Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach.

AIMS/HYPOTHESIS: Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis. METHODS: Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013-2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument. RESULTS: Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA1c reduction was similar between SGLT2i and DPP4i (-0.3 mmol/mol [-1.6, 1.1], -0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (-4 mmol/mol [4.8, -3.1], -0.4% [-0.4, -0.3]). CONCLUSIONS/INTERPRETATION: Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes.

An implementation of integrated information theory in resting-state fMRI.

Integrated Information Theory was developed to explain and quantify consciousness, arguing that conscious systems consist of elements that are integrated through their causal properties. This study presents an implementation of Integrated Information Theory 3.0, the latest version of this framework, to functional MRI data. Data were acquired from 17 healthy subjects who underwent sedation with propofol, a short-acting anaesthetic. Using the PyPhi software package, we systematically analyze how Φmax, a measure of integrated information, is modulated by the sedative in different resting-state networks. We compare Φmax to other proposed measures of conscious level, including the previous version of integrated information, Granger causality, and correlation-based functional connectivity. Our results indicate that Φmax presents a variety of sedative-induced behaviours for different networks. Notably, changes to Φmax closely reflect changes to subjects' conscious level in the frontoparietal and dorsal attention networks, which are responsible for higher-order cognitive functions. In conclusion, our findings present important insight into different measures of conscious level that will be useful in future implementations to functional MRI and other forms of neuroimaging.

Exploring electroencephalography with a model inspired by quantum mechanics.

An outstanding issue in cognitive neuroscience concerns how the brain is organized across different conditions. For instance, during the resting-state condition, the brain can be clustered into reliable and reproducible networks (e.g., sensory, default, executive networks). Interestingly, the same networks emerge during active conditions in response to various tasks. If similar patterns of neural activity have been found across diverse conditions, and therefore, different underlying processes and experiences of the environment, is the brain organized by a fundamental organizational principle? To test this, we applied mathematical formalisms borrowed from quantum mechanisms to model electroencephalogram (EEG) data. We uncovered a tendency for EEG signals to be localized in anterior regions of the brain during "rest", and more uniformly distributed while engaged in a task (i.e., watching a movie). Moreover, we found analogous values to the Heisenberg uncertainty principle, suggesting a common underlying architecture of human brain activity in resting and task conditions. This underlying architecture manifests itself in the novel constant KBrain, which is extracted from the brain state with the least uncertainty. We would like to state that we are using the mathematics of quantum mechanics, but not claiming that the brain behaves as a quantum object.

α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism.

Oxidative stress and α-synuclein aggregation both drive neurodegeneration in Parkinson's disease, and the protein kinase c-Abl provides a potential amplifying link between these pathogenic factors. Suppressing interactions between these factors may thus be a viable therapeutic approach for this disorder. To evaluate this possibility, pre-formed α-synuclein fibrils (PFFs) were used to induce α-synuclein aggregation in neuronal cultures. Exposure to PFFs induced oxidative stress and c-Abl activation in wild-type neurons. By contrast, α-synuclein - deficient neurons, which cannot form α-synuclein aggregates, failed to exhibit either oxidative stress or c-Abl activation. N-acetyl cysteine, a thiol repletion agent that supports neuronal glutathione metabolism, suppressed the PFF - induced redox stress and c-Abl activation in the wild-type neurons, and likewise suppressed α-synuclein aggregation. Parallel findings were observed in mouse brain: PFF-induced α-synuclein aggregation in the substantia nigra was associated with redox stress, c-Abl activation, and dopaminergic neuronal loss, along with microglial activation and motor impairment, all of which were attenuated with oral N-acetyl cysteine. Similar results were obtained using AAV-mediated α-synuclein overexpression as an alternative means of driving α-synuclein aggregation in vivo. These findings show that α-synuclein aggregates induce c-Abl activation by a redox stress mechanism. c-Abl activation in turn promotes α-synuclein aggregation, in a feed-forward interaction. The capacity of N-acetyl cysteine to interrupt this interaction adds mechanistic support its consideration as a therapeutic in Parkinson's disease.

The Emergence of Integrated Information, Complexity, and 'Consciousness' at Criticality.

Integrated Information Theory (IIT) posits that integrated information ( Φ ) represents the quantity of a conscious experience. Here, the generalized Ising model was used to calculate Φ as a function of temperature in toy models of fully connected neural networks. A Monte-Carlo simulation was run on 159 normalized, random, positively weighted networks analogous to small five-node excitatory neural network motifs. Integrated information generated by this sample of small Ising models was measured across model parameter spaces. It was observed that integrated information, as an order parameter, underwent a phase transition at the critical point in the model. This critical point was demarcated by the peak of the generalized susceptibility (or variance in configuration due to temperature) of integrated information. At this critical point, integrated information was maximally receptive and responsive to perturbations of its own states. The results of this study provide evidence that Φ can capture integrated information in an empirical dataset, and display critical behavior acting as an order parameter from the generalized Ising model.

Technical and Comparative Aspects of Brain Glycogen Metabolism.

It has been known for over 50 years that brain has significant glycogen stores, but the physiological function of this energy reserve remains uncertain. This uncertainty stems in part from several technical challenges inherent in the study of brain glycogen metabolism, and may also stem from some conceptual limitations. Factors presenting technical challenges include low glycogen content in brain, non-homogenous labeling of glycogen by radiotracers, rapid glycogenolysis during postmortem tissue handling, and effects of the stress response on brain glycogen turnover. Here, we briefly review aspects of glycogen structure and metabolism that bear on these technical challenges, and discuss ways these can be overcome. We also highlight physiological aspects of glycogen metabolism that limit the conditions under which glycogen metabolism can be useful or advantageous over glucose metabolism. Comparisons with glycogen metabolism in skeletal muscle provide an additional perspective on potential functions of glycogen in brain.

Hyoid bone fracture: an unrecognised complication of intubation or transoesophageal echocardiogram?

A 55-year-old man sustained a compound hyoid fracture in the perioperative period surrounding coronary artery bypass surgery. The two most likely mechanisms of injury were external laryngeal pressure sustained either during transoesophageal echocardiogram (TOE) or intubation. He was managed operatively and made an uneventful recovery. The procedure that led to the hyoid fracture was not determined. Of note, this has not been previously described as a complication of either procedure.

Predicting lymph node metastases in cutaneous squamous cell carcinoma: use of a morphological scoring system.

BACKGROUND: Predicting which patients will develop nodal metastasis from cutaneous squamous cell carcinoma (cSCC) remains difficult. This study evaluates a recently described histological risk model validated for mucosal head and neck SCC (HNSCC) when applied to cutaneous tumours. In this model, morphologic variables including worst pattern of invasion, lymphocytic host response and perineural invasion were shown to predict disease recurrence, loco regional recurrence and overall survival in mucosal HNSCC. METHODS: Patients with cSCC and known metastatic spread were identified from the author's database over a 5-year period between July 2007 and July 2012. Histology specimens from the original primary tumour were separately analysed by 2 histopathologists. Scores were compared against T-Stage matched control specimens without metastatic spread. RESULTS: 27 patients with metastatic cSCC were identified. Scores for worst pattern of invasion (WPOI) were significantly higher in individuals with lymph node metastases (p=0.02). CONCLUSIONS: Adverse pattern of invasion, defined as presence of small tumour islands or tumour satellites may be an independent risk factor for developing nodal metastases in cSCC. These tumours are difficult to investigate histopathologically as it is difficult to be confident the correct primary is chosen for study.

Airway complications of pediatric extracorporeal membrane oxygenation.

OBJECTIVES: Prolonged intubation is a risk factor for the development of laryngotracheal stenosis. Children who undergo extracorporeal membrane oxygenation (ECMO) usually remain intubated for an extended period. It is unclear whether the impaired cardiorespiratory status that necessitated ECMO places these children at a higher risk of laryngotracheal stenosis. This study was performed to assess the incidences of laryngotracheal stenosis and tracheostomy in children who undergo ECMO. METHODS: We identified all patients under 18 years of age who underwent ECMO over a 10-year period concluding July 1, 2009, by use of the extracorporeal life support database of Royal Children's Hospital, Melbourne. All children in this database who underwent either a diagnostic or a therapeutic surgical procedure on the airway were identified. RESULTS: The 218 patients included in the study had an overall survival rate of 51.4%. A total of 14 patients (6.4%) required a surgical procedure on the airway, and 11 of these (5.0%) needed tracheostomy. Ten of these 14 patients (71.4%) survived; of these, 2 presented with congenital laryngotracheal stenosis, 3 developed clinically significant laryngotracheal stenosis as a likely consequence of ECMO, and 5 required tracheostomy alone for long-term ventilation. The rate of airway stenosis was 2.7% in survivors. CONCLUSIONS: The rate of laryngotracheal stenosis in children who require ECMO is acceptably low.

Hoarseness - what is the voice trying to tell you?

BACKGROUND: Most episodes of hoarseness are benign and self limiting. METHODS: This article describes the causes and management of hoarseness in adults, outlines the features of common causes of voice disturbance in adults, and highlights a number of red flags that should trigger urgent referral. DISCUSSION: Patients with hoarseness lasting more than 3 weeks require specialist assessment to visualise the larynx.

Association between the coronary artery disease risk locus on chromosome 9p21.3 and abdominal aortic aneurysm.

BACKGROUND: Recent genome-wide studies have shown a significant association of a locus on chromosome 9p21.3 and coronary artery disease. We performed a case-control study to investigate the association between this locus and abdominal aortic aneurysm (AAA). METHODS AND RESULTS: A total of 1714 patients (899 patients with AAA and 815 controls) were genotyped for the lead single-nucleotide polymorphism, rs1333049, on chromosome 9p21. The frequency of the C (risk) allele of rs1333049 in the control group was 0.471. There was a significant association between the C allele and AAA (odds ratio, 1.22; 95% confidence interval, 1.06 to 1.39; P=0.004). The genotypic-specific odds ratios (compared with the GG genotype) were 1.17 (95% confidence interval, 0.93 to 1.47; P=0.191) for the GC genotype and 1.50 (95% confidence interval, 1.14 to 1.97; P=0.004) for the CC genotype. In logistic regression modeling, the association of the CC genotype with AAA was independent of the presence of clinical coronary artery disease (odds ratio, 1.46; 95% confidence interval, 1.11 to 1.94; P=0.008). CONCLUSIONS: Our study shows that the recently identified chromosome 9 variant that increases risk of coronary artery disease is also associated with the presence of AAA. The findings suggest that the effect of this locus on risk of cardiovascular disease extends beyond the coronary circulation.

The interleukin-10-1082 'A' allele and abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysms (AAA) are caused by inflammatory processes in the wall of the aorta resulting in degradation of structural proteins. This inflammatory process is mediated, in part, by cytokines, and interleukin-10 (IL-10) is a predominantly anti-inflammatory cytokine. A single nucleotide polymorphism in the promoter region of the IL-10 gene that affects transcription has been associated with AAA in a small study. The aim of this study was to determine whether this polymorphism is associated with AAA and also examine its effect on the growth of small AAA. METHODS AND RESULTS: A case control study was performed. A total of 389 patients with AAA and 404 healthy controls were recruited. IL-10-1082 polymorphisms were determined by polymerase chain reaction-based methods. In the case of patients with small AAA (<5.5 cm), serial size measurements were recorded to determine mean growth rate. There was a statistically significant difference both in allele and genotype frequencies between the case and control groups with the IL-10-1082 'A' allele being more common in the AAA group (P = .006). In the AAA group, genotype frequencies were as follows: GG 84, GA 201, and AA 104. In the control group, the genotype frequencies were GG 118, GA 205, and AA 81. The odds ratio for the 'A' allele as a risk factor for AAA was 1.50 (95% confidence interval 1.09 to 2.07). Regression modeling revealed that the IL-10-1082 genotype was, however, not independently associated with AAA if age, tobacco use, hypertension, and history of coronary or peripheral artery disease was taken into account. There was a trend towards lower plasma IL-10 level in IL-10 AA carriers, but the IL-10 'A' allele did not have any discernible effect on the growth of small AAA. CONCLUSIONS: This study demonstrates that the IL-10-1082 'A' allele is associated with AAA, although this association is likely to be secondary to an association between IL-10-1082 genotype and other markers of cardiovascular disease rather than AAA per se.

Functional outcomes following total laryngopharyngectomy.

BACKGROUND: Despite increasing use of laryngeal preserving protocols, laryngopharyngectomy remains the gold standard treatment for locally advanced hypopharyngeal and upper oesophageal tumours and for salvage following failed chemoradiotherapy. Nevertheless, improved perioperative medical care and experience in reconstruction have reduced mortality and improved functional outcomes. METHODS: All patients undergoing total laryngopharyngectomy between July 2001 and July 2006 were prospectively recorded in a head and neck database. Demographics and functional outcomes were recorded. RESULTS: Eighteen patients underwent laryngopharyngectomies with 5 having failed chemoradiotherapy and 13 presented with locally advanced tumours. Patients were reconstructed using free jejunal interposition if the lower anastomosis was in the neck (50%). They developed early fistulas (33%), late strictures (33%) and 44% spoke with a tracheo-oesophageal puncture, the rest with an electrolarynx. If the lower anastomosis was below the manubrium, patients required a gastric pull-up (38.9%). Gastric pull-up patients had fewer fistulas but more number of chest complications. More gastric pull-up patients tolerated solid diet and 43% managed oesophageal speech, the remainder using an electrolarynx. Overall, 88.9% of jejunums and 100% of gastric pull-ups tolerated oral alimentation and 100% used verbal communication. During a mean follow up of 34 months, 7 patients (38.9%) died; four patients died of local recurrence, two of distant metastases and one of unrelated causes. CONCLUSION: Surgical treatment of neoplasms of the hypopharynx and cervical oesophagus is technically demanding and involves careful postoperative care to manage complications. Despite having a poor tumour-related prognosis, laryngopharyngectomy may be carried out in selected patients with low mortality and acceptable functional and survival results.

The value of urgent carotid surgery for crescendo transient ischemic attacks.

OBJECTIVE: This study audited operative risk in patients undergoing urgent carotid surgery for crescendo transient ischemic attacks (TIAs). METHODS: Interrogation of the vascular unit database (January 1992 to July 2004) identified 42 patients operated on urgently for crescendo TIAs, which were defined as>or=3 TIAs within the preceding 7 days. Stroke, death, and any major cardiac events were analyzed. RESULTS: Thirty-nine patients underwent conventional endarterectomy, and three underwent interposition vein bypass. Crescendo TIA patients had sustained a median of five TIAs (range, 3 to 20) in the 7 days before surgery. Three patients died or had a stroke after surgery, for a combined stroke/death rate of 7%. This compares with 2.4% in 1000 patients undergoing elective carotid endarterectomy in this unit during the same time period. The combined stroke/death/major cardiac event rate was 14% (n=6). CONCLUSIONS: The combined risk of neurologic and cardiac complications after urgent carotid surgery for crescendo TIA is higher than that expected after elective cases but is still acceptable considering the natural history of patients with unstable neurologic symptoms.

Subintimal recanalization of the femoropopliteal segment to promote healing of an ulcerated below-knee amputation stump.

PURPOSE: To describe the use of the subintimal technique to revascularize an ulcerated below-knee amputation stump. CASE REPORT: A 64-year-old man with persistent ulceration of a below-knee amputation stump underwent attempted percutaneous revascularization. Via antegrade puncture, the femoropopliteal occlusion was recanalized subintimally and eventually opened into a large medial geniculate collateral branch, improving the stump flow. The procedure was uneventful, and at 6 months, the patient was pain-free and able to mobilize with his prosthetic limb. CONCLUSION: Subintimal revascularization of a critically-ischemic below-knee amputation stump may be a useful option and should be considered in clinical situations like this.

Simultaneous superficial venous surgery and on-table subintimal angioplasty in the treatment of venous leg ulcers with arterial compromise.

PURPOSE: To determine the feasibility of synchronous superficial venous surgery and on-table subintimal angioplasty in the treatment of venous ulcers with arterial compromise. METHODS: Between January 1992 and December 2004, 9 patients (8 women; median age 83 years, range 72-92) underwent the synchronous procedure. No patient had deep venous reflux; 4 patients presented with rest pain and 2 were diabetic. Their medical records were retrospectively reviewed to gather data on clinical assessment, ankle-brachial index (ABI), lower limb arterial and venous duplex scans, and treatment variables. RESULTS: Angioplasty was technically successful (median ABI improvement 0.31, range 0.23-0.34) in all procedures, which lasted a median 85 minutes (range 60-160). The procedure was performed under general anesthesia in 7 patients, local in 1, and spinal in 1. Superficial venous surgery was performed first in 8 patients: 6 had great saphenous vein (GSV) ligation without stripping, followed by subintimal angioplasty, and 1 also had small saphenous vein (SSV) ligation. One patient underwent SSV ligation first, followed by angioplasty; another had GSV disconnection and stripping, followed by angioplasty. In 1 patient, angioplasty preceded GSV surgery. One patient required repeat angioplasty 1 week later for re-occlusion. All ulcers healed (median 4 months, range 1-36). Five patients died during a median 32-month follow-up (range 4-82) from unrelated causes; there was 1 ulcer recurrence at 3 years in a patient who declined further investigation and treatment. CONCLUSIONS: Simultaneous superficial venous surgery and on-table subintimal angioplasty is a safe and novel strategy in the management of a select subgroup of patients with venous ulcers and coexistent arterial compromise.

Does carotid endarterectomy lead to a decline in cognitive function or health related quality of life?

Carotid endarterectomy has been shown to reduce the long-term risk of stroke in selected patients. The present study was designed to examine cognitive function and health related quality of life in a series of carotid endarterectomy patients. One hundred and nine patients undergoing carotid endarterectomy were assessed before surgery and at 6 months post op (n = 100) on standard cognitive function tests and quality of life surveys. Microembolisation was detected using transcranial Doppler ultrasonography. Multivariate repeated measures analysis if variance identified evidences of significant impairments on some tests. Further analysis revealed that particulate Microembolisation detected during the procedure was a significant risk factor associated with declining cognitive function. Patients' self-reported health related quality of life had not deteriorated at 6 month following surgery.