The indirect costs of human papillomavirus-related cancer in Central and Eastern Europe: years of life lost and productivity costs.

BACKGROUND: Human papilloma virus (HPV) is a common cause of several types of cancer, including head and neck (oral cavity, pharynx, oropharynx, hypopharynx, nasopharynx, and larynx), cervical, vulval, vaginal, anal, and penile cancers. As HPV vaccines are available, there is potential to prevent HPV-related disease burden and related costs. METHOD: A model was developed for nine Central Eastern European (CEE) countries (Bulgaria, Croatia, Czechia, Hungary, Poland, Romania, Serbia, Slovakia, Slovenia). This model considered cancer patients who died from 11 HPV-related cancers (oropharynx, oral cavity, nasopharynx, hypopharynx, pharynx, anal, larynx, vulval, vaginal, cervical, and penile) in 2019. Due to data limitations, Bulgaria only included four cancer types. The model estimated the number of HPV-related deaths and years of life lost (YLL) based on published HPV-attributable fractions. YLL was adjusted with labor force participation, retirement age and then multiplied by mean annual earnings, discounted at a 3% annual rate to calculate the present value of future lost productivity (PVFLP). RESULTS: In 2019, there were 6,832 deaths attributable to HPV cancers resulting in 107,846 YLL in the nine CEE countries. PVFLP related to HPV cancers was estimated to be €46 M in Romania, €37 M in Poland, €19 M in Hungary, €15 M in Czechia, €12 M in Croatia, €10 M in Serbia, €9 M in Slovakia, €7 M in Bulgaria and €4 M in Slovenia. CONCLUSIONS: There is a high disease burden of HPV-related cancer-related deaths in the CEE region, with a large economic impact to society due to substantial productivity losses. It is critical to implement and reinforce public health measures with the aim to reduce the incidence of HPV-related diseases, and the subsequent premature cancer deaths. Improving HPV screening and increasing vaccination programs, in both male and female populations, could help reduce this burden.

Economic impact analysis of a minimally invasive temperature-controlled radiofrequency device versus nasal surgery for the treatment of nasal airway obstruction in the United States.

Objective: To determine the economic impact of a minimally invasive temperature-controlled radiofrequency (TCRF) device for treating nasal airway obstruction (NAO).Methods: A budget impact model was developed for two scenarios: a reference scenario of functional rhinoplasty surgery with concomitant septoplasty and inferior turbinate reduction (ITR) performed in the hospital outpatient department where TCRF is not an available a treatment option and a new scenario consisting of in-office TCRF treatment of the nasal valve and ITR. A payor perspective was adopted with a hypothetical population plan size of one million members. Costs were estimated over a time horizon of 4 years. The eligible population included patients with severe/extreme NAO and nasal valve collapse (NVC) as the primary cause or significant contributor. Data inputs were sourced from targeted literature reviews. Uncertainty within the model structure and input parameters was assessed using one-way sensitivity analysis.Results: The introduction of a TCRF device resulted in population-level cost savings of $20,015,123 and per-responder average cost savings of $3,531 through a 4-year time horizon due to lower procedure costs and complication rates of the device relative to the surgical comparator. Results were robust when varying parameter values in sensitivity analyses, with cost savings being most sensitive to the prevalence of NAO and estimated response rates to functional rhinoplasty and TCRF.Conclusions: In patients with severe/extreme NAO, with NVC as the primary or major contributor, introducing TCRF with ITR as a treatment option demonstrates the potential for significant cost savings over functional rhinoplasty with septoplasty and ITR.

Nasal valve dysfunction is a common cause of nasal airway obstruction (NAO) that has significant impact on heath and quality of life for affected individuals. Previously, patients were offered temporary measures or a type of surgery called functional rhinoplasty which is a highly complex surgery that can be costly, requires recovery time and, in rare cases, not be successful. Recently, a new minimally invasive treatment alternative for NAO called temperature-controlled radiofrequency (TCRF) that may be performed in a surgery center or a doctor's office has become available. This paper provides results of budget impact analysis performed to assess whether adding the TCRF procedure in place of surgery as a choice for patients with NAO will result in a cost savings to an insurance payer with 1 million covered individuals in the United States over a period of 4 years. Results show that TCRF may result in an average of 9,416 fewer rhinoplasty surgeries, provide an average 4-year cost-savings of $3,531 for every patient that responds to TCRF treatment and a savings of $20,015,123 over 4 years for the insurance provider. These potential cost savings over 4 years would likely be due to reduced procedure costs and complication rates compared to surgery.

OptoProfilin: A Single Component Biosensor of Applied Cellular Stress.

The actin cytoskeleton is a biosensor of cellular stress and a potential prognosticator of human disease. In particular, aberrant cytoskeletal structures such as stress granules formed in response to energetic and oxidative stress are closely linked to ageing, cancer, cardiovascular disease, and viral infection. Whether these cytoskeletal phenomena can be harnessed for the development of biosensors for cytoskeletal dysfunction and, by extension, disease progression, remains an open question. In this work, we describe the design and development of an optogenetic iteration of profilin, an actin monomer binding protein with critical functions in cytoskeletal dynamics. We demonstrate that this optically activated profilin ('OptoProfilin') can act as an optically triggered biosensor of applied cellular stress in select immortalized cell lines. Notably, OptoProfilin is a single component biosensor, likely increasing its utility for experimentalists. While a large body of preexisting work closely links profilin activity with cellular stress and neurodegenerative disease, this, to our knowledge, is the first example of profilin as an optogenetic biosensor of stress-induced changes in the cytoskeleton.

The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening.

NLRP3 is an intracellular sensor protein that detects a broad range of danger signals and environmental insults. Its activation results in a protective pro-inflammatory response designed to impair pathogens and repair tissue damage via the formation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent secretory release of the pro-inflammatory cytokines IL-1ß and IL-18 as well as to gasdermin d-mediated pyroptotic cell death. Herein, we describe the discovery of a novel indazole series of high affinity, reversible inhibitors of NLRP3 activation through screening of DNA-encoded libraries and the potent lead compound 3 (BAL-0028, IC50 = 25 nM) that was identified directly from the screen. SPR studies showed that compound 3 binds tightly (KD range 104-123 nM) to the NACHT domain of NLRP3. A CADD analysis of the interaction of compound 3 with the NLRP3 NACHT domain proposes a binding site that is distinct from those of ADP and MCC950 and includes specific site interactions. We anticipate that compound 3 (BAL-0028) and other members of this novel indazole class of neutral inhibitors will demonstrate significantly different physical, biochemical, and biological properties compared to NLRP3 inhibitors previously identified.

Optogenetic Regulation of EphA1 RTK Activation and Signaling.

Eph receptors are ubiquitous class of transmembrane receptors that mediate cell-cell communication, proliferation, differentiation, and migration. EphA1 receptors specifically play an important role in angiogenesis, fetal development, and cancer progression; however, studies of this receptor can be challenging as its ligand, ephrinA1, binds and activates several EphA receptors simultaneously. Optogenetic strategies could be applied to circumvent this requirement for ligand activation and enable selective activation of the EphA1 subtype. In this work, we designed and tested several iterations of an optogenetic EphA1 - Cryptochrome 2 (Cry2) fusion, investigating their capacity to mimic EphA1-dependent signaling in response to light activation. We then characterized the key cell signaling target of MAPK phosphorylation activated in response to light stimulation. The optogenetic regulation of Eph receptor RTK signaling without the need for external stimulus promises to be an effective means of controlling individual Eph receptor-mediated activities and creates a path forward for the identification of new Eph-dependent functions.

Omernik's Ecoregion Framework: a Legacy for Understanding Regional Patterns in Attainable Resource Quality.

An initial and comprehensive map of ecological regions across the conterminous United States was provided by Omernik in 1987. Because that paper was the most-cited published by the Annals of the American Association of Geographers, we sought to assess and quantify its contribution to science. To do so, we conducted a scientometric analysis to address the following main questions: 1) What are the temporal and spatial citation trends? We expected that Omernik's paper would still be employed 36 years after its publication, and mostly in the United States of America. 2) For what types of environments and organisms has it been applied? Based on its generality, we expected that it had been applied to both terrestrial and aquatic ecosystems. 3) What are the main applications of Omernik's article? We predicted that it would mostly be used for describing and delineating study sites and management areas, as well as for selecting regional reference sites. The number of citations presented a positive temporal increase, indicating its continued applicability. Most papers dealt with aquatic environments, mainly in streams carried out predominantly in the United States of America, as was one of its earliest applications. The usefulness of ecoregions for assessing and managing biotic and abiotic patterns and distributions were the main topics addressed by scientists. Ecoregions have offered a general framework for developing regional expectations and rational regional management policies across large areas, as was their original intent. In addition, ecoregion maps were used for communicating patterns-or the lack of them-to interested scientists, citizens, and decision-makers. That comprehensiveness of Omernik's ecoregion approach has led to its widespread applicability and continued usefulness to a diverse set of scientific and management disciplines.

Factors associated with weight loss and health gains in a structured lifestyle modification programme for adults with severe obesity: a prospective cohort study.

Background: Individual responses to behavioural weight loss interventions can vary significantly, and a better understanding of the factors associated with successful treatment might help to target interventions for those who will benefit the most. We sought to identify demographic and clinical characteristics that predicted intervention "success" (defined as ≥5% weight loss) and other health gains in patients with severe obesity attending a ten-week structured lifestyle modification programme. Methods: We conducted a prospective cohort study of all 1122 patients (751 (66.9%) female, mean age 47.3 ± 11.9 years, mean body mass index (BMI) 46.7 ± 7.8 kgm-2) referred from our hospital-based obesity clinic, who started the structured lifestyle programme between 2012-2019. We compared routine clinical measures such as weight, fitness, blood pressure, lipids and HbA1c at baseline and follow-up. We also used validated questionnaires to quantify anxiety, depression and health-related quality of life. Results: Of 1122 patients who started, 877 (78.2%) completed the programme and attended for follow up. Of these, 12.8% lost ≥5% body weight. The amount of weight lost was a strong and consistent predictor of improvements in metabolic, cardiovascular, and mental health, even after adjusting for age, sex, programme attendance and baseline fitness. Older age, male sex, being physically active and having lower anxiety and depression scores at baseline predicted greater weight loss. Younger age, depression and longer wait time to start the intervention were associated with drop-out. Conclusions: In adults with severe obesity completing a structured lifestyle modification programme, older age and good mental health were associated with programme completion and attaining ≥5% weight loss. The magnitude of weight lost was a strong predictor of improvements in cardiovascular, metabolic and mental health associated with programme completion.

Periodic arrays of structurally complex oxide nanoshells and their use as substrate-confined nanoreactors.

Sacrificial templates present an effective pathway for gaining high-level control over nanoscale reaction products. Atomic layer deposition (ALD) is ideally suited for such approaches due to its ability to replicate the surface topography of a template material through the deposition of an ultrathin conformal layer. Herein, metal nanostructures are demonstrated as sacrificial templates for the formation of architecturally complex and deterministically positioned oxide nanoshells, open-topped nanobowls, vertically standing half-shells, and nanorings. The three-step process sees metal nanocrystals formed in periodic arrays, coated with an ALD-deposited oxide, and hollowed out with a selective etch through nanopores formed in the oxide shell. The procedure is further augmented through the use of a directional ion beam that is used to sculpt the oxide shells into bowl- and ring-like configurations. The functionality of the so-formed materials is demonstrated through their use as substrate-confined nanoreactors able to promote the growth and confinement of nanomaterials. Taken together, the work expands the design space for substrate-based nanomaterials, creates a platform for advancing functional surfaces and devices and, from a broader perspective, advances the use of ALD in forming complex nanomaterials.

OptoProfilin: A Single Component Biosensor of Applied Cellular Stress.

The actin cytoskeleton is a biosensor of cellular stress and a potential prognosticator of human disease. In particular, aberrant cytoskeletal structures such as cofilin-actin rods and stress granules formed in response to energetic and oxidative stress are closely linked to neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Whether these cytoskeletal phenomena can be harnessed for the development of biosensors for cytoskeletal dysfunction and, by extension, neurodegenerative disease progression, remains an open question. In this work, we describe the design and development of an optogenetic iteration of profilin, an actin monomer binding protein with critical functions in cytoskeletal dynamics. We demonstrate that this optically activated profilin ('OptoProfilin') can act as an optically triggered biosensor of applied cellular stress in select immortalized cell lines. Notably, OptoProfilin is a single component biosensor, likely increasing its utility for experimentalists. While a large body of preexisting work closely links profilin activity with cellular stress and neurodegenerative disease, this, to our knowledge, is the first example of profilin as an optogenetic biosensor of stress-induced changes in the cytoskeleton.

Effects on child and adolescent health of climate change mitigation policies: A systematic review of modelling studies.

There is a growing body of modelling evidence that demonstrates the potential for immediate and substantial benefits to adult health from greenhouse gas mitigation actions, but the effects on the health of younger age groups is largely unknown. We conducted a systematic review to identify the available published evidence of the modelled effects on child and adolescent health (≤18 years of age) of greenhouse gas mitigation. We searched six databases of peer-reviewed studies published between January 1, 1990 and July 27, 2022, screened 27,282 original papers and included 23 eligible papers. All included studies were set in high- and middle-income countries; and all studies modelled the effects of interventions that could mitigate greenhouse gas emissions and improve air quality. Most of the available evidence suggests positive benefits for child and adolescent respiratory health from greenhouse gas mitigation actions that simultaneously reduce air pollution (specifically PM2.5 and nitrogen dioxide). We found scant evidence on child and adolescent health from regions more vulnerable to climate change, or on mitigation interventions that could affect exposures other than air pollution.

A comparison of the effect of patient-specific versus weight-based protocols to treat vaso-occlusive episodes in the emergency department.

BACKGROUND: Vaso-occlusive crises (VOCs) cause debilitating pain and are a common cause of emergency department (ED) visits, for people with sickle cell disease (SCD). Strategies for achieving optimal pain control vary widely despite evidence-based guidelines. We tested existing guidelines and hypothesized that a patient-specific pain protocol (PSP) written by their SCD provider may be more effective than weight-based (WB) dosing of parenteral opiate medication, in relieving pain. METHODS: This study was a prospective, randomized controlled trial comparing a PSP versus WB protocol for patients presenting with VOCs to six EDs. Patients were randomized to a PSP or WB protocol prior to an ED visit. The SCD provider wrote their protocol and placed it in the electronic health record for future ED visits with VOC exclusion criteria that included preexisting PSP excluding parenteral opioid analgesia or outpatient use of buprenorphine or methadone or highly suspected for COVID-19. Pain intensity scores, side effects, and safety were obtained every 30 min for up to 6 h post-ED bed placement. The primary outcome was change in pain intensity score from placement in an ED space to disposition or 6 h. RESULTS: A total of 328 subjects were randomized; 104 participants enrolled (ED visit, target n = 230) with complete data for 96 visits. The study was unable to reach the target sample size and stopped early due to the impact of COVID-19. We found no significant differences between groups in the primary outcome; patients randomized to a PSP had a shorter ED length of stay (p = 0.008), and the prevalence of side effects was low in both groups. Subjects in both groups experienced both a clinically meaningful and a statistically significant decrease in pain (27 mm on a 0- to 100-mm scale). CONCLUSIONS: We found a shorter ED length of stay for patients assigned to a PSP. Patients in both groups experienced good pain relief without significant side effects.

Predicting climate heating impacts on riverine fish species diversity in a biodiversity hotspot region.

Co-occurring biodiversity and global heating crises are systemic threats to life on Earth as we know it, especially in relatively rare freshwater ecosystems, such as in Iran. Future changes in the spatial distribution and richness of 131 riverine fish species were investigated at 1481 sites in Iran under optimistic and pessimistic climate heating scenarios for the 2050s and 2080s. We used maximum entropy modeling to predict species' potential distributions by hydrologic unit (HU) occupancy under current and future climate conditions through the use of nine environmental predictor variables. The most important variable determining fish occupancy was HU location, followed by elevation, climate variables, and slope. Thirty-seven species were predicted to decrease their potential habitat occupancy in all future scenarios. The southern Caspian HU faces the highest future species reductions followed by the western Zagros and northwestern Iran. These results can be used by managers to plan conservational strategies to ease the dispersal of species, especially those that are at the greatest risk of extinction or invasion and that are in rivers fragmented by dams.

Patterns in and predictors of stream and river macroinvertebrate genera and fish species richness across the conterminous USA.

Both native and non-native taxa richness patterns are useful for evaluating areas of greatest conservation concern. To determine those patterns, we analyzed fish and macroinvertebrate taxa richness data obtained at 3475 sites collected by the USEPA's National Rivers and Streams Assessment. We also determined which natural and anthropogenic variables best explained patterns in regional richness. Macroinvertebrate and fish richness increased with the number of sites sampled per region. Therefore, we determined residual taxa richness from the deviation of observed richness from predicted richness given the number of sites per region. Regional richness markedly exceeded average site richness for both macroinvertebrates and fish. Predictors of macroinvertebrate-genus and fish-species residual-regional richness differed. Air temperature was an important predictor in both cases but was positive for fish and negative for macroinvertebrates. Both natural and land use variables were significant predictors of regional richness. This study is the first to determine mean site and regional richness of both fish and aquatic macroinvertebrates across the conterminous USA, and the key anthropogenic drivers of regional richness. Thus, it offers important insights into regional USA biodiversity hotspots.

Parental experiences of the impacts of Covid-19 on the care of young children; qualitative interview findings from the Nairobi Early Childcare in Slums (NECS) project.

INTRODUCTION: The Covid-19 pandemic, and societal attempts to control it, have touched almost every aspect of people's lives around the world, albeit in unequal ways. In particular, there is considerable concern about the way that stringent 'lockdowns', as implemented in Kenya and many other countries, affected young children, especially those living in informal settlements. However, to date, there has been little research attempting to unpack and understand how the pandemic has impacted on the care of young children. METHODS: In-depth telephone interviews were conducted with 21 parents/carers of children aged under five years living in three Nairobi slums between May and September 2021 exploring the ways in which Covid-19, and policies to control the pandemic, impacted on their household and the care of their child/children. RESULTS: The impacts of Covid-19 control measures on the care of children have been widely felt, deep and multiple. The impact of economic hardship has been significant, reportedly undermining food security and access to services including healthcare and childcare. Respondents reported an associated increase in domestic and community violence. Many people relied on help from others; this was most commonly reported to be in the form of variable levels of flexibility from landlords and help from other community members. No direct harms from Covid-19 disease were reported by respondents. CONCLUSION: The impacts of Covid-19 control measures on the care of young children in informal settlements have been indirect but dramatic. Given the breadth and depth of these reported impacts, and the particular vulnerability of young children, deeper consideration ought to inform decisions about approaches to implementation of stringent disease control measures in future. In addition, these findings imply a need for both short- and long-term policy responses to ameliorate the impacts described.

Cost sharing in managed care and the ethical question of business purpose.

For-profit managed care organizations face decisions about cost sharing that can involve a tradeoff between the interests of investors and the interests of patients. No successful business can ignore the interests of its investors, but moral philosophy points to ethical reasons for managed care organizations to make patients' health, rather than investors' profit, their primary goal. One reason is the ethical obligation of all businesses to avoid wrongful exploitation of vulnerable customers. An insurance company's cost-sharing policy can exploit customers either by collecting an unfairly large amount of money from them or by unfairly deterring them from making claims for resources they medically need. Another reason stems from the fact that managed care organizations' profits derive in part from the existence of artificial barriers to access to medicine, notably including patents. Putting a fence around a water well in the desert is legitimate only if doing so facilitates a financial arrangement that maximizes people's access to water they need. Likewise, patents and other artificial barriers to access to medically necessary drugs are legitimate only if they are used to help finance access to medical resources people need. For these reasons, managed care organizations should make cost-sharing decisions that maximize the sustainable availability of effective drugs to patients who need them. DISCLOSURES: The thoughts and opinions expressed in this article are those of the author only and are not the thoughts and opinions of any current or former employer of the author. Nor is this publication made by, on behalf of, or endorsed or approved by any current or former employer of the author.