The economic burden of obesity in 4 south-eastern European countries associated with obesity-related co-morbidities.

OBJECTIVE: To provide an assessment of the cost burden of obesity across a spectrum of obesity-related comorbidities (ORCs) for four countries in South-Eastern Europe (SEE). METHODS: A micro-costing analysis from the public payer perspective was conducted to estimate direct healthcare costs associated with ten obesity-related comorbidities (ORCs) in Czech Republic, Greece, Hungary, and Romania. A survey was administered to obtain healthcare resource use and unit cost data. Cost estimates were validated by local steering committees which comprised at least one public sector clinician and a panel of independent industry experts. RESULTS: Chronic kidney disease and cardiovascular diseases were the costliest ORCs across all 4 countries, where annual cost burden per ORC exceeded 1,500 USD per patient per year. In general, costs were driven by the tertiary care resources allocated to address treatment-related adverse events, disease complications, and associated inpatient procedures. CONCLUSIONS: Our findings confirm that the high prevalence of obesity and its comorbidities result in substantial financial burden to all 4 SEE public payers. By quantifying the burden of obesity from a public healthcare perspective, our study aims to support policy efforts that promote health education and promotion in combating obesity in the region.

Connectivity Alterations in Emotional and Cognitive Networks During a Manic State Induced by Direct Electrical Stimulation.

Mania is characterized by affective and cognitive alterations, with heightened external and self-awareness that are opposite to the alteration of awareness during epileptic seizures. Electrical stimulations carried out routinely during stereotactic intracerebral EEG (SEEG) recordings for presurgical evaluation of epilepsy may represent a unique opportunity to study the pathophysiology of such complex emotional-behavioral phenomenon, particularly difficult to reproduce in experimental setting. We investigated SEEG signals-based functional connectivity between different brain regions involved in emotions and in consciousness processing during a manic state induced by electrical stimulation in a patient with drug-resistant focal epilepsy. The stimulation inducing manic state and an asymptomatic stimulation of the same site, as well as a seizure with alteration of awareness (AOA) were analyzed. Functional connectivity analysis was performed by measuring interdependencies (nonlinear regression analysis based on the h2 coefficient) between broadband SEEG signals and within typical sub-bands, before and after stimulation, or before and during the seizure with AOA, respectively. Stimulation of the right lateral prefrontal cortex induced a manic state lasting several hours. Its onset was associated with significant increase of broadband-signal functional coupling between the right hemispheric limbic nodes, the temporal pole and the claustrum, whereas significant decorrelation between the right lateral prefrontal and the anterior cingulate cortex was observed in theta-band. In contrast, ictal alteration of awareness was associated with increased broadband and sub-bands synchronization within and between the internal and external awareness networks, including the anterior and middle cingulate, the mesial and lateral prefrontal, the inferior parietal and the temporopolar cortex. Our data suggest the existence of network- and frequency-specific functional connectivity patterns during manic state. A transient desynchronization of theta activity between the external and internal awareness network hubs is likely to increase awareness, with potential therapeutic effect.

A European questionnaire survey on epilepsy monitoring units' current practice for postoperative psychogenic nonepileptic seizures' detection.

BACKGROUND: In cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures' outcome and the clinical management. We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES. METHODS: We developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project. RESULTS: Twenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 ( ±â€¯19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5 ±â€¯7.5 years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project. CONCLUSION: Postoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES.

The Economic Impact of Obesity in Turkey: A Micro-Costing Analysis.

Background: Turkey currently has the highest obesity prevalence among its European counterparts. 32% and 61% of the population live with obesity and overweight, respectively. Overweight and obesity are linked to non-communicable diseases that incur incremental health and economic costs. The significant public health concern warrants an assessment of the cost of obesity. Methods: A micro-costing approach from the public payer perspective was conducted to estimate direct healthcare costs associated with ten obesity-related comorbidities (ORCs) in Turkey. Clinical practice guidelines and a systematic literature review informed ORCs and the respective cost categories. This was subsequently validated by a steering committee comprising seven experts. Seventy public sector physicians were surveyed to estimate healthcare resource use. Unit costs were derived from Social Security Institute's Healthcare Implementation Communique. Cost items were summed to determine the annual cost per patient per ORC, which was validated by the steering committee. Medical inflation was considered in a scenario analysis that varied resource unit costs. Results: Chronic kidney disease, heart failure and type 2 diabetes are the costliest ORCs, incurring an annual cost of 28,600 TRY, 16,639 TRY and 11,993 TRY, respectively. Individuals in Turkey with any ORC triggered direct healthcare costs ranging 1857-28,600 TRY annually. Costs were driven by tertiary care resources arising from treatment-related adverse events, disease complications and inpatient procedures. In the scenario analysis, medical resource unit costs were inflated by 18.7% and 39.4%, triggering an average increase in cost across all ORCs of 1998 TRY and 4210 TRY, respectively. Conclusion: Our findings confirm that obesity and its complications result in significant financial burden to the public healthcare system. By quantifying the burden of obesity across a comprehensive spectrum of ORCs, our study aims to support the economic case for investing in appropriate obesity interventions.

The economic impact of obesity in Kuwait: a micro-costing study evaluating the burden of obesity-related comorbidities.

OBJECTIVE: 44% of Kuwait's population live with obesity and the health consequences place a significant burden on the public health system. This study provides an assessment of the cost burden of obesity-related comorbidities (ORC). METHODS: A retrospective micro-costing analysis was conducted to quantify the direct cost associated with ORCs. ORCs and their cost categories were informed by a systematic literature review and validated by a local steering committee comprising three experts. Seventy public sector clinicians and eight hospital procurement staff were surveyed to provide healthcare resource utilization estimates and medical resource cost data, respectively. The annual cost of each ORC and the cost drivers were also validated by the steering committee. RESULTS: Individuals in Kuwait with any single ORC incurred direct healthcare costs ranging 1,748-4,205 KWD annually. Asthma, chronic kidney disease and type 2 diabetes were the costliest ORCs, incurring an annual cost that exceeds 3,500 KWD per patient. Hypertension, angina and atrial fibrillation were the least costly ORCs. In general, costs were driven by drug costs and resources allocated to address treatment-related adverse events. LIMITATIONS: In the absence of an official patient registry in Kuwait, our study provides a conservative estimate of direct costs derived from a nationwide survey. Additionally, the cost estimates in this study assumes that a patient with obesity will only experience one ORC. In reality, multi-morbid states may incur additional costs that are not currently captured. CONCLUSIONS: Our study confirms that ORCs generate a significant financial burden to the public payer. The study provides an economic case for policymakers to recognize the exigency for obesity prevention and control in accordance with the ORC prevalence, and the need for sustainable investments towards body-mass index management to prevent individuals from developing multiple comorbidities.

Physician Perceptions of the Clinical, Economic and Humanistic Burden of Disease and Unmet Needs in Myelofibrosis: Preliminary Findings from the MPN Landmark Survey in Indonesia.

Background/ Objective: Myelofibrosis (MF) is a severe form of Myeloproliferative Neoplasms (MPNs). It is a rare disease in Indonesia and is reportedly associated with symptoms resulting in poor quality-of-life, pre-mature mortality, disability, and loss of productivity. As the disease is rare, there are limited published information around MF, particularly in Indonesia. METHODS: A cross-sectional survey was designed and administered between November and December 2021 among practicing Haematologists-Medical Oncologists who are experienced in treating patients with MF. The objectives of the survey were to assess physician's understanding of the overall diagnosis of MF, the disease burden, current treatment practices and remaining unmet needs. Outcomes were analysed descriptively. RESULT: The survey was completed by 30 respondents. The findings suggest that symptom burden is high and has a significant negative impact on quality-of-life. Treatment burden is also high which can result in high healthcare resource utilisation. Physicians expressed need for novel therapeutic options and improved access and coverage for such options. There is also a need to improve access and coverage for JAK V617F testing locally and local hospital infrastructures should be upgraded to ensure MF is accurately diagnosed. Patient may benefit from information on MPN, which may result in earlier presentation, diagnosis and treatment which can improve outcomes. CONCLUSION: The findings align with previous international research reporting that symptoms and treatment burden are high, and that novel therapeutic options are needed. Additional patient research might be required to better understand the patient experience of MF and how this can be improved.

COVID-19: Mental Health Prevention and Care for Healthcare Professionals.

The Coronavirus Disease 2019 (COVID-19) pandemic exposed health professionals to high stress levels inducing significant psychological impact. Our region, Grand Est, was the most impacted French region during the first COVID-19 wave. In this context, we created CoviPsyHUS, local mental health prevention and care system dedicated explicitly to healthcare workers affected by the COVID-19 pandemic in one of this region's tertiary hospitals. We deployed CoviPsyHUS gradually in 1 month. To date, CoviPsyHUS comprises 60 mental health professionals dedicated to 4 complementary components: (i) a mental health support hotline (170 calls), (ii) relaxation rooms (used by 2,120 healthcare workers with 110 therapeutic workshops offered), (iii) mobile teams (1,200 contacts with healthcare staff), and (iv) a section dedicated to patients and their families. Among the critical points to integrate mental health care system during a crisis, we identified: (i) massive dissemination of mental health support information with multimodal communication, (ii) clear identification of the mental health support system, (iii) proactive mobile teams to identify healthcare professionals in difficulty, (iv) concrete measures to relieve the healthcare professionals under pressure (e.g., the relay in communication with families), (v) support for primary needs (body care (physiotherapy), advice and first-line therapy for sleep disorders), and (vi) psychoeducation and emotion management techniques. The different components of CoviPsyHUS are vital elements in meeting the needs of caregivers in situations of continuous stress. The organization of 4 targeted, modular, and rapidly deployable components makes CoviPsyHUS an innovative, reactive, and replicable mental health prevention and care system that could serve as a universal support model for other COVID-19 affected teams or other exceptional health crises in the future.

Refining "Long-COVID" by a Prospective Multimodal Evaluation of Patients with Long-Term Symptoms Attributed to SARS-CoV-2 Infection.

INTRODUCTION: COVID-19 long-haulers, also decribed as having "long-COVID" or post-acute COVID-19 syndrome, represent 10% of COVID-19 patients and remain understudied. METHODS: In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation, including clinical, psychologic, virologic and specific immunologic assays and were followed longitudinally. A group of 17 convalescent COVID-19 individuals without persistent symptoms were included as a comparison group. RESULTS: The median age was 40 [interquartile range: 35-54] years and 18 (60%) were female. At a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients, although the median fatigue and pain visual analog scales were 7 [5-8] and 5 [2-6], respectively. Extensive biologic studies were unremarkable, and multiplex cytokines and ultra-sensitive interferon-α2 measurements were similar between long-haulers and convalescent COVID-19 individuals without persistent symptoms. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with evidence of a lack of immune response, or a waning immune response, in two patients. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively. CONCLUSIONS: Half of patients seeking medical help for post-acute COVID-19 syndrome lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity, or not, had no consequence on the clinical or biologic characteristics of post-acute COVID-19 syndrome patients, all of whom reported severe fatigue, altered quality of life and psychologic distress.

Use of suggestive seizure manipulation methods in the investigation of patients with possible psychogenic nonepileptic seizures-An international ILAE survey.

Video-encephalographic (vEEG) seizure recordings make essential contributions to the differentiation of epilepsy and psychogenic nonepileptic seizures (PNES). The yield of vEEG examinations can be increased through suggestive seizure manipulation (SSM) (ie, activation/provocation/cessation procedures), but its use has raised ethical concerns. In preparation for guidelines on the investigation of patients with PNES, the ILAE PNES Task Force carried out an international survey to investigate practices of and opinions about SSM. An online questionnaire was developed by the ILAE PNES Task Force. Questions were asked at clinical unit or individual respondent level. All ILAE chapters were encouraged to send questionnaires to their members. The survey was open from July 1, 2019, to August 31, 2019. A total of 487 clinicians from 411 units across 94 countries responded. Some form of SSM was used in 296/411 units (72.0%). Over 90% reported the use of verbal suggestion, over 80% the use of activation procedures also capable of eliciting epileptic activity (hyperventilation or photic stimulation). Only 26.3% of units used techniques specifically intended to provoke PNES (eg, saline injection). Fewer than 10% of units had established protocols for SSM, only 20% of units required written patient consent, in 12.2% of units patients received explicitly false information to provoke seizures. Clinicians using SSM tended to perceive no ethical problems, whereas those not using SSM were likely to have ethical concerns about these methods. We conclude that the use of invasive nocebo techniques intended to provoke PNES in diagnostic settings has declined, but SSM is commonly combined with activation procedures also capable of eliciting epileptic activity. While research suggests that openness about the use of PNES-specific nocebo techniques does not reduce diagnostic yield, very few units have suggestion protocols or seek patient consent. This could be addressed through establishing consensus guidance for the practice of SSM.

A purified C-terminally truncated human adenosine A(2A) receptor construct is functionally stable and degradation resistant.

Recent high resolution structures of modified G-protein coupled receptors (GPCRs) have provided major insight into the mechanisms of receptor-ligand binding. However understanding of the complete mechanism of GPCR function remains limited. This study characterised C-terminally truncated versions of the human adenosine A(2A) receptor (A(2A)R) with a view to producing protein suitable for structural studies. The constructs terminated at residue A316, removing the intracellular C-terminal tail, or V334, producing a C-terminal tail equivalent in length to that of rhodopsin. Higher levels of functional receptor before and after solubilisation were obtained for both C-terminally truncated constructs compared to the wild-type receptor (WT) as assessed by radioligand binding analysis using [(3)H]ZM241385. The construct which yielded the highest level of functional receptor, V334 A(2A)R, was purified in DDM to high homogeneity with a final yield of 2 mg/L. Binding analysis revealed that the purified receptor had a specific activity of 20.2+/-1.2 nmol/mg, close to the theoretical maximum. Pure V334 A(2A)R was resistant to degradation over 15 days when stored at 4 degrees C or 20 degrees C and showed remarkable functional stability when stored at 4 degrees C, retaining 84% of initial functionality after 30 days. This construct is an excellent candidate for structural studies.

Large-scale functional expression of WT and truncated human adenosine A2A receptor in Pichia pastoris bioreactor cultures.

BACKGROUND: The large-scale production of G-protein coupled receptors (GPCRs) for functional and structural studies remains a challenge. Recent successes have been made in the expression of a range of GPCRs using Pichia pastoris as an expression host. P. pastoris has a number of advantages over other expression systems including ability to post-translationally modify expressed proteins, relative low cost for production and ability to grow to very high cell densities. Several previous studies have described the expression of GPCRs in P. pastoris using shaker flasks, which allow culturing of small volumes (500 ml) with moderate cell densities (OD600 ~15). The use of bioreactors, which allow straightforward culturing of large volumes, together with optimal control of growth parameters including pH and dissolved oxygen to maximise cell densities and expression of the target receptors, are an attractive alternative. The aim of this study was to compare the levels of expression of the human Adenosine 2A receptor (A2AR) in P. pastoris under control of a methanol-inducible promoter in both flask and bioreactor cultures. RESULTS: Bioreactor cultures yielded an approximately five times increase in cell density (OD600 ~75) compared to flask cultures prior to induction and a doubling in functional expression level per mg of membrane protein, representing a significant optimisation. Furthermore, analysis of a C-terminally truncated A2AR, terminating at residue V334 yielded the highest levels (200 pmol/mg) so far reported for expression of this receptor in P. pastoris. This truncated form of the receptor was also revealed to be resistant to C-terminal degradation in contrast to the WT A2AR, and therefore more suitable for further functional and structural studies. CONCLUSION: Large-scale expression of the A2AR in P. pastoris bioreactor cultures results in significant increases in functional expression compared to traditional flask cultures.

A cost-effectiveness model for the use of a cannabis-derived oromucosal spray for the treatment of spasticity in multiple sclerosis.

BACKGROUND: Severity of spasticity in multiple sclerosis (MS) directly correlates with the level and cost of care required. This study assessed whether a tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray for treatment of moderate-severe MS spasticity is a cost-effective use of healthcare resources in Wales. METHODS: A Markov model was developed to compare THC/CBD plus standard of care (SoC) treatments with SoC alone. RESULTS: At 30 years, total incremental cost for THC/CBD plus SoC treatment was estimated at £3,836/patient (ICER: £10,891/quality-adjusted life year [QALY]). Hospital admission costs had the greatest effect on the base case ICER. Inclusion of carer cost led to incremental cost of -£33,609/patient (ICER: -£95,423/QALY). CONCLUSIONS: The THC/CBD spray was found to be cost-effective for the treatment of spasticity in MS, and dominant, if home carer costs were included. Use of THC/CBD has the potential to generate cost savings by significantly improving the symptoms of moderate to severe MS spasticity.

Sativex® in multiple sclerosis spasticity: a cost-effectiveness model.

BACKGROUND: Multiple sclerosis (MS) is a chronic, progressive disease that carries a high socioeconomic burden. Spasticity (rigidity and spasms) is common in MS and a key contributor to MS-related disability. OBJECTIVES: This study evaluated the cost-effectiveness of Sativex®, a 9-d-tetrahydrocannabinol/cannabidiol-based oromucosal spray that acts as an endocannabinoid system modulator. Sativex was recently approved for the management of resistant MS spasticity as add-on medication. METHODS: A Markov model-based analysis was performed over a 5-year horizon from a German and Spanish healthcare payer perspective. The incremental cost of Sativex was low compared with current spasticity treatments, and provided a quality-adjusted life-year gain over the current standard of care. RESULTS: The base-case incremental cost-effectiveness ratio for Sativex was estimated at €11,214/quality-adjusted life-year in Germany, while the drug was the dominant option in Spain, providing savings of €3496/patient over a 5-year period (year of costing: 2010). This was seen because the lower severity of spasticity in patients who had improved led to reduced resource consumption (e.g., physiotherapy and medications). CONCLUSION: Despite having a relatively high acquisition cost, Sativex was shown to be a cost-effective treatment option for patients with MS-related spasticity.

Screening for high-yielding Pichia pastoris clones: the production of G protein-coupled receptors as a case study.

Pichia pastoris is an established host for the production of a wide range of recombinant proteins including membrane proteins. The system has a particularly good track record for the production of G protein-coupled receptors (GPCRs). Generation and screening of expression clones with this system use standard molecular biology techniques. Multiple clones can be generated and screened in a matter of a few weeks making this similar to Escherichia coli in terms of speed. In addition, basic buffer components and the lack of expensive equipment make small-scale expression screening in P. pastoris very cost-effective. Here we describe the procedures used for small-scale GPCR production screening.

Large-scale production of membrane proteins in Pichia pastoris: the production of G protein-coupled receptors as a case study.

One of the major advantages of using Pichia pastoris is that it is readily adapted to large-scale culture in bioreactors. Bioreactors allow precise regulation of cell growth parameters increasing both yields and reproducibility of the culture. P. pastoris cultures grow to very high cell densities which helps minimise culture volume and facilitates downstream processing of the sample. Here, we provide protocols for the large-scale production of the human adenosine A(2A) receptor (A(2A)R) and provide some details of how bioreactor cultures can be used for optimisation of expression of the human dopamine D2 receptor (D2DR).