Irregular optogenetic stimulation waveforms can induce naturalistic patterns of hippocampal spectral activity.

Objective. Therapeutic brain stimulation is conventionally delivered using constant-frequency stimulation pulses. Several recent clinical studies have explored how unconventional and irregular temporal stimulation patterns could enable better therapy. However, it is challenging to understand which irregular patterns are most effective for different therapeutic applications given the massively high-dimensional parameter space.Approach. Here we applied many irregular stimulation patterns in a single neural circuit to demonstrate how they can enable new dimensions of neural control compared to conventional stimulation, to guide future exploration of novel stimulation patterns in translational settings. We optogenetically excited the septohippocampal circuit with constant-frequency, nested pulse, sinusoidal, and randomized stimulation waveforms, systematically varying their amplitude and frequency parameters.Main results.We first found equal entrainment of hippocampal oscillations: all waveforms provided similar gamma-power increase, whereas no parameters increased theta-band power above baseline (despite the mechanistic role of the medial septum in driving hippocampal theta oscillations). We then compared each of the effects of each waveform on high-dimensional multi-band activity states using dimensionality reduction methods. Strikingly, we found that conventional stimulation drove predominantly 'artificial' (different from behavioral activity) effects, whereas all irregular waveforms induced activity patterns that more closely resembled behavioral activity.Significance. Our findings suggest that irregular stimulation patterns are not useful when the desired mechanism is to suppress or enhance a single frequency band. However, novel stimulation patterns may provide the greatest benefit for neural control applications where entraining a particular mixture of bands (e.g. if they are associated with different symptoms) or behaviorally-relevant activity is desired.

Current global status of male reproductive health.

BACKGROUND: The widespread interest in male reproductive health (MRH), fueled by emerging evidence, such as the global decline in sperm counts, has intensified concerns about the status of MRH. Consequently, there is a pressing requirement for a strategic, systematic approach to identifying critical questions, collecting pertinent information, and utilizing these data to develop evidence-based strategies. The methods for addressing these questions and the pathways toward their answers will inevitably vary based on the variations in cultural, geopolitical, and health-related contexts. To address these issues, a conjoint ESHRE and Male Reproductive Health Initiative (MRHI) Campus workshop was convened. OBJECTIVE AND RATIONALE: The three objectives were: first, to assess the current state of MRH around the world; second, to identify some of the key gaps in knowledge; and, third, to examine how MRH stakeholders can collaboratively generate intelligent and effective paths forward. SEARCH METHODS: Each expert reviewed and summarized the current literature that was subsequently used to provide a comprehensive overview of challenges related to MRH. OUTCOMES: This narrative report is an overview of the data, opinions, and arguments presented during the workshop. A number of outcomes are presented and can be summarized by the following overarching themes: MRH is a serious global issue and there is a plethora of gaps in our understanding; there is a need for widespread international collaborative networks to undertake multidisciplinary research into fundamental issues, such as lifestyle/environmental exposure studies, and high-quality clinical trials; and there is an urgent requirement for effective strategies to educate young people and the general public to safeguard and improve MRH across diverse population demographics and resources. LIMITATIONS REASONS FOR CAUTION: This was a workshop where worldwide leading experts from a wide range of disciplines presented and discussed the evidence regarding challenges related to MRH. While each expert summarized the current literature and placed it in context, the data in a number of areas are limited and/or sparse. Equally, important areas for consideration may have been missed. Moreover, there are clear gaps in our knowledge base, which makes some conclusions necessarily speculative and warranting of further study. WIDER IMPLICATIONS: Poor MRH is a global issue that suffers from low awareness among the public, patients, and heathcare professionals. Addressing this will require a coordinated multidisciplinary approach. Addressing the significant number of knowledge gaps will require policy makers prioritizing MRH and its funding. STUDY FUNDING/COMPETING INTERESTS: The authors would like to extend their gratitude to ESHRE for providing financial support for the Budapest Campus Workshop, as well as to Microptic S.L. (Barcelona) for kindly sponsoring the workshop. P.B. is the Director of the not-for-profit organization Global Action on Men's Health and receives fees and expenses for his work, (which includes the preparation of this manuscript). Conflicts of interest: C.J.D.J., C.L.R.B., R.A.A., P.B., M.P.C., M.L.E., N.G., N.J., C.K., AAP, M.K.O., S.R.-H., M.H.V.-L.: ESHRE Campus Workshop 2022 (Travel support-personal). C.J.D.J.: Cambridge University Press (book royalties-personal). ESHRE Annual Meeting 2022 and Yale University Panel Meeting 2023 (Travel support-personal). C.L.R.B.: Ferring and IBSA (Lecture), RBMO editor (Honorarium to support travel, etc.), ExSeed and ExScentia (University of Dundee), Bill & Melinda Gates Foundation (for research on contraception). M.P.C.: Previously received funding from pharmaceutical companies for health economic research. The funding was not in relation to this work and had no bearing on the contents of this work. No funding from other sources has been provided in relation to this work (funding was provided to his company Global Market Access Solutions). M.L.E.: Advisor to Ro, Doveras, Next, Hannah, Sandstone. C.K.: European Academy of Andrology (Past president UNPAID), S.K.: CEO of His Turn, a male fertility Diagnostic and Therapeutic company (No payments or profits to date). R.I.M.: www.healthymale.org.au (Australian Government funded not for profit in men's health sector (Employed as Medical Director 0.2 FET), Monash IVF Pty Ltd (Equity holder)). N.J.: Merck (consulting fees), Gedeon Richter (honoraria). S.R.-H.: ESHRE (Travel reimbursements). C.N.: LLC (Nursing educator); COMMIT (Core Outcomes Measures for Infertility Trials) Advisor, meeting attendee, and co-author; COMMA (Core Outcomes in Menopause) Meeting attendee, and co-author; International Federation of Gynecology and Obstetrics (FIGO) Delegate Letters and Sciences; ReproNovo, Advisory board; American Board of Urology Examiner; American Urological Association Journal subsection editor, committee member, guidelines co-author Ferring Scientific trial NexHand Chief Technology Officer, stock ownership Posterity Health Board member, stock ownership. A.P.: Economic and Social Research Council (A collaborator on research grant number ES/W001381/1). Member of an advisory committee for Merck Serono (November 2022), Member of an advisory board for Exceed Health, Speaker fees for educational events organized by Mealis Group; Chairman of the Cryos External Scientific Advisory Committee: All fees associated with this are paid to his former employer The University of Sheffield. Trustee of the Progress Educational Trust (Unpaid). M.K.O.: National Health and Medical Research Council and Australian Research Council (Funding for research of the topic of male fertility), Bill and Melinda Gates Foundation (Funding aimed at the development of male gamete-based contraception), Medical Research Future Fund (Funding aimed at defining the long-term consequences of male infertility). M.H.V.-L.: Department of Sexual and Reproductive Health and Research (SRH)/Human Reproduction Programme (HRP) Research Project Panel RP2/WHO Review Member; MRHI (Core Group Member), COMMIT (member), EGOI (Member); Human Reproduction (Associate Editor), Fertility and Sterility (Editor), AndroLATAM (Founder and Coordinator).

Identifying factors that can be used to assess a country's readiness to deploy a new vaccine or improve uptake of an underutilised vaccine: a scoping review.

OBJECTIVES: Identifying whether a country is ready to deploy a new vaccine or improve uptake of an existing vaccine requires knowledge of a diverse range of interdependent, context-specific factors. This scoping review aims to identify common themes that emerge across articles, which include tools or guidance that can be used to establish whether a country is ready to deploy a new vaccine or increase uptake of an underutilised vaccine. DESIGN: Scoping review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines. DATA SOURCES: Embase, CINAHL, Cochrane Library, Google Scholar, MEDLINE, PsycINFO and Web of Science were searched for articles published until 9 September 2023. Relevant articles were also identified through expert opinion. ELIGIBILITY CRITERIA: Articles published in any year or language that included tools or guidance to identify factors that influence a country's readiness to deploy a new or underutilised vaccine. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened records and performed data extraction. Findings were synthesised by conducting a thematic analysis. RESULTS: 38 articles met our inclusion criteria; these documents were created using methodologies including expert review panels and Delphi surveys and varied in terms of content and context-of-use. 12 common themes were identified relevant to a country's readiness to deploy a new or underutilised vaccine. These themes were as follows: (1) legal, political and professional consensus; (2) sociocultural factors and communication; (3) policy, guidelines and regulations; (4) financing; (5) vaccine characteristics and supply logistics; (6) programme planning; (7) programme monitoring and evaluation; (8) sustainable and integrated healthcare provision; (9) safety surveillance and reporting; (10) disease burden and characteristics; (11) vaccination equity and (12) human resources and training of professionals. CONCLUSIONS: This information has the potential to form the basis of a globally applicable evidence-based vaccine readiness assessment tool that can inform policy and immunisation programme decision-makers.

Identifying characteristics that enable resilient immunisation programmes: a scoping review.

OBJECTIVES: The COVID-19 pandemic highlighted the fragility of immunisation programmes and resulted in a significant reduction in vaccination rates, with increasing vaccine-preventable disease outbreaks consequently reported. These vulnerabilities underscore the importance of resilient immunisation programmes to ensure optimal performance during crises. To date, a framework for assessing immunisation programme resilience does not exist. We conducted a scoping review of immunisation programmes during times of crisis to identify factors that characterise resilient immunisation programmes, which may inform an Immunisation Programme Resilience Tool. DESIGN: Scoping review design followed the Arksey and O'Malley framework, and manuscript reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines. DATA SOURCES: CINAHL, CENTRAL, Embase, Google Scholar, MEDLINE, PsycINFO and Web of Science and databases were searched between 1 January 2011 and 2 September 2023. Citation searching of identified studies was also performed. ELIGIBILITY CRITERIA: We included primary empirical peer-reviewed studies that discussed the resilience of immunisation programme to crises, shocks or disruptions. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened records and performed data extraction. We extracted data on study location and design, crisis description, and resilience characteristics discussed, and identified evidence gaps in the literature. Findings were synthesised using tabulation and an evidence gap map. RESULTS: Thirty-seven studies met the eligibility criteria. These studies captured research conducted across six continents, with most concentrated in Africa, Asia and Europe. One study had a randomised controlled trial design, while 36 studies had observational designs (15 analytical and 21 descriptive). We identified five characteristics of resilient immunisation programmes drawing on the Health System Resilience Index (Integration, Awareness, Resource Availability and Access, Adaptiveness and Self-regulation) and several evidence gaps in the literature. CONCLUSIONS: To our knowledge, no immunisation programme resilience tool exists. We identified factors from the Health System Resilience Index coupled with factors identified through primary empirical evidence, which may inform development of an immunisation programme resilience tool.

Estimating Public Economic Gains from Early Breast Cancer and Curative Treatment: A Case Study in Human Epidermal Growth Factor Receptor (HER-2) Positive Targeted Therapies.

INTRODUCTION: Cancer diagnosis influences the choices that patients make regarding current and future labor market activity. These choices have implications for governments based on resulting changes in taxes paid and benefits received. In this analysis we explore how human growth receptor 2 (HER2)-positive residual invasive breast cancer and different treatments influence government accounts excluding health costs. METHODS: HER2-positive early breast cancer (eBC) health states from a published disease model were used to establish likelihood of working and wage impact at different stages of disease. The indirect productivity losses for an average woman aged 49 years were translated into fiscal consequences to government by applying an established government perspective-modeling framework. The fiscal projections (discounted) include gross tax revenue by disease stage, government transfer costs related to time off work and early retirement ,and net fiscal balance (e.g., gross taxes-transfers) in three countries Canada, Portugal, and Brazil. RESULTS: The net fiscal balance in Canada for a healthy woman was C$109,551 compared with a HER2-positive eBC woman treated with trastuzumab emtansine (C$69,767) or trastuzumab (C$62,971). A similar pattern was observed in the three countries but reflecting the overall tax burden in each country, labor force activity, and available public benefits. Age at diagnosis was an important determinant of the likely net fiscal balance, as this influences the remaining working years. DISCUSSION: Women diagnosed with HER2-positive eBC were estimated to pay less lifetime gross taxes and receive more in sickness benefits compared with healthy women. Treatments that improve outcomes are likely to offer fiscal gains for government from improved work force participation.

Fiscal analysis of the pediatric immunization program in Belgium applying a lifetime government perspective framework.

OBJECTIVES: A public economic framework was used to explore lifetime government costs and benefits in relation to the Pediatric Immunization Program (PIP) in Belgium based on cases and deaths averted. METHODS: To estimate changes in net government revenue, we developed a decision-analytic model that quantifies lifetime tax revenues and transfers based on changes in morbidity and mortality arising from Belgium's Pediatric Immunization Program (PIP). The model considered differences in incidence rates with vaccines included in Belgium's PIP: compared with the pre-vaccine era. Changes in deaths and comorbid conditions attributed to PIP on the Belgium 2020 birth cohort were used to estimate gross lifetime earnings changes, tax revenue gains attributed to averted morbidity and mortality avoidance, disability transfer cost savings, and averted special education costs associated with each vaccine. RESULTS: Vaccinating a single birth cohort according to the PIP gives rise to fiscal gains of €56 million in averted tax revenue loss, €8 million disability savings, and €6 million special education cost-savings. Based on the costs of implementing the PIP, we estimate the fiscal benefit-cost ratio (fBCR) of €2.2 investment return for the government from every €1 invested excluding longevity costs. CONCLUSIONS: Reducing vaccine-preventable conditions generates tax revenue for the government, providing fiscal justification for sustained immunization investments.

"It just wasn't right down there": Surgical treatment of small bowel evisceration after hysterectomy with indocyanine green angiography, a case report.

This is a case of a 70-year-old female with small bowel evisceration through vaginal cuff dehiscence 14 months after hysterectomy. She presented with a loop of ileum herniated through the vagina. The bowel was irreducible and she was taken to the operating room for exploratory laparotomy, reduction of herniated bowel contents, and repair of vaginal cuff. During surgery, the eviscerated bowel had questionable viability and indocyanine green angiography was used to assess perfusion. After the repair of the vaginal cuff, indocyanine green angiography was performed and the bowel was saved from resection. In the discussion, light is shed upon the rarity of vaginal cuff dehiscence and the few cases of small bowel evisceration after a dehiscence. Possible causes of the evisceration, updates to technique, and recommendations for management are also discussed. The ultimate recommendation is for use of indocyanine green angiography in assessment of intestinal viability during surgical exploration for small bowel evisceration.

Assessing the Fiscal Burden of Obesity in Canada by Applying a Public Economic Framework.

INTRODUCTION: Rising obesity prevalence is a health priority for many governments because of its impact on population health and economic consequences. We sought to estimate the broader consequences of obesity in Canada by applying a government perspective framework that captures lost tax revenues and increased government spending on social benefit programs. METHODS: An age-specific prevalence-based model was built to quantify the fiscal burden of disease for government attributed to people living with obesity. The model was populated with age-specific wages, employment activity and government benefits received to estimate taxes and transfer costs. A targeted literature search was conducted to identify modifiers of employment status, wages and disability status attributed to people with obesity, and applied to employment and epidemiological projections which enabled us to estimate government costs and tax losses. Government tax revenue and costs attributed to obesity were projected over a 10-year period and discounted at 3%. RESULTS: The fiscal burden of obesity in Canada is estimated at CAD$22,974 million (2021). This figure consists of obesity-attributed revenue losses of CAD$9404 million from direct taxes due to decreased employment activity and CAD$2374 million from indirect tax revenue losses due to reduced consumption taxes. Healthcare costs are estimated at CAD$7881 million annually and disability costs of CAD$3686 million annually. This fiscal burden of disease distributed amongst taxpayers in 2021 is estimated to be CAD$752 per capita. We estimate for every 1% reduction in obesity prevalence, CAD$229.7 million net fiscal gains can be achieved annually. CONCLUSIONS: Obesity is associated with substantial clinical and economic burden not only to the healthcare system but also to wider government budgets as demonstrated using fiscal analysis. Reductions in obesity prevalence are likely to have positive fiscal gains for government from reduced spending on public benefits and increased tax revenue attributed to employment changes.

Public economic gains from tax-financed investments in childhood immunization in the United States.

The emergence of COVID-19 has displayed the importance of immunization and the need for continued public investment in vaccination programs. Globally, national vaccination programs rely heavily on tax-financed expenditure, requiring upfront investments and ongoing financial commitments. To evaluate annual public investments, we conducted a fiscal analysis that quantifies the public economic consequences to government in the United States attributable to childhood vaccination. To estimate the change in net government revenue, we developed a decision-analytic model that quantifies lifetime tax revenues and transfers based on changes in morbidity and mortality arising from vaccination of the 2017 U.S. birth cohort. Reductions in deaths and comorbid conditions attributed to pediatric vaccines were used to derive gross lifetime earnings gains, tax revenue gains attributed to averted morbidity and mortality avoided, disability transfer cost savings, and averted special education costs associated with each vaccine. Our analysis indicates a fiscal dividend of $41.7 billion from vaccinating this cohort. The bulk of this gain for government reflects avoiding the loss of $30.6 billion in present-value tax revenues. All pediatric vaccines raise tax revenues by reducing vaccine-preventable morbidity and mortality in amounts ranging from $7.3 million (hepatitis A) to $20.3 billion (diphtheria) over the life course. Based on public investments in pediatric vaccines, a benefit-cost ratio of 17.8 was calculated for each dollar invested in childhood immunization. The public economic yield attributed to childhood vaccination in the U.S. is significant from a government perspective, providing fiscal justification for ongoing investment.

The Hidden Economic Consequences of Migraine to the UK Government: Burden-of-Disease Analysis Using a Fiscal Framework.

Background: Migraine is a highly prevalent and incapacitating neurological disorder associated with the highest global disability burden in people aged 15 to 49 years. Europe has the fourth-highest prevalence of migraine, after North America, South America, and Central America, and above Asia and Africa. Migraine leads to relatively modest direct healthcare expenditure but has substantial indirect costs due to reduced productivity. Methods: The economic burden of migraine was estimated in comparison with the general population of the United Kingdom (UK) using an analytical fiscal modeling framework applying the government cost perspective. Published measures of migraine's impact on labor participation were applied to rates of economic activity/inactivity of the general population. The model estimates lifetime changes to earnings from employment, direct and indirect taxes paid, and financial support requirements over the life course. Incremental differences between those affected and unaffected by migraine are reported as net fiscal consequences to public accounts. Fiscal costs are reported as the discounted average per capita over a 20-year time horizon and for the entire annual UK cohort with prevalent migraine. Results: People affected by migraine are more likely to be absent from work, unemployed, and disabled, and to retire early. A 44-year-old individual affected by migraine was associated with £19 823 in excess fiscal costs to the UK government, £1379 per year living with the condition, compared with someone not affected by the disease. Annually, migraine was estimated to represent £12.20 billion to the public economy, approximately £130.63 per migraine episode. The model predicted annual productivity losses in the health and social care workforce to be £2.05 billion and total annual productivity losses to be over £5.81 billion. Conclusions: This fiscal analysis monetizes the occupational consequences of migraine to the UK government, both in terms of lost tax revenue and transfer payments. The findings are substantial and useful to characterize disease severity and to inform the body of evidence considered by decision makers appraising the cost-effectiveness of health technologies.

The Lifetime Burden of Schizophrenia as Estimated by a Government-Centric Fiscal Analytic Framework.

Objective: To estimate the fiscal consequences of schizophrenia compared to the general US population using a "government perspective" fiscal analytic modeling framework capturing lost tax revenue and broader government costs in 2021.Methods: Schizophrenia was modeled from age 23 using a cohort-based Markov chain with 6-week cycles, simulating the effect of antipsychotic treatment sequences on remission and relapse. Markov states were defined using efficacy and safety outcomes from short- and long-term clinical trials. Mortality was based on US lifetables, schizophrenia-related suicide, and cardiovascular risks. A semi-Markov model with annual cycles simulated the likelihood and costs of incarceration and homelessness in community-based individuals. Lifetime fiscal consequences were estimated conditionally to survival, remission/relapse status, and likelihood of socioeconomic outcomes. Costs and life years were discounted at 3.0% annually. Uncertainty was explored in 1-way and scenario analyses.Results: Unemployment, disability, incarceration, homelessness, health care use, and productivity losses were more common in people living with schizophrenia. Schizophrenia was associated with a $1,540,042 per person lifetime fiscal loss to the government, with $56,707 per life year lived with schizophrenia. Health care costs represented 41.9% of the fiscal losses, 39.4% were due to criminal and homelessness costs, and 17.5% related to foregone tax revenue. Considering a 1.19% prevalence of schizophrenia, the estimated annual fiscal burden in the US was $173.6 billion.Conclusions: The fiscal framework illustrates how schizophrenia influences taxation and government transfer payments over time. These findings can be used to augment cost-effectiveness analyses and inform stakeholders of the fiscal impact of schizophrenia to inform priority interventions.

The Entrainment of the Substantia Nigra During Temporal Lobe Seizures is Dependent on the Seizure Onset Pattern.

Rationale: Temporal lobe (TL) epilepsy is the most common form of drug-resistant epilepsy. While the limbic circuit and the structures composing the TL have been a major focus of human and animal studies on TL seizures, there is also evidence suggesting that the basal ganglia have an active role in the propagation and control of TL seizures. Studies in patients have shown that TL seizures can cause changes in the oscillatory activity of the basal ganglia when the seizures spread to extratemporal structures. Preclinical studies have found that inhibition of the substantia nigra pars reticulata (SN), a major output structure of the basal ganglia, can reduce the duration and severity of TL seizures in animal models. These findings suggest the SN plays a role critical in the maintenance or propagation of TL seizures. Two stereotyped onset patterns commonly observed in TL seizures are low-amplitude fast (LAF) and high-amplitude slow (HAS). Both onset patterns can arise from the same ictogenic circuit, however seizures with LAF onset pattern typically spread farther and have a larger onset zone than HAS. Therefore, we would expect LAF seizures to entrain the SN more so than HAS seizures. Here, we use a nonhuman primate (NHP) model of TL seizures to confirm the implication of the SN in TL seizure and to characterize the relationship between TL seizure onset pattern and the entrainment of the SN. Methods: Recording electrodes were implanted in the hippocampus (HPC) and SN in 2 NHPs. One subject was also implanted with extradural screws for recording activity in the somatosensory cortex (SI). Neural activity from both structures was recorded at a 2 kHz sampling rate. Seizures were induced by intrahippocampal injection of penicillin, which produced multiple spontaneous, nonconvulsive seizures over 3-5 hours. The seizure onset patterns were manually classified as LAF, HAS or other/undetermined. Across all seizures, spectral power and coherence were calculated for the frequency bands 1-7 Hz, 8-12 Hz and 13-25 Hz from/between both structures and compared between the 3 seconds before the seizure, the first 3 seconds of the seizure, and the 3 seconds before seizure offset. These changes were then compared between the LAF and HAS onset patterns. Results: During temporal lobe seizures, the 8-12 Hz and 13-25 Hz power in the SN along with the 1-7 Hz and 13-15 Hz power in the SI was significantly higher during onset than before the seizure. Both the SN and SI had an increase in coherence with the HPC in the 13-25 Hz and 1-7 Hz frequency ranges, respectively. Comparing these differences between LAF and HAS, both were associated with the increase in the HPC/SI coherence, while the increase in HPC/SN increase was specific to LAF. Conclusion: Our findings suggest that the SN may be entrained by temporal lobe seizures secondary to the SI during the farther spreading of LAF seizures, which supports the theory that the SN plays a role in the generalization and/or maintenance of temporal lobe seizures and helps explains the anti-ictogenic effect of SN inhibition.

Investing in the Prevention of Communicable Disease Outbreaks: Fiscal Health Modelling-The Tool of Choice for Assessing Public Finance Sustainability.

National strategies for preparedness for future outbreaks of COVID-19 often include timely preparedness with vaccines. Fiscal health modelling (FHM) has recently been brought forward as an additional analysis by defining the public economic impact from a governmental perspective. As governments are the main decision-makers concerning pandemic preparedness, this study aimed to develop an FHM framework for infectious diseases in the Netherlands. Based on the Dutch COVID-19 outbreak of 2020 and 2021 and publicly available data on tax income and gross domestic product (GDP), the fiscal impact of COVID-19 was assessed using two approaches. Approach I: Prospective modelling of future fiscal impact based on publicly available laboratory-confirmed COVID-19 cases; and Approach II: Retrospective assessment of the extrapolated tax and benefit income and GDP. Approach I estimated the consequences that can be causally linked to the population counts reducing income taxes by EUR 266 million. The total fiscal loss amounted to EUR 164 million over 2 years (excluding pension payments averted). The total losses in terms of tax income (2020 and 2021) and GDP (2020) (Approach II), were estimated at, respectively, EUR 13.58 billion and EUR 96.3 billion. This study analysed different aspects of a communicable disease outbreak and its influence on government public accounts. The choice of the two presented approaches depends on the perspective of the analysis, the time horizon of the analysis and the availability of data.

Cost-effectiveness of infant hypoallergenic formulas to manage cow's milk protein allergy in France.

Background: Clinician's choice of hypoallergenic formulas in the first-line management of cow's milk protein allergy (CMPA) should be informed by evidence on clinical efficacy and cost-effectiveness. Objective: We compare the cost-effectiveness of amino acid-based formula (AAF), extensively hydrolyzed casein formula with Lactobacillus rhamnosus Gorbach Goldin (EHCF+LGG), extensively hydrolyzed whey formula (EHWF), and rice hydrolyzed formula (RHF) in non-breastfed children in France. Methods: Immunotolerance and atopic manifestations' prevalence were based on a prospective non-randomized study with a 36-month follow-up. Resource utilization was sourced from a survey of French clinicians, and unit costs were based on national data. Costs and health consequences were discounted at 2.5% annually. Results were reported using the Collective and French National Health Insurance perspectives. Results: Children receiving EHCF+LGG were predicted to require less healthcare resources, given their reduced prevalence of CMPA symptoms at 3 years. In the base case, EHCF+LGG led to savings of at least €674 per child compared to AAF, EHWF, and RHF at 3 years, from both perspectives. Nutrition had the highest economic burden in CMPA, driven by hypoallergenic formulas and dietetic replacements costs. Results were robust to one-way and probabilistic sensitivity analyses. Conclusions: EHCF+LGG was associated with more symptom-free time, higher immune tolerance, and lower costs.

Rare case of an exceedingly enlarged mediastinal mass in 22-year-old male.

Masses of the mediastinum develop from anatomic structures that pass through or are normally located within this space; they may also occur secondary to metastatic spread from malignancies from other locations. The anterior compartment of the mediastinum can give rise to thymomas, which tend to be restricted to the thymus as well as nearby structures. Their symptoms are associated with their size and impact on nearby structures. This patient, a 22-year-old male with no medical history, presented to the emergency department for evaluation of a cough ongoing for 3 weeks. Chest X-ray and computed tomography (CT) scan of the thorax demonstrated a mass measuring up to 17.2 cm. Afterwards, a CT-guided biopsy was performed, which revealed findings consistent with a benign thymic neoplasm, though due to the specimen being scant, patient was referred to cardiothoracic surgery for resection and excisional biopsy of the mediastinal mass.

Valuing live births from assisted reproduction: A health economics viewpoint.

Infertility is a medical condition that can be overcome, thanks to advances in medically assisted reproductive (MAR) therapies. Despite the ultimate measure of MAR efficacy being the birth of a new human being, there are ethical and methodological questions as to which outcome best translates the value of MAR in cost-effectiveness analyses. Many authors favour cost per life birth outcomes instead of more traditional cost per quality-adjusted life years (QALYs), which raises generalizability issues for decision-makers. Nonetheless, infertility and infertility treatments substantially differ from other health conditions and health treatments, particularly in the way they affect the quality of life of the infertile couple. Collecting quality of life measures in infertility and pregnancy is also surrounded by challenges not easily overcome. We reflect on cost-effectiveness methods applied to MAR technologies, on ethical considerations for valuing a MAR-generated life, and on its broader societal value for consideration by decision-makers.

Meta-Bayesian Optimization for Deep Brain Stimulation.

Deep brain stimulation (DBS) is becoming a fundamental tool for the treatment and study of neurological and psychiatric diseases and disorders. Recently developed DBS devices and electrodes have allowed for more flexible and precise stimulation. Densely packed stimulation contacts can be independently stimulated to shape the electric field, targeting pathways of interest, and avoiding those that may cause side-effects. However, this flexibility comes at a cost. Each additional stimulation setting causes an exponential increase in the number of potential stimulation settings. Recent works have addressed this problem using Bayesian optimization. However, this approach has a limited ability to learn from multiple subjects to improve performance. In this study we extend a recently developed meta-Bayesian optimization algorithm to the DBS domain. We evaluated this approach compared to classical Bayesian optimization and a random search using data collected from a nonhuman primate during stimulation of the subthalamic nucleus while recording evoked potentials in the motor cortex and locally within the subthalamic nucleus. On the task of finding the stimulation setting that maximized the evoked potential across a distribution of generated objective functions, meta-Bayesian optimization significantly outperformed the other approaches with a cumulative reward of 8.93±0.70, compared to 7.17±1.64 for Bayesian optimization (p < 10-9) and 6.89±1.56 for the random search (p < 10-9). Moreover, the algorithm outperformed Bayesian optimization when tested on an objective function not used during training. These results demonstrate that meta-Bayesian optimization can take advantage of the structure underlying a distribution of objective function and learn an optimal search strategy that can generalize beyond the objective functions that were not part of the training data. Clinical Relevance - This extends a meta-Bayesian optimization approach for optimizing DBS stimulation settings that outperforms state-of-art algorithms by 24.6%.

Managing Cow's Milk Protein Allergy in Indonesia: A Cost-effectiveness Analysis of Hypoallergenic Milk Formulas from the Private Payers' Perspective.

Background: Cow's milk protein allergy is very common in early childhood. Extensively hydrolyzed formulas are recommended in the first-line management of cow's milk protein allergy in non-breastfed children. Choice of formulas should be informed by efficacy and cost data. Objectives: This study aims to compare the cost-effectiveness of extensively hydrolyzed casein formula with Lacticaseibacillus rhamnosus Gorbach Goldin (EHCF+LGG), extensively hydrolyzed whey formula (EHWF), amino acid formula, and soy formula in the first-line management of cow's milk protein allergy in non-breastfed children in Indonesia. Methods: A trial-based decision analytic cohort model was adapted to simulate the occurrence of cow's milk protein allergy symptoms or being symptom free. The model was based on a prospective nonrandomized study that followed up children for 36 months. Costs and health consequences were discounted at 3% annually. Resources required to manage cow's milk protein allergy and unit costs for clinical appointments and exams were based on a panel of 15 clinicians, from a private payers' perspective. Other unit costs were based on publicly available national data. Results were reported as cost per additional child free from allergic manifestations or per additional immunotolerant child at 3 years, and per life-years under the same conditions. Uncertainty was assessed using deterministic and probabilistic sensitivity analysis. Results: Children receiving EHCF+LGG were associated with more symptom-free time, a higher probability of cow's milk tolerance at 3 years, and lower healthcare resources and transportation use when compared with children receiving other formulas (with 38%-49% lower costs). Formula costs were lower for soy, but EHCF+LGG was predicted to save 9% and 54% of overall costs compared with extensively hydrolyzed whey formula and amino acid formula, respectively. Results were robust to sensitivity analyses. Conclusion: Use of EHCF+LGG resulted in more symptom-free time and the highest 3-year probability of cow's milk tolerance. It also led to healthcare resource and transportation savings when compared with other hypoallergenic milk formulas. Soy formula remained an alternative if formula price represents a major constraint.

Rare case of papillary fibroelastoma resection with concomitant cox-maze IV procedure.

Primary cardiac tumors represent 0.1% of all cardiac tumors, making them a rare pathologic phenomenon. The second most common cardiac tumors are papillary fibroelastomas, which also represent the most common valvular tumors. This report examines a rare case of a patient that underwent resection of papillary fibroelastoma with simultaneous Cox-Maze IV procedure for treatment of atrial fibrillation. This 67-year-old male patient was initially scheduled for transcatheter ablation for treatment of rate-controlled atrial fibrillation. During a pre-procedural trans-thoracic echocardiogram, it was discovered that the patient had a moderately sized pedunculated mass on the aortic valve, suspicious of papillary fibroelastoma. Despite the patient having no history of embolic events or aortic insufficiency from the papillary fibroelastoma, the transcatheter ablation procedure was canceled. He was referred to cardiothoracic surgery for further evaluation, and it was determined that this patient was a candidate for papillary fibroelastoma resection along with Cox-Maze IV procedure for atrial fibrillation.