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Melanin, a ubiquitous dark pigment, plays important roles in the immune system, including scavenging reactive oxygen species formed in response to ultraviolet radiation absorption, absorbing metals, thermal regulation, drug uptake, innate immune system functions, redox, and energy transduction. Many tissue types, including brain, heart, arteries, ovaries, and others, contain melanin. Almost all cells contain precursors to melanin. A growing number of diseases in which there is a loss of melanin and/or neuromelanin are increasingly thought to have infectious etiologies, for example, Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy Body Dementia (LBD), and vitiligo. AD, PD, LBD, and vitiligo have been linked with herpesvirus, which enters melanosomes and causes apoptosis, and with gut dysbiosis and inflammation. Herpesvirus is also linked with gut dysbiosis and inflammation. We theorize that under normal healthy states, melanin retains some of the energy it absorbs from electromagnetic radiation, which is then used to fuel cells, and energy from ATP is used to compliment that energy supply. We further theorize that loss of melanin reduces the energy supply of cells, which in the case of AD, PD, and LBD results in an inability to sustain immune system defenses and remove the plaques associated with the disease, which appear to be part of the immune system’s attempt to eradicate the pathogens seen in these neurodegenerative diseases. In addition, in an attempt to explain why removing these plaques does not result in improvements in cognition and mood and why cognitions and moods in these individuals have ebbs and flows, we postulate that it is not the plaques that cause the cognitive symptoms but, rather, inflammation in the brain resulting from the immune system's response to pathogens. Our theory that energy retained in melanin fuels cells in an inverse relationship with ATP is supported by studies showing alterations in ATP production in relationship to melanin levels in melanomas, vitiligo, and healthy cells. Therefore, alteration of melanin levels may be at the core of many diseases. We propose regulating melanin levels may offer new avenues for treatment development.

Abstract Background Lynch syndrome is an underdiagnosed hereditary condition carrying an increased lifetime risk for colorectal and endometrial cancer and affecting nearly 1 million people in the United States. Cascade screening, systematic screening through family members of affected patients, could improve identification of Lynch syndrome, but this strategy is underused due to multi-level barriers including low knowledge about Lynch syndrome, low access to genetics services, and challenging family dynamics. Methods We used intervention mapping, a 6-step methodology to create stakeholder-driven interventions that meet the needs of a target population, to develop an intervention to improve cascade screening for Lynch syndrome. The intervention development process was guided by input from key stakeholders in Lynch syndrome care and patients. We conducted usability testing on the intervention with Lynch syndrome patients using qualitative semi-structured interviewing and rapid qualitative analysis. Results We developed a workbook intervention named Let’s Talk that addresses gaps in knowledge, skills, self-efficacy, outcome expectancy and other perceived barriers to cascade screening for Lynch syndrome. Let’s Talk contained educational content, goal setting activities, communication planning prompts and supplemental resources for patients to plan family communication. Evidence-based methods used in the workbook included information chunking, guided practice, goal setting and gain-framing. We conducted usability testing focused on the complexity and relative advantage of the intervention through 45-min virtual interviews with 10 adult patients with Lynch syndrome recruited from a national advocacy organization in the United States. Usability testing results suggested the intervention was acceptable in terms of complexity and relative advantage to other available resources, but additional information for communication with young or distant family members and a web-based platform could enhance the intervention’s usability. Conclusions Intervention mapping provided a framework for intervention development that addressed the unique needs of Lynch syndrome patients in overcoming barriers to cascade screening. Future work is needed to transform Let’s Talk into a web-based tool and evaluate the effectiveness of the intervention in clinical practice with patients and genetic counselors. Intervention mapping can be useful to researchers as an evidence-based technique to develop stakeholder-centered interventions for addressing the needs of other unique populations.

Abstract Aims Ventricular longitudinal function measured as basal‐apical atrioventricular plane displacement (AVPD) or global longitudinal strain (GLS) is a potent predictor of mortality and could potentially be a predictor of heart failure‐associated morbidity. We hypothesized that low AVPD and GLS are associated with the combined endpoint of cardiovascular mortality and heart failure‐associated morbidity. Methods and results Two hundred eighty‐seven patients (age 62 ± 12 years, 78% male) with heart failure with reduced (≤40%) ejection fraction (HFrEF) referred to a cardiovascular magnetic resonance exam were included. Ventricular longitudinal function, ventricular volume, and myocardial fibrosis or infarction were analysed from cine and late gadolinium enhancement images. National registries provided data on causes of cardiovascular hospitalizations and cardiovascular mortality for the combined endpoint. Time‐to‐event analysis capable of including reoccurring events was employed with a 5‐year follow‐up. HFrEF patients had EF 26.5 ± 8.0%, AVPD 7.8 ± 2.4 mm, and GLS −7.5 ± 3.0%. In contrast, ventricular longitudinal function was approximately twice as large in an age‐matched control group (AVPD 15.3 ± 1.6 mm; GLS −20.6 ± 2.0%; P −6.1%) overall experienced more than 3 times as many events as the top tertile (>8.8 mm or

Background Both myocardial perfusion single‐photon emission computed tomography (MPS) and exercise ECG (Ex‐ECG) carry prognostic information in patients with stable chest pain. However, it is not fully understood if combining the findings of MPS and Ex‐ECG improves risk prediction. Current guidelines no longer recommend Ex‐ECG for diagnostic evaluation of chronic coronary syndrome, but Ex‐ECG could still be of incremental prognostic importance. Methods and Results This study comprised 908 consecutive patients (age 63.3±9.4 years, 49% male) who performed MPS with Ex‐ECG. Subjects were followed for 5 years. The end point was a composite of cardiovascular death, acute myocardial infarction, unstable angina, and unplanned percutaneous coronary intervention. National registry data and medical charts were used for end point allocation. Combining the findings of MPS and Ex‐ECG resulted in concordant evidence of ischemia in 72 patients or absence of ischemia in 634 patients. Discordant results were found in 202 patients (MPS−/Ex‐ECG+, n=126 and MPS+/Ex‐ECG−, n=76). During follow‐up, 95 events occurred. Annualized event rates significantly increased across groups (MPS−/Ex‐ECG− =1.3%, MPS−/Ex‐ECG+ =3.0%, MPS+/Ex‐ECG− =5.1% and MPS+/Ex‐ECG+ =8.0%). In multivariable analyses MPS was the strongest predictor regardless of Ex‐ECG findings (MPS+/Ex‐ECG−, hazard ratio [HR], 3.0, P=0.001 or MPS+/Ex‐ECG+, HR,4.0, P

Summary: During evolution, humans are acclimatized to the stresses of natural radiation and circadian rhythmicity. Radiosensitivity of mammalian cells varies in the circadian period and adaptive radioprotection can be induced by pre-exposure to low-level radiation (LDR). It is unclear, however, if clock proteins participate in signaling LDR radioprotection. Herein, we demonstrate that radiosensitivity is increased in mice with the deficient Period 2 gene (Per2def) due to impaired DNA repair and mitochondrial function in progenitor bone marrow hematopoietic stem cells and monocytes. Per2 induction and radioprotection are also identified in LDR-treated Per2wt mouse cells and in human skin (HK18) and breast (MCF-10A) epithelial cells. LDR-boosted PER2 interacts with pGSK3β(S9) which activates β-catenin and the LEF/TCF mediated gene transcription including Per2 and genes involved in DNA repair and mitochondrial functions. This study demonstrates that PER2 plays an active role in LDR adaptive radioprotection via PER2/pGSK3β/β-catenin/Per2 loop, a potential target for protecting normal cells from radiation injury.

RationaleSince many modern exergames include a multiplayer component, this study aimed to compare the physiological and perceptual responses between playing a cycling exergame alone or with others.MethodsIn this randomized crossover study, 15 healthy individuals aged between 10 and 30 years completed a single-player and a multiplayer exergaming session. The main outcomes were exercise intensity, measured as oxygen uptake (V°O2) and heart rate (HR), and perceived enjoyment, pleasure, and exertion.ResultsPeak HR was significantly higher during multiplayer (172 ± 23 beats per minute [bpm]) vs. single-player exergaming (159 ± 27 bpm) with a mean difference of 13 bpm (95% CI: 2 to 24, p = 0.02). Peak V°O2 was 33.6 ± 9.5 mL·kg−1·min−1 and 30.4 ± 9.1 mL·kg−1·min−1 during multiplayer and single-player exergaming, respectively with no statistically significant difference between conditions (3.2, 95% CI: −0.2–6.6 mL·kg−1·min−1, p = 0.06). Average HR, average V°O2 and perceptual responses did not differ between single- and multiplayer exergaming.ConclusionOther than inducing a higher HR, multiplayer exergaming showed no significant benefits on exercise intensity or perceptual responses over single-player exergaming. However, the higher peak HR and a tendency of higher peak V°O2 intensity during multiplayer exergaming imply that multiplayer exergaming may offer some advantages over single-player exergaming that could impact the potential health benefits of exergaming.

Abstract Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously, are increasingly generating data that can be used as additional evidence for or against variant pathogenicity. Such assays have the potential to resolve variants of uncertain significance, thereby increasing the clinical utility of genomic testing. Existing standards from the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) and new guidelines from the Clinical Genome Resource (ClinGen) establish the role of functional data in variant interpretation, but do not address the specific challenges or advantages of using functional data derived from multiplexed assays. Here, we build on these existing guidelines to provide recommendations to experimentalists for the production and reporting of multiplexed functional data and to clinicians for the evaluation and use of such data. By following these recommendations, experimentalists can produce transparent, complete, and well-validated datasets that are primed for clinical uptake. Our recommendations to clinicians and diagnostic labs on how to evaluate the quality of multiplexed functional datasets, and how different datasets could be incorporated into the ACMG/AMP variant-interpretation framework, will hopefully clarify whether and how such data should be used. The recommendations that we provide are designed to enhance the quality and utility of multiplexed functional data, and to promote their judicious use.

The current COVID-19 pandemic has unfortunately resulted in many significant concerns for individuals with genetic disorders and their relatives, regarding the viral infection and, particularly, its specific implications and additional advisable precautions for individuals affected by genetic disorders. To address this, the resulting requirement for guidance and information for the public and for genetics professionals was discussed among colleagues nationally, on the ScotGEN Steering Committee, and internationally on the Education Committee of the European Society of Human Genetics (ESHG). It was agreed that the creation of an online hub of genetics-related COVID-19 information resources would be particularly helpful. The proposed content, divided into a web page for professionals and a page for patients, was discussed with, and approved by, genetics professionals. The hub was created and provided online at www.scotgen.org.uk and linked from the ESHG’s educational website for genetics and genomics, at www.eurogems.org. The new hub provides links, summary information and representative illustrations for a wide range of selected international resources. The resources for professionals include: COVID-19 research related hubs provided by Nature, Science, Frontiers, and PubMed; clinical guidelines; the European Centre for Disease Prevention and Control; the World Health Organisation; and molecular data sources including coronavirus 3D protein structures. The resources for patients and families include links to many accessible sources of support and relevant information. Since the launch of the pages, the website has received visits from over 50 countries worldwide. Several genetics consultants have commented on usefulness, clarity, readability, and ease of navigation. Visits have originated most frequently in the United Kingdom, Kuwait, Hong Kong, Moldova, United States, Philippines, France, and Qatar. More links have been added since the launch of the hub to include additional international public health and academic resources. In conclusion, an up-to-date online hub has been created and made freely available for healthcare professionals, patients, relatives and the public, providing categorised easily navigated links to a range of worldwide resources related to COVID-19. These pages are receiving a rapidly growing number of return visits and the authors continue to maintain and update the pages’ content, incorporating new developments in this field of enormous worldwide importance.

RationaleExergaming may be a viable alternative to more traditional exercise. As high-intensity exercise can provide substantial health benefits, the purpose of this study was to investigate the long-term effectiveness of providing inactive adults with access to a high-intensity exergaming platform.MethodsIn this study, 52 inactive adults (

ObjectivesThe aims of this pilot study were to investigate oxygen uptake (V̇O2) while playing a cycling exergame to assess exercise intensity to determine its potential as a feasible exercise alternative to improve aerobic fitness, and to assess the validity of using heart rate (HR) to estimate V̇O2 in exergaming.MethodsFive males (age: 32±8; peak oxygen uptake (V̇O2peak): 47.9±7.8 mL·kg−1·min−1) and five females (age: 27±3; V̇O2peak: 33.9±4.6 mL·kg−1·min−1) played the cycling exergame ‘Pedal Tanks’ for 45 min, with measurements of HR and V̇O2.ResultsAverage and peak V̇O2 during exergaming were 61.7±10.1% and 78.3±11.7% of V̇O2peak, respectively, whereas average and peak HR were 80.0±9.4% and 91.5%±6.7% of HRpeak. There was a strong positive correlation between V̇O2 and HR for all participants (p

RationaleThe main purposes of this study were to compare mitochondrial respiration in M. triceps brachii and M. vastus lateralis between elite cross-country (XC) skiers and physically active controls (CON), and to explore the associations between mitochondrial respiration in these muscles and peak oxygen uptake (V˙O2peak) in arm- and leg-dominant exercise modes.MethodsThirteen male elite XC skiers (age: 25 ± 4; peak oxygen uptake (V˙O2peak): 75.5 ± 4.2 mL⋅kg-1⋅min-1) and twelve CON (age: 26 ± 3; V˙O2peak: 57.2 ± 6.4 mL⋅kg-1⋅min-1) had microbiopsies taken from M. vastus lateralis and M. triceps brachii, which were analyzed for various measures of mitochondrial respiration using high-resolution respirometry. Thereafter, all participants tested V˙O2peak in both running (RUN) and upper body poling (UBP).ResultsXC skiers had generally higher mitochondrial respiration in M. triceps brachii compared to CON (P < 0.001), whereas no significant group-differences in mitochondrial respiration in M. vastus lateralis were revealed. XC skiers had higher mitochondrial respiration in M. triceps brachii compared to M. vastus lateralis (P = 0.005–0.058), whereas in CON, most mitochondrial respiration measures were higher in M. vastus lateralis than in M. triceps brachii (P < 0.01). When all athletes were pooled, there was a strong positive correlation between V˙O2peak in UBP and mitochondrial respiration in M. triceps brachii on several measures (P < 0.01), whereas no correlation was found for RUN.ConclusionThe higher mitochondrial respiration found in M. triceps brachii compared to M. vastus lateralis among our elite XC skiers demonstrates the potential for the arm muscles to adapt to aerobic endurance training. The opposite pattern found in CON, clearly showed lower mitochondrial respiration in M. triceps brachii compared to XC skiers, whereas respiration in M. vastus lateralis did not differ between groups. The strong positive correlation between mitochondrial respiration in M. triceps brachii and V˙O2peak in UBP indicate that arm muscles’ respiratory function may be a limiting factor for V˙O2peak in arm-dominant exercise modes.

Experiences of shame and psychological suffering by foodbank clients Foodbanks have existed for over ten years in the Netherlands. They provide weekly food parcels to 94,000 households, according to the most recent figures published by the national Dutch food bank organization at the end of 2014. The national foodbank organizations set qualifying criteria for clients who wish to receive a food parcel on a weekly basis. Foodbanks in the Netherlands have different ways of distributing the food to their clients. In some foodbanks the clients need to stand in line and receive a pre-packaged food parcel. In other foodbanks, clients can choose which products they take home. The food is donated, which means that the contents of the food parcels vary in terms of both the amount of food that they contain and the type of food. Research shows that most clients of foodbanks in the Netherlands have a very low income and are in debt. International and Dutch studies show that many foodbank clients suffer from health problems and chronic diseases. Psychological problems are also common among foodbank clients.In this article we aim to provide an insight into the psychological suffering, shame and other emotions that foodbank clients can experience. The findings are based on qualitative research, which was completed as part of an external PhD research study. We analysed 45 in-depth interviews with foodbank clients. We also related our findings to the results of studies on foodbank clients as well as studies about shame and stigma in relation to poverty. In the Netherlands, few studies have been conducted about foodbanks and their users, and in international studies too, the perspective of foodbank clients is missing. Our study fills this gap by focusing on these actors’ point of view.For this research, we selected foodbank clients in Amsterdam based on quota sampling. We approached clients at the foodbank or by phone and conducted in-depth interviews with 18 men and 27 women. The interviews were transcribed verbatim and analysed in Atlas.ti by two researchers, using attribute and structural coding.Our results show that foodbank clients use a combination of different strategies to cope with living on tight budgets. Most of them save money on food, non-food and social activities. Another strategy is to ask for support from family or friends for money, clothing or food. Some respondents are almost completely dependent on gifts from friends and the food parcel and some also reported being restricted in their social life and having lost friends. We found that lack of money is related to psychological suffering: sleeplessness, stress, fear, panic, depression and feelings of sadness. The causes mentioned for this suffering were: debts, persistent letters from creditors, and not being able to afford consumer goods and/or activities. Some respondents reported seeking to numb these feelings through the use of alcohol or cannabis. Others avoided opening letters or answering telephone calls.In the interviews, foodbank clients expressed their feelings about their situation. Shame was the most frequently mentioned emotion and related to the label of “foodbank client”, the working method of the foodbank or not being able to consume what they wanted to. Firstly, respondents felt ashamed about being a foodbank client, because this is not acceptable in their social and cultural environment, and there is a negative stigma associated with being a foodbank client rather than a “normal working citizen”. Some of the respondents try to hide the fact that they use a foodbank, while others stated that they liked to form friendships with other foodbank clients because they would be more likely to accept and understand them. Another reaction was to downplay the situation. Secondly, shame was connected to the way that the foodbank operates. Clients feel ashamed to have to show their administration in the assessment interview before they can qualify for a food parcel. Shame is also felt when going to the foodbank and as result of the lack of choice of food. Thirdly, we found a category of shame that was related to the restrictions of consumption. The foodbank clients feel that they are unable to buy the food or clothing that they want or to take part in activities.In conclusion, we found, in line with other studies, that foodbank clients experience psychological suffering and feelings of shame. These feelings of shame relate to the stigma attached to being a foodbank client and are reinforced by the way the foodbanks operate. Foodbank clients feel that they have a lack of choice, not only at the foodbank, but also in the wider context of the consumer society. SAMENVATTINGErvaringen van schaamte en psychologisch lijden door voedselbankklanten Voedselbanken bestaan al meer dan tien jaar in Nederland en groeien in aantal en omvang. Er is beperkt wetenschappelijk onderzoek gedaan naar voedselbankklanten in Nederland en ook in internationale studies ontbreekt het klantperspectief. In dit artikel presenteren wij bevindingen uit 45 diepte-interviews met voedselbankklanten in Amsterdam, waarbij wij hun ervaring centraal stelden. De centrale vraag die wij in dit artikel beantwoorden is: welke rol spelen financiële problemen, schaamte en andere emoties bij voedselbankklanten in Amsterdam? Voedselbankklanten zeggen dat zij besparen op consumptiemiddelen en activiteiten vanwege hun gelimiteerde budget. Het gebrek aan geld beperkt een aantal respondenten in hun sociale leven. In reactie op geldzorgen laten sommigen hun post ongeopend of zij verdoven zich. De respondenten uiten dat zij stress, slapeloosheid, angst, paniek, depressie en/of somberheid door geldgebrek ervaren. Dit vatten wij samen als psychologisch lijden. Hiernaast is schaamte een veel genoemde emotie. Ook uit andere studies bleek dat schaamte veel voorkomt bij voedselbankklanten. Wij zagen hiervoor drie verschillende oorzaken: het stempel voedselbankklant, de werkwijze van de voedselbank en het beperkt zijn qua consumptiemogelijkheden. Reacties op de schaamte zijn: relativeren, afstand nemen of juist verbinding zoeken met andere voedselbankklanten. Hiernaast zijn er respondenten die proberen te verbergen dat zij voedselbankklant zijn.

The recent development of multiplex ligation-dependent probe amplification (MLPA) has provided an efficient and reliable assay for dosage screening of multiple loci in a single reaction. However, a drawback to this method is the time-consuming process of generating a probe set by cloning in single-stranded bacteriophage vectors. We have developed a synthetic probe set to screen for deletions in a region spanning 18.5 Mb within chromosome 3q. In a pilot study, we tested 15 synthetic probes on 4 control samples and on 2 patients previously found to possess a heterozygous deletion in the region 3q26–q28. These synthetic probes detected deletions at all previously known deleted loci. Furthermore, using synthetic probes, the variability of results within samples was similar to that reported for commercially available M13-derived probes. Our results demonstrate that this novel approach to MLPA provides a generic solution to the difficulties of probe development by cloning; such synthetically generated probes may be used to screen a large number of loci in a single reaction. We conclude that the use of synthetic probes for MLPA is a rapid, robust, and efficient alternative for research (and potentially diagnostic) deletion and duplication screening of multiple genomic loci.

It is wrong to think that questions of interpretation are significant in informal logic only to the extent that they contribute to the assessment of an argument's conclusion. For one thing, logic is essentially about validity, about that in virtue of which conclusions do or do not follow from given premises, and not about the truth or falsity of conclusions by themselves. Secondly, the evaluation of a given argument requires first determining what the given argument is. Moreover, since arguments are given in rational discourse in order to persuade-in order to arrive, by reason, at agreement-it is necessary to address the very arguments that arguers actually intend.

Cochlear implants (CIs) provide hundreds of thousands of users with increased access to sound, particularly speech, but experiences of music are more varied. Can greater engagement by CI users in the music mixing process mutually benefit them as well as audio engineers? This paper presents an exploratory mixed-methods study that leverages insights from CI users and professional audio engineers (AEs) in the investigation of techniques to enhance CI user music enjoyment and promote empathetic practices in AEs. Analysis of data collected over a multi-step process of surveys, interviews, and iterative cycles of sound mixing and feedback revealed two mixing strategies—namely essentializing and exaggeration of musical elements—common among mixes preferred by CI users. Participant responses also highlighted systemic ableism and audism in the music industry—an industry from which CI users report feeling excluded. Specifically, AEs felt inadequately trained around aural diversity considerations and experienced anxiety around their own aural diversity. In sum, this work contributes to insights into CI user music listening preferences; how AEs approach mixing for an aurally diverse audience; and discussion around the efficacy of CI simulation, user feedback, and AE peer feedback on mix enjoyment by CI users. Based on these findings, we offer several design insights that emphasize the need for customizable music listening tools centered around user agency and enjoyment.