Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms.

AIMS: To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate. MATERIALS/METHODS: Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons. RESULTS: Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise. CONCLUSIONS: GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Early constipation predicts faster dementia onset in Parkinson's disease.

Constipation is a common but not a universal feature in early PD, suggesting that gut involvement is heterogeneous and may be part of a distinct PD subtype with prognostic implications. We analysed data from the Parkinson's Incidence Cohorts Collaboration, composed of incident community-based cohorts of PD patients assessed longitudinally over 8 years. Constipation was assessed with the MDS-UPDRS constipation item or a comparable categorical scale. Primary PD outcomes of interest were dementia, postural instability and death. PD patients were stratified according to constipation severity at diagnosis: none (n = 313, 67.3%), minor (n = 97, 20.9%) and major (n = 55, 11.8%). Clinical progression to all three outcomes was more rapid in those with more severe constipation at baseline (Kaplan-Meier survival analysis). Cox regression analysis, adjusting for relevant confounders, confirmed a significant relationship between constipation severity and progression to dementia, but not postural instability or death. Early constipation may predict an accelerated progression of neurodegenerative pathology.

Progression of Neuropsychiatric Symptoms over Time in an Incident Parkinson's Disease Cohort (ICICLE-PD).

BACKGROUND: Cross-sectional studies have identified that the prevalence of neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) ranges from 70-89%. However, there are few longitudinal studies determining the impact of NPS on quality of life (QoL) in PD patients and their caregivers. We seek to determine the progression of NPS in early PD. METHODS: Newly diagnosed idiopathic PD cases (n = 212) and age-matched controls (n = 99) were recruited into a longitudinal study. NPS were assessed using the Neuropsychiatric Inventory with Caregiver Distress scale (NPI-D). Further neuropsychological and clinical assessments were completed by participants, with reassessment at 18 and 36 months. Linear mixed-effects modelling determined factors associated with NPI-D and QoL over 36 months. RESULTS: Depression, anxiety, apathy and hallucinations were more frequent in PD than controls at all time points (p < 0.05). Higher motor severity at baseline was associated with worsening NPI-D scores over time (ß = 0.1, p < 0.05), but not cognition. A higher NPI total score was associated with poorer QoL at any time point (ß = 0.3, p < 0.001), but not changed in QoL scores. CONCLUSION: NPS are significantly associated with poorer QoL, even in early PD. Screening for NPS from diagnosis may allow efficient delivery of better support and treatment to patients and their families.

The Role of Endobronchial Ultrasound in Early-Stage Non-Small Cell Lung Cancer.

Aim The aim of this study is to assess the impact of EBUS on the concordance of clinical and pathological NSCLC staging in our center. Methods Data was collected retrospectively from the hospital database regarding patients who underwent surgical resection for early stage NSCLC between 2012 and 2017. Results A total of 251 patients were included. The mean age was 67 (±9), 55% (n=137) were male and 83% (n=209) were current/former smokers. In group A (n=154, 61%) clinical nodal stage (cN) was established from a combination of CT, PET CT and mediastinoscopy. Group B underwent additional EBUS (n=97, 39%). cN and pathological nodal staging (pN) were concordant in 78% (n=120) in group A versus 62% (n=60) in group B (p=0.009). Conclusion This study demonstrated higher rates of nodal discordance in patients who underwent EBUS which contrasts existing data that demonstrates improved concordance with EBUS. We describe these findings and potential explanations further in this study.

Safety of percutaneous renal cryoablation: an international multicentre experience from the EuRECA retrospective percutaneous database.

OBJECTIVE: To investigate the safety profile of percutaneous cryoablation of renal tumours < 7 cm, utilising data extracted from an international multicentre registry. MATERIALS AND METHODS: A retrospective review of all immediate and delayed complications from a multicentre database was performed and was categorised according to the Clavien-Dindo classification. Statistical analysis was performed for both overall complications (all Clavien-Dindo) and major complications (Clavien-Dindo 3 to 5). The following criteria were identified as potential predictive factors for complications: centre number, modality of image guidance, tumour size (≤ 4 cm vs. > 4 cm), number of tumours treated in the same session (1 vs. > 1) and tumour histology. RESULTS: A total of 713 renal tumours underwent ablation in 647 individual sessions. In 596 of the cases, one tumour was treated; in the remaining 51 cases, several tumours were treated per session. Mean lesion size was 2.8 cm. Fifty-four complications (Clavien-Dindo 1 to 5) occurred as a result of the 647 procedures, corresponding to an overall complication rate of 8.3%. The most frequent complication was bleeding (3.2%), with 9 cases (1.4%) requiring subsequent treatment. The rate of major complication was 3.4%. The only statistically significant prognostic factor for a major complication was a tumour size > 4 cm. CONCLUSION: Percutaneous renal cryoablation is associated with a low rate of complications. Tumours measuring more than 4 cm are associated with a higher risk of major complications. KEY POINTS: • Percutaneous kidney cryoablation has a low rate of complications. • Bleeding is the most frequent complication. • A tumour size superior to 4 cm is a predictive factor of major complication.

Adaptive statistical iterative reconstruction improves image quality without affecting perfusion CT quantitation in primary colorectal cancer.

OBJECTIVES: To determine the effect of Adaptive Statistical Iterative Reconstruction (ASIR) on perfusion CT (pCT) parameter quantitation and image quality in primary colorectal cancer. METHODS: Prospective observational study. Following institutional review board approval and informed consent, 32 patients with colorectal adenocarcinoma underwent pCT (100 kV, 150 mA, 120 s acquisition, axial mode). Tumour regional blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were determined using identical regions-of-interests for ASIR percentages of 0%, 20%, 40%, 60%, 80% and 100%. Image noise, contrast-to-noise ratio (CNR) and pCT parameters were assessed across ASIR percentages. Coefficients of variation (CV), repeated measures analysis of variance (rANOVA) and Spearman' rank order correlation were performed with statistical significance at 5%. RESULTS: With increasing ASIR percentages, image noise decreased by 33% while CNR increased by 61%; peak tumour CNR was greater than 1.5 with 60% ASIR and above. Mean BF, BV, MTT and PS differed by less than 1.8%, 2.9%, 2.5% and 2.6% across ASIR percentages. CV were 4.9%, 4.2%, 3.3% and 7.9%; rANOVA P values: 0.85, 0.62, 0.02 and 0.81 respectively. CONCLUSIONS: ASIR improves image noise and CNR without altering pCT parameters substantially.

Discontinuation and non-publication of neurodegenerative disease trials: a cross-sectional analysis.

BACKGROUND AND PURPOSE: Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases. METHODS: ClinicalTrials.gov was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease. Publications from these trials were identified by extensive online searching and contact with authors, and multiple logistic regression analysis was performed to identify characteristics associated with trial discontinuation and non-publication. RESULTS: In all, 362 eligible trials were identified, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after 5 years. Trial discontinuation was independently associated with number of patients (P = 0.015; more likely in trials with ≤100 patients; odds ratio 2.65, 95% confidence interval 1.21-5.78) and phase of trial (P = 0.009; more likely in phase IV than phase III trials; odds ratio 3.90, 95% confidence interval 1.41-10.83). Trial non-publication was independently associated with blinding status (P = 0.005; more likely in single-blind than double-blind trials; odds ratio 5.63, 95% confidence interval 1.70-18.71), number of centres (P = 0.010; more likely in single-centre than multi-centre trials; odds ratio 2.49, 95% confidence interval 1.25-4.99), phase of trial (P = 0.041; more likely in phase II than phase IV trials; odds ratio 2.88, 95% confidence interval 1.04-7.93) and sponsor category (P = 0.001; more likely in industry-sponsored than university-sponsored trials; odds ratio 5.05, 95% confidence interval 1.87-13.63). CONCLUSIONS: There is evidence of non-dissemination bias in randomized trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non-publication were similar to findings in other diseases. These biases may distort the therapeutic information available to inform clinical practice.

Imaging appearances at follow-up after image-guided solid-organ abdominal tumour ablation.

The role of minimally invasive, locoregional therapies in cancer is increasingly driven by the detection of small asymptomatic disease either incidentally or under surveillance for a known primary malignancy. Percutaneous image-guided ablation has become established as a parenchyma-sparing tool in the management of small volume primary and metastatic disease in the liver as well as solitary renal masses. As ablation is non-extirpative, post-ablation imaging is critical for the assessment of treatment completion, recurrence, and complications. Within established regional cancer networks, understanding of normal post-ablation imaging appearances is essential for the early identification of primary treatment failure or local recurrence, which may be amenable to repeat treatment. We provide an imaging primer of two common ablation sites - kidney and liver - focusing on normal appearances and appreciation of local disease progression.

Radon testing in rapid access lung clinics: an opportunity for secondary prevention.

BACKGROUND: Radon is a naturally occurring radioactive gas and a level 1 carcinogen. It acts synergistically with cigarette smoke to cause lung cancer. In Ireland, radon is estimated to be associated with 13 % of all lung cancers. Rapid access lung cancer clinics (RALC's) were established in the UK and Ireland to improve lung cancer management outcomes. There has been no attempt to date to provide advice on household radon exposure assessments in this setting. AIMS: We performed a prospective feasibility study of radon assessment in our RALC to test the hypothesis that patients would avail of this service and that it would provide an opportunity for secondary prevention in at risk persons. METHODS: We investigated household radon levels in consecutive patients who were newly referred with symptoms of lung cancer to the RALC in Galway University Hospital, Ireland over a 6-month period. RESULTS: Of 50 patients enrolled, 42 returned valid results. Overall 21 % of patients had radon levels recorded above the national reference level. Only 5 % of patients were aware of the association between radon gas and lung cancer. Smokers were significantly less likely to engage fully in radon testing. CONCLUSIONS: The development of RALC's offers a novel opportunity to integrate the concepts of radon exposure, cigarette smoking and the development of lung cancer, and to reinforce this message in the minds of at risk patients.

Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation.

Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT.

Leprosy: a 'common' and curable cause of peripheral neuropathy with skin lesions.

Leprosy (or Hansen's disease) is a curable chronic infectious disease caused by the acid-fast bacillus Mycobacterium leprae. While leprosy remains one of the most common causes of neuropathy worldwide, its rarity in the UK means that many doctors are unfamiliar with the typical clinical features. This is problematic because early recognition and treatment is vital in order to minimise disease-related complications such as nerve injury. We describe a 75-year-old man who presented with multiple mononeuropathy (mononeuritis multiplex, particularly affecting the ulnar nerves) and typical granulomatous skin lesions, in whom the diagnosis was made on the basis of skin biopsy. We highlight the clinical features, investigations and treatment of the patient, and provide information about the epidemiology and pathogenesis of leprosy.

Predictors of recurrence after radiotherapy for non-melanoma skin cancer.

Predictive factors of recurrence were examined in 448 non-melanoma skin cancers (72% basal cell carcinoma, 28% squamous cell carcinoma) treated with radiotherapy. The overall recurrence rate was 15.8% at a median follow-up of 18.4 months. In multivariate analysis, significant factors for recurrence were age (p = 0.0197), tumour size 2 cm or greater (p = 0.0095), immunosuppression (p = 0.0082), and treatment modality (p = 0.0009).

"Dancing eye syndrome" secondary to opsoclonus-myoclonus syndrome in small-cell lung cancer.

Among paraneoplastic neurologic disorders (PND), opsoclonus-myoclonus syndrome, so-called "dancing eye syndrome," is a rare disorder combining multivectorial eye movements, involuntary multifocal myoclonus, and cerebellar ataxia. Although several paraneoplastic antibodies against postsynaptic or cell-surface antigens have been reported, usually most patients are serum antibody negative. We report a 65-year-old patient with opsoclonus-myoclonus syndrome revealing a small-cell lung carcinoma. If serologic antineuronal anti-body screening was negative, autoantibodies against glutamic acid decarboxylase (anti-GAD) were positive. Despite the specific anticancer treatment and high dose corticosteroids, the patient developed a severe and progressive encephalopathy and died 10 days later.

Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle.

Insulin resistance is associated with mitochondrial dysfunction, but the mechanism by which mitochondria inhibit insulin-stimulated glucose uptake into the cytoplasm is unclear. The mitochondrial permeability transition pore (mPTP) is a protein complex that facilitates the exchange of molecules between the mitochondrial matrix and cytoplasm, and opening of the mPTP occurs in response to physiological stressors that are associated with insulin resistance. In this study, we investigated whether mPTP opening provides a link between mitochondrial dysfunction and insulin resistance by inhibiting the mPTP gatekeeper protein cyclophilin D (CypD) in vivo and in vitro. Mice lacking CypD were protected from high fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle. The mitochondria in CypD knockout muscle were resistant to diet-induced swelling and had improved calcium retention capacity compared to controls; however, no changes were observed in muscle oxidative damage, insulin signaling, lipotoxic lipid accumulation or mitochondrial bioenergetics. In vitro, we tested 4 models of insulin resistance that are linked to mitochondrial dysfunction in cultured skeletal muscle cells including antimycin A, C2-ceramide, ferutinin, and palmitate. In all models, we observed that pharmacological inhibition of mPTP opening with the CypD inhibitor cyclosporin A was sufficient to prevent insulin resistance at the level of insulin-stimulated GLUT4 translocation to the plasma membrane. The protective effects of mPTP inhibition on insulin sensitivity were associated with improved mitochondrial calcium retention capacity but did not involve changes in insulin signaling both in vitro and in vivo. In sum, these data place the mPTP at a critical intersection between alterations in mitochondrial function and insulin resistance in skeletal muscle.

The journey of mesothelioma: from postmortem to FNA.

A 73-year-old man, non-smoker presented with an 8-week history of left-sided chest pain and shortness of breath on exertion. He had no significant medical history. He worked in construction for 40 years, but denied definite asbestos exposure. His initial chest X-ray demonstrated a large left-sided pleural effusion. Subsequent CT thorax revealed circumferential thickening of the pleura with associated pleural plaques and calcification. A provisional diagnosis of mesothelioma was made. Initial ultrasound-guided thoracocentesis revealed a transudate with negative cytology. In addition, thoracoscopy and CT-guided pleural biopsy failed to obtain a definitive diagnosis. A surgical biopsy was planned, but at the time of admission, the patient developed unilateral neck swelling. Ultrasound-guided fine-needle aspiration (FNA) and core biopsies of the lymph node were diagnostic for pleural mesothelioma. Treatment with palliative chemotherapy was planned, but the patient's clinical status rapidly deteriorated and he passed away prior to the beginning of therapy.

Implications for Australian anaesthetists and proceduralists of a recent court decision regarding informed consent and patient positioning.

This article discusses the medicolegal implications of a recent judgment in relation to a patient who suffered significant morbidity as a result of patient positioning during an operative procedure. The patient developed an unexpected serious complication following surgery, in the context of a preoperative consent that did not cover every potential complication or contingency. The court held that the failure to warn of a particular risk that would have prevented the patient from undergoing a procedure but did not occur will not necessarily result in a finding of negligence in relation to another risk where the harm did occur. This finding is well aligned to current clinical practice and at the same time does not abrogate the practitioner's duty to provide a comprehensive list of possible complications during the consent process for any proceduralist. In the context of a procedure requiring anaesthesia, the importance of communication and understanding between the anaesthetist and proceduralist as to which aspects of the consent process are undertaken by whom, and to ensure the process is done comprehensively, is of great importance and is indirectly highlighted by this recent judgment.

Malignant pleural effusion.

Malignant pleural effusion (MPE) refers to the presence of neoplastic cells in the pleural fluid. Approximately 40 000 people per year in the UK are affected by MPE and it is associated with significant morbidity and an overall poor prognosis. Management should be prompt and care plans should be individualized and involve a multidisciplinary team of healthcare professionals. This article reviews the pathophysiology of MPE along with available investigations and management strategies for these patients.