A gut-secreted peptide suppresses arousability from sleep.

Suppressing sensory arousal is critical for sleep, with deeper sleep requiring stronger sensory suppression. The mechanisms that enable sleeping animals to largely ignore their surroundings are not well understood. We show that the responsiveness of sleeping flies and mice to mechanical vibrations is better suppressed when the diet is protein rich. In flies, we describe a signaling pathway through which information about ingested proteins is conveyed from the gut to the brain to help suppress arousability. Higher protein concentration in the gut leads to increased activity of enteroendocrine cells that release the peptide CCHa1. CCHa1 signals to a small group of dopamine neurons in the brain to modulate their activity; the dopaminergic activity regulates the behavioral responsiveness of animals to vibrations. The CCHa1 pathway and dietary proteins do not influence responsiveness to all sensory inputs, showing that during sleep, different information streams can be gated through independent mechanisms.

Sleep quality and patterns of young West Balkan adults during the third wave of COVID-19 pandemic: a cross-sectional study.

OBJECTIVES: To evaluate the sleep patterns among young West Balkan adults during the third wave of the COVID-19 pandemic. DESIGN AND SETTING: Cross-sectional study conducted using an anonymous online questionnaire based on established sleep questionnaires Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) (February-August 2021). PARTICIPANTS: Young adults of Bosnia and Herzegovina, Croatia and Serbia. RESULTS: Of 1058 subjects, mean age was 28.19±9.29 years; majority were women (81.4%) and students (61.9%). Compared with before the pandemic, 528 subjects (49.9%) reported a change in sleeping patterns during the pandemic, with 47.3% subjects reporting sleeping less. Mean sleeping duration during the COVID-19 pandemic was 7.71±2.14 hours with median sleep latency of 20 (10.0-30.0) min. Only 91 (8.6%) subjects reported consuming sleeping medications. Of all, 574 (54.2%) subjects had ISI score >7, with majority (71.2%) having subthreshold insomnia, and 618 (58.4%) PSQI score ≥5, thus indicating poor sleep quality. Of 656 (62.0%) tested subjects, 464 (43.9%) were COVID-19 positive (both symptomatic and asymptomatic) who were 48.8%, next to women (70%), more likely to have insomnia symptoms; and 66.9% were more likely to have poor sleep quality. Subjects using sleep medication were 44 times, and subjects being positive to ISI 15.36 times more likely to have poor sleep quality. In contrast, being a student was a negative independent predictor for both insomnia symptoms and poor sleep quality, and mental labour and not working were negative independent predictors for insomnia symptoms. CONCLUSIONS: During the third wave of the pandemic, sleep patterns were impaired in about half of young West Balkan adults, with COVID-19-positive subjects and being women as positive independent predictors and being a student as negative independent predictor of impaired sleep pattern. Due to its importance in long-term health outcomes, sleep quality in young adults, especially COVID-19-positive ones, should be thoroughly assessed.

Health impacts of air pollution exposure from 1990 to 2019 in 43 European countries.

Air pollution is the fourth greatest overall risk factor for human health. Despite declining levels in Europe, air pollution still represents a major health and economic burden. We collected data from the Global Burden of Disease Study 2019 regarding overall, as well as ischemic heart disease (IHD), stroke, and tracheal, bronchus and lung cancer-specific disability adjusted life years (DALYs), years of life lost (YLL) and mortality attributable to air pollution for 43 European countries between 1990 and 2019. Concentrations of ambient particulate matter (aPM2.5), ozone, and household air pollution from solid fuels were obtained from State of Global Air 2020. We analysed changes in air pollution parameters, as well as DALYs, YLL, and mortality related to air pollution, also taking into account gross national income (GNI) and socio-demographic index (SDI). Using a novel calculation, aPM2.5 ratio (PMR) change and DALY rate ratio (DARR) change were used to assess each country's ability to decrease its aPM2.5 pollution and DALYs to at least the extent of the European median decrease within the analysed period. Finally, we created a multiple regression model for reliably predicting YLL using aPM2.5 and household air pollution. The average annual population-weighted aPM2.5 exposure in Europe in 1990 was 20.8 µg/m3 (95% confidence interval (CI) 18.3-23.2), while in 2019 it was 33.7% lower at 13.8 µg/m3 (95% CI 12.0-15.6). There were in total 368 006 estimated deaths in Europe in 2019 attributable to air pollution, a 42.4% decrease compared to 639 052 in 1990. The majority (90.4%) of all deaths were associated with aPM2.5. IHD was the primary cause of death making up 44.6% of all deaths attributable to air pollution. The age-standardised DALY rate and YLL rate attributable to air pollution were more than 60% lower in 2019 compared to 1990. There was a strong positive correlation (r = 0.911) between YLL rate and aPM2.5 pollution in 2019 in Europe. Our multiple regression model predicts that for 10% increase in aPM2.5, YLL increases by 16.7%. Furthermore, 26 of 43 European countries had a positive DARR change. 31 of 43 European countries had a negative PMR change, thus not keeping up with the European median aPM2.5 concentration decrease. When categorising countries by SDI and GNI, countries in the higher brackets had significantly lower aPM2.5 concentration and DALY rate for IHD and stroke. Overall, air pollution levels, air pollution-related morbidity and mortality have decreased considerably in Europe in the last three decades. However, with the growing European population, air pollution remains an important public health and economic issue. Policies targeting air pollution reduction should continue to be strongly enforced to further reduce one of the greatest risk factors for human health.

Pharmacogenomics at the center of precision medicine: challenges and perspective in an era of Big Data.

Pharmacogenomics (PGx) is one of the core elements of personalized medicine. PGx information reduces the likelihood of adverse drug reactions and optimizes therapeutic efficacy. St Catherine Specialty Hospital in Zagreb/Zabok, Croatia has implemented a personalized patient approach using the RightMed® Comprehensive PGx panel of 25 pharmacogenes plus Facor V Leiden, Factor II and MTHFR genes, which is interpreted by a special counseling team to offer the best quality of care. With the advent of significant technological advances comes another challenge: how can we harness the data to inform clinically actionable measures and how can we use it to develop better predictive risk models? We propose to apply the principles artificial intelligence to develop a medication optimization platform to prevent, manage and treat different diseases.

Cystic fibrosis presentation in del. F508 and p. Tyr109Glyfs compound heterozygote CFTR state: a case report.

The diagnosis of cystic fibrosis (CF) is commonly confirmed by molecular genetics with the presence of specific mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene. We report a case of cystic fibrosis (CF) in a 15-year-old female patient who is a compound heterozygote for CFTR gene, with delta F508 and Tyr109Glyfs mutations detected. This is the first detailed description of such a case in the medical literature. The primary CF presentation occurred at the age of 9 in the form of gastrointestinal symptoms including greasy, bulky, and foul-smelling stool. The patient exhibited delayed growth, with her height and weight being below the 5th centile for age according to the World Health Organization growth curves. Pancreatic enzyme supplement treatment was started immediately, alongside high-fat and high-calorie diet, resulting in patient's recovery and development. DNA analysis of CFTR gene demonstrated the presence of del. F508 mutation and a rare combining deletion and insertion mutation p. Tyr109Glyfs. The combination of the two mutations is very rare in CF patients and is therefore valuable to document this case in order to provide information on disease progression, therapy options, and outcomes. With standard treatment and early diagnosis, the patient is currently doing well and is not restricted by the disease in her daily and sports activities.

Dasatinib-induced nephrotic syndrome: a case of phenoconversion.

We present the case of a 33-year-old chronic myeloid leukemia (CML) female patient, in whom the occurrence of nephrotic syndrome, during the treatment with tyrosine kinase activity inhibitors (TKIs), was potentially influenced by transient phenoconversion. Seven years after the CML diagnosis in 2004 and complete response, the patient experienced pain in the mandible and extremities. After this, imatinib was replaced by nilotinib, but generalized maculopapular rash was presented and successfully treated with antihistamines. The therapy was then discontinued due to planned pregnancy, and the patient experienced a relapse of CML with BCR-ABL/ABL1 transcripts of 18.9%. Dasatinib was introduced, and CML was in remission. Two years later, urine protein levels (6.19 g/L) and erythrocyte sedimentation rate were elevated (ESR=90 mm/3.6 ks). The patient was diagnosed with nephrotic syndrome. With dasatinib dose reduction, urine protein level returned to the reference range. In order to determine the best genotype-guided therapy, the patient underwent pharmacogenomic testing, showing a homozygous CYP3A4 genotype *1/*1, associated with extensive metabolizer (EM) enzyme phenotype, typical for normal rates of drug metabolism for TKIs. However, this was inconsistent with nephrotic syndrome occurrence. A possible explanation would be CYP3A4 EM genotype coding a poor metabolizer enzyme phenotype, leading to the drug accumulation in the patient's blood. This transient phenoconversion can be explained by inflammation with elevated ESR during nephrotic syndrome. This case shows that a broader approach that recognizes genetic, clinical, and epigenomic factors is required for a quality decision on the personalized therapy regimen.