The Genetics of Brugada Syndrome.

Brugada syndrome is a heritable channelopathy characterized by a peculiar electrocardiogram (ECG) pattern and increased risk of cardiac arrhythmias and sudden death. The arrhythmias originate because of an imbalance between the repolarizing and depolarizing currents that modulate the cardiac action potential. Even if an overt structural cardiomyopathy is not typical of Brugada syndrome, fibrosis and structural changes in the right ventricle contribute to a conduction slowing, which ultimately facilitates ventricular arrhythmias. Currently, Mendelian autosomal dominant transmission is detected in less than 25% of all clinical confirmed cases. Although 23 genes have been associated with the condition, only SCN5A, encoding the cardiac sodium channel, is considered clinically actionable and disease causing. The limited monogenic inheritance has pointed toward new perspectives on the possible complex genetic architecture of the disease, involving polygenic inheritance and a polygenic risk score that can influence penetrance and risk stratification.

Metformin inhibits paclitaxel-induced mechanical allodynia by activating opioidergic pathways and reducing cytokines production in the dorsal root ganglia and thalamus.

It has been shown that AMP-activated protein kinase (AMPK) is involved in the nociceptive processing. This observation has prompted us to investigate the effects of the AMPK activator metformin on the paclitaxel-induced mechanical allodynia, a well-established model of neuropathic pain. Mechanical allodynia was induced by four intraperitoneal (i.p) injections of paclitaxel (2 mg/kg.day) in mice. Metformin was administered per os (p.o.). Naltrexoneandglibenclamide were used to investigate mechanisms mediating metformin activity. Concentrations of cytokines in the dorsal root ganglia (DRG) and thalamus were determined. After a single p.o. administration, the two highest doses of metformin (500 and 1000 mg/kg) attenuated the mechanical allodynia. This response was attenuated by all doses of metformin (250, 500 and 1000 mg/kg) when two administrations, 2 h apart, were carried out. Naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, p.o.), attenuated metformin activity. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and CXCL-1 in the DRG were increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentrations of TNF-α, IL-1ß and CXCL-1 in the DRG. Concentration of IL-6, but not TNF-α, in the thalamus was increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentration of IL-6 in the thalamus. In summary, metformin exhibits activity in the model of neuropathic pain induced by paclitaxel. This activity may be mediated by activation of opioidergic pathways and reduced production of TNF-α, IL-1ß and CXCL-1 in the DRG and IL-6 in the thalamus.

Molecular Flexibility in Solvated Crystals of the Dimer, Au2(µ-1,2-bis(diphenylphosphino)ethane)2I2, with Three-Coordinate Gold(I).

We report the ability to trap the dimer Au2(µ-dppe)2I2 (dppe is 1,2-bis(diphenylphosphino)ethane) with different separations between the three-coordinate gold ions in crystalline solvates. All of these solvates ((Au2(µ-dppe)2I2·4(CH2Cl2) (1), Au2(µ-dppe)2I2·2(CH2Cl2) (2), the polymorphs α-Au2(µ-dppe)2I2·2(HC(O)NMe2) (3) and ß-Au2(µ-dppe)2I2·2(HC(O)NMe2) (4), and Au2(µ-dppe)2I2·4(CHCl3) (5)) along with polymeric {Au(µ-dppe)I}n·n(CHCl3) (6)) originated from the same reaction, only the solvent system used for crystallization differed. In the different solvates of Au2(µ-dppe)2I2, the Au···Au separation varied from 3.192(1) to 3.7866(3) Å. Computational studies undertaken to understand the flexible nature of these dimers indicated that the structural differences were primarily a result of crystal packing effects with aurophillic interactions having a minimal effect.

Time-resolved fluorescence and diffuse reflectance for lung squamous carcinoma margin detection.

OBJECTIVES: A major challenge in non-small cell lung cancer surgery is the occurrence of positive tumor margins. This may lead to the need for additional surgeries and has been linked to poor patient prognosis. This study aims to develop an in vivo surgical tool that can differentiate cancerous from noncancerous lung tissue at the margin. METHODS: A time-resolved fluorescence and diffuse reflectance bimodal device was used to measure the lifetime, spectra, and intensities of endogenous fluorophores as well as optical properties of lung tissue. The tumor and fibrotic tissue data, each containing 36 samples, was obtained from patients who underwent surgical removal of lung tissue after being diagnosed with squamous carcinoma but before any other treatment was administered. The normal lung tissue data were obtained from nine normal tissue samples. RESULTS: The results show a statistically significant difference between cancerous and noncancerous tissue. The results also show a difference in metabolic related optical properties between fibrotic and normal lung tissue samples. CONCLUSIONS: This work demonstrates the feasibility of a device that can differentiate cancerous and noncancerous lung tissue for patients diagnosed with squamous cell carcinoma.

Programmed Ventricular Stimulation as an Additional Primary Prevention Risk Stratification Tool in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Study.

BACKGROUND: A novel risk calculator based on clinical characteristics and noninvasive tests that predicts the onset of clinical sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been proposed and validated by recent studies. It remains unknown whether programmed ventricular stimulation (PVS) provides additional prognostic value. METHODS: All patients with a definite ARVC diagnosis, no history of sustained VAs at diagnosis, and PVS performed at baseline were extracted from 6 international ARVC registries. The calculator-predicted risk for sustained VA (sustained or implantable cardioverter defibrillator treated ventricular tachycardia [VT] or fibrillation, [aborted] sudden cardiac arrest) was assessed in all patients. Independent and combined performance of the risk calculator and PVS on sustained VA were assessed during a 5-year follow-up period. RESULTS: Two hundred eighty-eight patients (41.0±14.5 years, 55.9% male, right ventricular ejection fraction 42.5±11.1%) were enrolled. At PVS, 137 (47.6%) patients had inducible ventricular tachycardia. During a median of 5.31 [2.89-10.17] years of follow-up, 83 (60.6%) patients with a positive PVS and 37 (24.5%) with a negative PVS experienced sustained VA (P<0.001). Inducible ventricular tachycardia predicted clinical sustained VA during the 5-year follow-up and remained an independent predictor after accounting for the calculator-predicted risk (HR, 2.52 [1.58-4.02]; P<0.001). Compared with ARVC risk calculator predictions in isolation (C-statistic 0.72), addition of PVS inducibility showed improved prediction of VA events (C-statistic 0.75; log-likelihood ratio for nested models, P<0.001). PVS inducibility had a 76% [67-84] sensitivity and 68% [61-74] specificity, corresponding to log-likelihood ratios of 2.3 and 0.36 for inducible (likelihood ratio+) and noninducible (likelihood ratio-) patients, respectively. In patients with a ARVC risk calculator-predicted risk of clinical VA events <25% during 5 years (ie, low/intermediate subgroup), PVS had a 92.6% negative predictive value. CONCLUSIONS: PVS significantly improved risk stratification above and beyond the calculator-predicted risk of VA in a primary prevention cohort of patients with ARVC, mainly for patients considered to be at low and intermediate risk by the clinical risk calculator.

Structure and Luminescence Studies of Salts of the Helical Dication, [Au2(µ-bis(diphenylphosphine)ethane)2]2+ and Comparison with Salts of [Au2(µ-bis(diphenylphosphine)propane)2]2.

Six salts ([Au2(µ-dppe)2](BF4)2·CHCl3, [Au2(µ-dppe)2](BF4)2·1,2-Cl2C2H4, [Au2(µ-dppe)2](PF6)2·CHCl3, [Au2(µ-dppe)2](PF6)2, [Au2(µ-dppe)2](SbF6)2, and [Au2(µ-dppe)2](OTf)2·2CHCl3), (dppe is bis(diphenylphosphine)ethane) containing the dication, [Au2(µ-dppe)2]2+, have been prepared and structurally characterized by single-crystal X-ray crystallography. Unlike the three-coordinate dppe-bridged dimers, Au2X2(µ-dppe)2 (X = Br, I), which show considerable variation in the distance between the gold(I) ions over the range 3.0995(10) to 3.8479(3) Å in various solvates, the structure of the helical dication, [Au2(µ-dppe)2], in the new salts is remarkably consistent with the Au···Au separation falling in the narrow range 2.8787(9) to 2.9593(5) Å. In the solid state, the six crystals display a green luminescence both at room temperature and at 77 K, which has been assigned as phosphorescence. However, solutions of the dication are not luminescent. Salts containing the analogous dication [Au2(µ-dppp)2](PF6)2 (dppp is bis(diphenylphosphine)propane) have been prepared to determine whether the longer bridging ligand might also twist into a helical shape. These salts include [Au2(µ-dppp)2](OTf)2 (OTf is triflate) and three crystalline forms of [Au2(µ-dppp)2](PF6)2: the solvate [Au2(µ-dppp)2](PF6)2·(CHCl3) and two polymorphs of the unsolvated salt. None of these crystals are luminescent, but all contain a similar dication, [Au2(µ-dppp)2]2+, that contains two nearly parallel, linear P-Au-P groups and a long separation between the gold ions that varies from 5.3409(4) to 5.6613(6)Å.

Self-Assembled Encapsulation of CuX2- (X = Br, Cl) in a Gold Phosphine Box-like Cavity with Metallophilic Au-Cu Interactions.

Synthetic routes to the crystallization of two new box-like complexes, [Au6(Triphos)4(CuBr2)](OTf)5·(CH2Cl2)3·(CH3OH)3·(H2O)4 (1) and [Au6(Triphos)4 (CuCl2)](PF6)5·(CH2Cl2)4 (2) (triphos = bis(2-diphenylphosphinoethyl)phenylphosphine), have been developed. The two centrosymmetric cationic complexes have been structurally characterized through single-crystal X-ray diffraction and shown to contain a CuX2- (X = Br or Cl) unit suspended between two Au(I) centers without the involvement of bridging ligands. These colorless crystals display green luminescence (λem = 527 nm) for (1) and teal luminescence (λem = 464 nm) for (2). Computational results document the metallophilic interactions that are involved in positioning the Cu(I) center between the two Au(I) ions and in the luminescence.

Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study.

AIMS: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. METHODS AND RESULTS: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. CONCLUSIONS: We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy.

Evaluation of Influence of Arthroscopy on the Range of Mandibular Movements Based on Medical Records.

The Temporomandibular Joint Dysfunction Syndrome (TJDS) is a group of pathologies that affect the temporomandibular joint, mastication muscles, and attached structures, 1 of the leading causes of orofacial pain. Arthroscopy is a technique used as a method of treatment for TJSD. This was a retrospective cohort study, and data were collected from the medical records of patients with TJDS. The diagnosis of TJDS was established based on computed tomography and nuclear magnetic resonance imaging tests, and clinical examination. All patients, who underwent arthroscopy, were operated on by the same surgeon in 2020. The variables analyzed in this study were: maximum mouth opening, laterality, and protrusion of patients undergoing arthroscopy at time intervals of 30, 90 days, and 6 months after surgery. Data from anamnesis of the medical records and findings on clinical examination were used to verify whether there was any correlation with good postoperative evolution. Afterward, these data were compared and submitted to statistical analysis (Wilcoxon (nonparametric and paired) and Mann-Whitney (nonparametric, unpaired) tests) to verify the degree of correlation between them. It could be concluded that in this sample, arthroscopy reduced the degree of pain in patients, increased mouth opening amplitude, and did not influence laterality and protrusion. The use of previous medication was correlated with a slight decrease in postoperative pain; patients who had undergone previous orthodontic treatment showed better results regarding maximum mouth opening without pain; patients who had previously felt pain on professional palpation had greater maximum mouth opening with and without pain after arthroscopy, and patients with noise at professional auscultation had greater maximum mouth opening without pain. Further studies should be conducted, with larger samples, associated with complementary exams (computed tomography and nuclear magnetic resonance) before and after arthroscopy.

Serotonin and Interleukin 10 Can Influence the Blood and Urine Viscosity in Gestational Diabetes Mellitus and Pregnancy-Specific Urinary Incontinence.

Serotonin and interleukin 10 (IL-10) may play a role in gestational diabetes mellitus. Hyperglycemic environment, the detrusor musculature of the bladder and pelvic floor muscles may become damaged, leading to urination problems and urine viscosity in pregnant women with gestational diabetes mellitus and pregnancy-specific urinary incontinence. Urine and blood samples were collected from pregnant women between 24 and 28 weeks of gestation. The serotonin concentration and cytokine IL-10 levels were evaluated in plasma and urine. In the total blood and urine, the viscosity was evaluated in the presence and absence of exogenous serotonin and IL-10. The plasma serotonin levels decreased, while the urine serotonin levels increased in the normoglycemic incontinent (NG-I), hyperglycemic continent (GDM-C), and hyperglycemic incontinent (GDM-I) groups. The IL-10 in the plasma decreased in the GDM-I group and was higher in the urine in the NG-I and GDM-I groups. The blood viscosity was higher, independently of urinary incontinence, in the GDM groups. The serotonin increased the blood viscosity from women with GDM-C and urine in the NG-I, GDM-C, and GDM-I groups. Blood and urine in the presence of IL-10 showed a similar viscosity in all groups studied. Also, no difference was observed in the viscosity in either the blood or urine when in the presence of serotonin and IL-10. These findings suggest that serotonin and IL-10 have the potential to reduce blood viscosity in pregnant women with gestational diabetes and specific urinary incontinence, maintaining values similar to those in normoglycemic women's blood.

Viability of ex-vivo myography as a diagnostic tool for rectus abdominis muscle electrical activity collected at Cesarean section within a diamater cohort study.

BACKGROUND: Ex-vivo myography enables the assessment of muscle electrical activity response. This study explored the viability of determining the physiological responses in muscles without tendon, as rectus abdominis muscle (RAM), through ex-vivo myography to assess its potential as a diagnostic tool. RESULTS: All tested RAM samples (five different samples) show patterns of electrical activity. A positive response was observed in 100% of the programmed stimulation. RAM 3 showed greater weight (0.47 g), length (1.66 cm), and width (0.77 cm) compared to RAM 1, RAM 2, RAM 4 and RAM 5 with more sustained electrical activity over time, a higher percentage of fatigue was analyzed at half the time of the electrical activity. The order of electrical activity (Mn) was RAM 3 > RAM 5 > RAM 1 > RAM 4 > RAM 2. No electrical activity was recorded in the Sham group. CONCLUSIONS: This study shows that it is feasible to assess the physiological responses of striated muscle without tendon as RAM, obtained at C-section, under ex vivo myography. These results could be recorded, properly analyzed, and demonstrated its potential as a diagnostic tool for rectus abdominis muscle electrical activity.

RI75, a curcumin analogue, inhibits tumor necrosis factor-α and interleukin-6 production and exhibits antiallodynic and antiedematogenic activities in mice.

Curcumin and its analogues exhibited anti-inflammatory activity in different experimental models. Recently, we synthesized (2E,3E)-3-buten-2-one-4-(4-hydroxy-3-methoxyphenyl)-2-(4-(4-methoxyphenyl)-2-thiazolyl)hydrazone (RI75), a curcumin analogue with a thiazolyl hydrazone moiety. In the present study, we investigated the effects induced by RI75 in different models of inflammation and pain in mice, as well as some underlying mechanisms. Pre-treatment with RI75 (40 mg/kg, intraperitoneal; i.p.) or curcumin (40 mg/kg, i.p.) reduced the mechanical allodynia and paw edema induced by intraplantar (i.pl) injection of carrageenan. RI75 antiallodynic activity was reduced by pre-treatment with naltrexone (5 and 10 mg/kg, i.p.) and cyproheptadine (10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, i.p.). In a model of neuropathic pain, a single i.p. administration of RI75 (40 mg/kg) or curcumin (40 mg/kg) attenuated the ongoing mechanical allodynia induced by repeated administrations of paclitaxel. Pre-treatment with RI75 (40 mg/kg, i.p.) or curcumin (40 mg/kg, i.p.) also reduced tumor necrosis factor-α and interleukin-6 production and myeloperoxidase activity induced by carrageenan. The results of the present study demonstrate that RI75, a synthetic curcumin analogue, exhibits antiallodynic and antiedematogenic activities. Activation of opioidergic and serotonergic mechanisms and reduced production of inflammatory mediators and neutrophil recruitment may underlie RI75 activities.

Metformin effect in models of inflammation is associated with activation of ATP-dependent potassium channels and inhibition of tumor necrosis factor-α production.

Metformin is an oral hypoglycemic drug widely used in the management of type 2 diabetes mellitus. We have recently demonstrated that metformin exhibits activity in models of nociceptive and neuropathic pain. However, little is known about its effects in experimental models of inflammation and inflammatory pain. Thus, the present study aimed to evaluate the activity of metformin in experimental models of inflammation and inflammatory pain in mice, as well as the underlying mechanisms. Previous (1 h) per os (p.o.) administration of metformin (250, 500 or 1000 mg/kg) inhibited the mechanical allodynia and paw edema induced by intraplantar (i.pl.) injection of carrageenan (600 µg) and also the pleurisy induced by this stimulus (200 µg, intrapleural). In the model of mechanical allodynia and paw edema induced by carrageenan, metformin also exhibited activity when administered after (1 h) the inflammatory stimulus. Metformin (1000 mg/kg) reduced the production of tumor necrosis factor-α induced by i.pl. injection of carrageenan. Metformin antiallodynic effect was not affected by previous administration of naltrexone (5 or 10 mg/kg, intraperitoneal) or cyproheptadine (5 or 10 mg/kg, p.o). However, this effect was abolished by previous administration of glibenclamide (20 or 40 mg/kg, p.o). In conclusion, the results demonstrate the activity of metformin in models of inflammation and inflammatory pain. In addition, the results indicate that the activity of metformin may be mediated by activation of ATP-sensitive potassium channels and reduction of production of inflammatory mediators. Altogether, these results stimulate the conduction of studies aiming to evaluate whether metformin may be repositioned in the treatment of patients with painful and inflammatory disorders.

Thiamine, riboflavin, and nicotinamide inhibit paclitaxel-induced allodynia by reducing TNF-α and CXCL-1 in dorsal root ganglia and thalamus and activating ATP-sensitive potassium channels.

Some B vitamins exhibit activities in models of nociceptive pain, inflammatory pain, and neuropathic pain induced by nerve lesions and also in certain painful conditions in humans. In the present study, we investigated the effects of thiamine, riboflavin, and nicotinamide in a neuropathic pain model induced by the chemotherapeutic paclitaxel in mice. Four intraperitoneal (i.p.) administrations of paclitaxel (2 mg/kg day, cumulative dose 8 mg/kg) induced a long-lasting mechanical allodynia. Per os (p.o.) administration of two doses of thiamine (150, 300 and 600 mg/kg), nicotinamide (250, 500 and 1000 mg/kg) or riboflavin (125, 250 and 500 mg/kg), on the seventh day after the first administration of paclitaxel, the mechanical allodynia was attenuated. The antinociceptive activity of all B vitamins was attenuated by glibenclamide (20 and 10 mg/kg, p.o.). Naltrexone (5 and 10 mg/kg, i.p.) attenuated the antinociceptive activity of thiamine. Thiamine, riboflavin, and nicotinamide also reduced the concentrations of tumor necrosis factor-α (TNF-α) and CXCL-1 in dorsal root ganglia (DRG) and thalamus. In conclusion, thiamine, riboflavin, and nicotinamide exhibit antinociceptive activity in the neuropathic pain model induced by paclitaxel. Inhibition of TNF-α and CXCL-1 production in DRG and thalamus, as well as activation of ATP-sensitive potassium channels, underly their antinociceptive activity.

Clindamycin inhibits nociceptive response by reducing tumor necrosis factor-α and CXCL-1 production and activating opioidergic mechanisms.

Clindamycin, a bacteriostatic semisynthetic lincosamide, is useful in the management of infections caused by aerobic and anaerobic Gram-positive cocci, including bacteremic pneumonia, streptococcal toxic shock syndrome and sepsis. It has been recently demonstrated that clindamycin inhibits in vitro and in vivo inflammatory cytokine production. In the present study, we investigated the effects of clindamycin in acute and chronic models of pain and inflammation in mice and the underlying mechanisms. Intraperitoneal (i.p.) administration of clindamycin (400 mg/kg) increased the animal's latency to exhibit the nociceptive behavior induced by noxious heat (hot plate model). Intrathecal injection of clindamycin (2, 10 and 50 µg) also increased the animals' latency to exhibit the nociceptive behavior. Tactile hypersensitivity and paw edema induced by intraplantar (i.pl.) injection of carrageenan were attenuated by previous administration of clindamycin (200 and 400 mg/kg, i.p.). Clindamycin (100, 200 and 400 mg/kg, i.p.) also attenuated ongoing tactile hypersensitivity and paw edema induced by i.pl. injection of complete Freund's adjuvant (CFA). The antinociceptive activity of clindamycin (400 mg/kg, i.p.) in the hot plate model was attenuated by previous administration of naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide or AM251. CFA-induced production of TNF-α and CXCL-1 was reduced by clindamycin (400 mg/kg, i.p.). Concluding, clindamycin exhibits activities in acute and chronic models of pain and inflammation. These effects are associated with reduced production of TNF-α and CXCL-1 and activation of opioidergic mechanisms. Altogether, these results indicate that the clindamycin's immunomodulatory effects may contribute to a pharmacological potential beyond its antibiotic property.

Public perspectives on disinvestments in drug funding: results from a Canadian deliberative public engagement event on cancer drugs.

BACKGROUND: Decisions relating to the funding of new drugs are becoming increasingly challenging due to a combination of aging populations, rapidly increasing list prices, and greater numbers of drug-indication pairs being brought to market. This is especially true in cancer, where rapid list price inflation is coupled with steeply rising numbers of incident cancer cases. Within a publicly funded health care system, there is increasing recognition that resource allocation decisions should consider the reassessment of, and potential disinvestment from, currently funded interventions alongside new investments. Public input into the decision-making process can help legitimize the outcomes and ensure priority-setting processes are aligned with public priorities. METHODS: In September 2014, a public deliberation event was held in Vancouver, Canada, to obtain public input on the topic of cancer drug funding. Twenty-four members of the general public were tasked with making collective recommendations for policy-makers about the principles that should guide funding decisions for cancer drugs in the province of British Columbia. Deliberative questions and decision aids were used to elicit individuals' willingness to make trade-offs between expenditures and health outcomes. RESULTS: Participants discussed the implications of disinvestment decisions from cancer drugs in terms of its impact on patient choice, fairness and quality of life. Their discussions indicate that in order for a decision to disinvest from currently-funded cancer drugs to be acceptable, it must align with three main principles: the decision must be accompanied by significant gains, described both in terms of cost savings and opportunities to re-invest elsewhere in the health care system; those who are currently prescribed a cancer drug should be allowed to continue their course of treatment (referred to as a continuance clause, or "grandfathering" approach); and it must consider how access to care for specialized populations is impacted. CONCLUSIONS: The results from this deliberation event provide insight into what is acceptable to British Columbians with respect to disinvestment decisions for cancer drugs. These recommendations can be considered within wider health system decision-making frameworks for funding decisions relating to all drugs, as well as for cancer drugs.

Trade-offs, fairness, and funding for cancer drugs: key findings from a deliberative public engagement event in British Columbia, Canada.

BACKGROUND: Spending on cancer drugs has risen dramatically in recent years compared to other areas of health care, due in part to higher prices associated with newly approved drugs and increased demand for these drugs. Addressing this situation requires making difficult trade-offs between cost, harms, and ability to benefit when using public resources, making it important for policy makers to have input from many people affected by the issue, including citizens. METHODS: In September 2014, a deliberative public engagement event was conducted in Vancouver, British Columbia (BC), on the topic of priority setting and costly cancer drugs. The aim of the study was to gain citizens' input on the topic and have them generate recommendations that could inform cancer drug funding decisions in BC. A market research company was engaged to recruit members of the BC general public to deliberate over two weekends (four days) on how best to allocate resources for expensive cancer treatments. Participants were stratified based on the 2006 census data for BC. Participants were asked to discuss disinvestment, intravenous versus oral chemotherapy delivery, and decision governance. All sessions were audio recorded and transcribed. Transcripts were analyzed using NVivo 11 software. RESULTS: Twenty-four individuals participated in the event and generated 30 recommendations. Participants accepted the principle of resource scarcity and the need of governments to make difficult trade-offs when allocating health-care resources. They supported the view that cost-benefit thresholds must be set for high-cost drugs. They also expected reasonable health benefits in return for large expenditures, and supported the view that some drugs do not merit funding. Participants also wanted drug funding decisions to be made in a non-partisan and transparent way. CONCLUSION: The recommendations from the Vancouver deliberation can provide guidance to policy makers in BC and may be useful in challenging pricing by pharmaceutical companies.

Difficulties of familes in caring for children and adolescents with mental disorders: an integrative review.

Objective To identify the difficulties of families with children and/or adolescents with mental disorder. Method This is an integrative review. In December 2013, an electronic search was performed on Latin American Caribbean Literature on Health Sciences databases (LILACS) and on Electronic Medicus Index of the National Library of Medicine (MEDLINE) indexed in the Health Virtual Library (BVS) using a combination of descriptors and boolean operators as follows: mental disorders and child or adolescent and caregivers and/not health staff. Results 557 studies were identified, of which 15 were selected for this study. The findings indicated difficulties related to the care for or to interaction with children/adolescents with mental disorder. Conclusion The studies revealed difficulties related to everyday practices of care and feelings expressed during care practices, as well as in relationships with children or adolescents with mental disorder.

Advancing epilepsy diagnosis: A meta-analysis of artificial intelligence approaches for interictal epileptiform discharge detection.

INTRODUCTION: Interictal epileptiform discharges (IEDs) in electroencephalograms (EEGs) are an important biomarker for epilepsy. Currently, the gold standard for IED detection is the visual analysis performed by experts. However, this process is expert-biased, and time-consuming. Developing fast, accurate, and robust detection methods for IEDs based on EEG may facilitate epilepsy diagnosis. We aim to assess the performance of deep learning (DL) and classic machine learning (ML) algorithms in classifying EEG segments into IED and non-IED categories, as well as distinguishing whether the entire EEG contains IED or not. METHODS: We systematically searched PubMed, Embase, and Web of Science following PRISMA guidelines. We excluded studies that only performed the detection of IEDs instead of binary segment classification. Risk of Bias was evaluated with Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Meta-analysis with the overall area under the Summary Receiver Operating Characteristic (SROC), sensitivity, and specificity as effect measures, was performed with R software. RESULTS: A total of 23 studies, comprising 3,629 patients, were eligible for synthesis. Eighteen models performed discharge-level classification, and 6 whole-EEG classification. For the IED-level classification, 3 models were validated in an external dataset with more than 50 patients and achieved a sensitivity of 84.9 % (95 % CI: 82.3-87.2) and a specificity of 68.7 % (95 % CI: 7.9-98.2). Five studies reported model performance using both internal validation (cross-validation) and external datasets. The meta-analysis revealed higher performance for internal validation, with 90.4 % sensitivity and 99.6 % specificity, compared to external validation, which showed 78.1 % sensitivity and 80.1 % specificity. CONCLUSION: Meta-analysis showed higher performance for models validated with resampling methods compared to those using external datasets. Only a minority of models use more robust validation techniques, which often leads to overfitting.