoms of epiphora and lower lid position were improved. The visual analogue scale of appearance was improved postoperatively. In some cases, particularly in the atrophic lower lid, the results were short lived and further surgery was required to achieve optimal results. CONCLUSION: In cases of isolated cutaneous deficit where the lid support mechanisms are intact, the procedure is both successful and aesthetically favourable for resurfacing this challenging area.

Electrophysiological effects of activating the peptidergic primary afferent innervation of rat mesenteric arteries.

1. Intracellular recording was used to investigate the electrophysiological effects of activating peptidergic primary afferent axons with capsaicin in the smooth muscle of rat mesenteric arteries in vitro. In addition, continuous amperometry was used to monitor the effects of capsaicin on noradrenaline release from the sympathetic nerves. 2. Capsaicin (1 microm) produced a hyperpolarization (-11+/-2 mV) and a reduction in the time constant of decay of excitatory junction potentials (e.j.p.'s) evoked by electrical stimulation of the perivascular sympathetic nerves. These effects of capsaicin were mimicked by calcitonin gene-related peptide (CGRP; 1 and 10 nm) but not by substance P (50 nm), which produced a small hyperpolarization (maximum -3+/-1 mV) but did not change excitatory junction potential (e.j.p.) time course. 3. The hyperpolarization produced by capsaicin and CGRP was blocked by glibenclamide (10 microm) but was not changed by the CGRP antagonist, CGRP8-37 (0.5 microm). Mechanical denudation of the endothelium also did not reduce the effect of capsaicin on membrane potential. 4. Capsaicin (1 microm) increased the amplitude of e.j.p.'s. This effect was not mimicked by CGRP or substance P nor blocked by glibenclamide or CGRP8-37. 5. All effects of capsaicin desensitized. 6. Capsaicin (1 microm) had no effect on noradrenaline-induced oxidation currents evoked by electrical stimulation, indicating that noradrenaline release was unchanged. 7. These results suggest that CGRP released from primary afferent axons hyperpolarizes vascular smooth muscle by activating glibenclamide-sensitive K+ channels. The findings also indicate that an unknown factor released by the primary afferent axons increases e.j.p. amplitude.