Case report: Early (molecular) diagnosis is the clue: report on ALDH7A1 deficiency in newborns.

The first-tier genetic testing for developmental and epileptic encephalopathies (DEE) is now increasingly used in routine clinical practice. Antiquitin deficiency, also referred to as pyridoxine-dependent epilepsy (PDE-ALDH7A1), represents an inherited metabolic disorder with the phenotype of an early infantile DEE. In addition to the fact that biochemical biomarkers of PDE-ALDH7A1, including α-aminoadipic semialdehyde dehydrogenase, pipecolic acid (PA), Δ1-piperideine-6-carboxylate, and 6-oxopipecolate (6-oxo-PIP), are well-characterized, and their analysis and usefulness have some limitations. Here, we describe the case of a newborn presenting with seizures from the first hours of life, who was resistant to standard antiepileptic drugs and was found to be a biallelic compound heterozygote of two clearly pathogenic variants in the ALDH7A1 gene based on targeted next-generation sequencing (NGS). The diagnostic process of PDE-ALDH7A1 was limited by the possibility to determine only urinary PA and 6-oxo-PIP (urinary organic acid profile using the GC-MS method), and the exogenous peak of levetiracetam, due to the fact that it has a similar retention time as 6-oxo-PIP, masked the detection of 6-oxo-PIP.

Hypertension-Mediated Organ Damage in Relation to Severity of Chronic Low Back Pain in Hypertensive Patients.

INTRODUCTION: Chronic pain triggers a stress response, which results in increased blood pressure (BP). We investigated whether chronic low back pain (cLBP) in hypertensive patients is associated with an increased risk of hypertension-related organ damage. METHODS: We studied 85 consecutive hypertensive patients with a median age of 62 years (55-67), who suffered from cLBP, the severity of which was evaluated according to the Oswestry Disability Index (ODI). Patients underwent transthoracic echocardiography, arterial ultrasonography and vascular tonometry. We assessed carotid artery atherosclerotic plaques, along with carotid-femoral pulse wave velocity (cf-PWV) and left ventricular mass index (LVMI). RESULTS: An equal to or higher than median (16 points) ODI score in 48 subjects (56.5%) was associated with the presence of carotid artery plaques (p = 0.014). In multivariate analysis, after adjusting for covariates, the presence of carotid artery plaques remained independently associated with an ODI score equal to or higher than the median (OR, 3.71; 95% CI, 1.04-13.25; p = 0.044). None of the other analyzed parameters of hypertension-related organ damage demonstrated a significant relationship with the ODI score. CONCLUSIONS: We observed that more severe cLBP is associated with a higher prevalence of carotid artery atherosclerotic plaques among hypertensive patients.

Osteoporosis in Relation to a Bone-Related Aging Biomarker Derived from the Urinary Proteomic Profile: A Population Study.

Screening for and prevention of osteoporosis and osteoporotic fractures is imperative, given the high burden on individuals and society. This study constructed and validated an aging-related biomarker derived from the urinary proteomic profile (UPP) indicative of osteoporosis (UPPost-age). In a prospective population study done in northern Belgium (1985-2019), participants were invited for a follow-up examination in 2005-2010 and participants in the 2005-2010 examination again invited in 2009-2013. Participants in both the 2005-2010 and 2009-2013 examinations (n = 519) constituted the derivation (2005-2016 data) and time-shifted validation (2009-2013 data) datasets; 187 participants with only 2005-2010 data formed the synchronous validation dataset. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. Analyses focused on 2372 sequenced urinary peptides (101 proteins) with key roles in maintaining the integrity of bone tissue. In multivariable analyses with correction for multiple testing, chronological age was associated with 99 urinary peptides (16 proteins). Peptides derived from IGF2 and MGP were upregulated in women compared to men, whereas COL1A2, COL3A1, COL5A2, COL10A1 and COL18A1 were downregulated. Via application of a 1000-fold bootstrapped elastic regression procedure, finally, 29 peptides (10 proteins) constituted the UPPost-age biomarker, replicated across datasets. In cross-sectional analyses of 2009-2013 data (n = 706), the body-height-to-arm-span ratio, an osteoporosis marker, was negatively associated with UPPost-age (p&;lt0.0001). Over 4.89 years (median), the 10-year risk of osteoporosis associated with chronological age and UPPost-age (53 cases including 37 fractures in 706 individuals) increased by 21% and 36% (p ≤ 0.044). Among 357 women, the corresponding estimates were 55% and 60% for incident osteoporosis (37 cases; p ≤ 0.0003) and 42% and 44% for osteoporotic fractures (25 cases; p ≤ 0.017). In conclusion, an aging-related UPP signature with focus on peptide fragments derived from bone-related proteins is associated with osteoporosis risk and available for clinical and trial research.

An outcome-driven threshold for pulse pressure amplification.

Pulse pressure amplification (PPA) is the brachial-to-aortic pulse pressure ratio and decreases with age and cardiovascular risk factors. This individual-participant meta-analysis of population studies aimed to define an outcome-driven threshold for PPA. Incidence rates and standardized multivariable-adjusted hazard ratios (HRs) of cardiovascular and coronary endpoints associated with PPA, as assessed by the SphygmoCor software, were evaluated in the International Database of Central Arterial Properties for Risk Stratification (n = 5608). Model refinement was assessed by the integrated discrimination (IDI) and net reclassification (NRI) improvement. Age ranged from 30 to 96 years (median 53.6). Over 4.1 years (median), 255 and 109 participants experienced a cardiovascular or coronary endpoint. In a randomly defined discovery subset of 3945 individuals, the rounded risk-carrying PPA thresholds converged at 1.3. The HRs for cardiovascular and coronary endpoints contrasting PPA < 1.3 vs ≥1.3 were 1.54 (95% confidence interval [CI]: 1.00-2.36) and 2.45 (CI: 1.20-5.01), respectively. Models were well calibrated, findings were replicated in the remaining 1663 individuals analyzed as test dataset, and NRI was significant for both endpoints. The HRs associating cardiovascular and coronary endpoints per PPA threshold in individuals <60 vs ≥60 years were 3.86 vs 1.19 and 6.21 vs 1.77, respectively. The proportion of high-risk women (PPA < 1.3) was higher at younger age (<60 vs ≥60 years: 67.7% vs 61.5%; P < 0.001). In conclusion, over and beyond common risk factors, a brachial-to-central PP ratio of <1.3 is a forerunner of cardiovascular coronary complications and is an underestimated risk factor in women aged 30-60 years. Our study supports pulse wave analysis for risk stratification.

Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders.

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders.

Management of hypertensive disorders in pregnancy: a Position Statement of the European Society of Hypertension Working Group 'Hypertension in Women'.

Hypertensive disorders in pregnancy (HDP), remain the leading cause of adverse maternal, fetal, and neonatal outcomes. Epidemiological factors, comorbidities, assisted reproduction techniques, placental disorders, and genetic predisposition determine the burden of the disease. The pathophysiological substrate and the clinical presentation of HDP are multifarious. The latter and the lack of well designed clinical trials in the field explain the absence of consensus on disease management among relevant international societies. Thus, the usual clinical management of HDP is largely empirical. The current position statement of the Working Group 'Hypertension in Women' of the European Society of Hypertension (ESH) aims to employ the current evidence for the management of HDP, discuss the recommendations made in the 2023 ESH guidelines for the management of hypertension, and shed light on controversial issues in the field to stimulate future research.

The experience sampling methodology in psychosis risk states: A systematic review.

The experience sampling method (ESM) is a structured diary technique, which is used to assess thoughts, mood and appraise subjective experiences in daily life. It has been recognized as a useful tool for understanding the characteristics, dynamics, and underlying mechanisms of prodromal symptoms of psychosis. The present systematic review aimed to provide a qualitative synthesis of findings provided by the ESM studies conducted in people with psychosis risk states. A systematic review of the MEDLINE, ERIC, Academic Search Ultimate, and Health Source: Nursing/Academic Edition databases, utilizing search terms related to the ESM and the risk of psychosis was conducted. Out of 1069 publication records identified, 77 studies met the inclusion criteria for the review. Data were synthesized around the following topics: 1) assessment of symptoms dynamics and social functioning; 2) assessment of the mechanisms contributing to the emergence of psychotic experiences and 3) assessment of stress sensitivity. The studies have shown that negative emotions are associated with subsequent development of paranoia. The tendency to draw hasty conclusions, aberrant salience, self-esteem, and emotion regulation were the most frequently reported mechanisms associated with the emergence of psychotic experiences. Studies using the ESM also provided evidence for the role of stress sensitivity, in the development of psychotic symptoms. The ESM has widely been applied to studies investigating psychosis risk states, using a variety of protocols. Findings from this systematic review might inform future studies and indicate potential targets for interventions.

Echocardiographic parameters as adjuncts to the Pulmonary Embolism Severity Index in predicting 30-day mortality in acute pulmonary embolism patients.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) is a validated tool to predict 30-day all-cause mortality in patients with acute pulmonary embolism (PE) but includes only clinical variables. AIMS: We aimed to determine the effectiveness of PESI extended with an echocardiographic parameter. METHODS: This cross-sectional observational study included consecutive patients with acute PE diagnosed with computed tomography pulmonary angiography. RESULTS: Of 117 subjects (57 men, 48.7%), at a median age of 69 (59-80) years, 16 patients died during the 30-day follow-up. Six modified models of PESI with an additional single echocardiographic parameter were created, which increased the predictive value of PESI (area under the curve [AUC] 0.8608): tricuspid annular plane systolic excursion (TAPSE) <18 mm, right ventricular (RV) free wall longitudinal strain (RVFWLS) >-23%, 60/60 sign, RV global longitudinal strain (RVGLS) >-16%, pulmonary ejection acceleration time (AcT) <67 ms, and thrombus in right heart cavities (AUC 0.8657 to 0.8976, respectively, all markers P <0.001). TAPSE, AcT, RVFWLS, and RVGLS showed significant correlations with the PESI score, but not a thrombus in the right heart cavity or the 60/60 sign. As PESI adjuncts, they independently predicted fatal outcomes: thrombus with hazard ratio (HR) 10.04 (95% confidence interval [CI], 2.81-37.12; P <0.001) and the 60/60 sign with HR 4.07 (95% CI, 1.27-12.81; P <0.001). CONCLUSIONS: The quantitative echocardiographic parameters of RV systolic function and pulmonary artery blood flow are associated with the PESI score and thus increase its predictive value to a limited extent. PE- specific findings: a thrombus in the right heart cavity and the 60/60 sign are effective adjuncts to the PESI score.

Lead-associated mortality in the US 1999-2020: a time-stratified analysis of a national cohort.

OBJECTIVES: We undertook time-stratified analyses of the National Health and Nutrition Examination Survey in the US to assess time trends (1999-2020) in the associations of blood lead (BL) with blood pressure, mortality, the BL-associated population attributable fraction (PAF). METHODS: Vital status of participants, 20-79 years old at enrolment, was ascertained via the National Death Index. Regressions, mediation analyses and PAF were multivariable adjusted and standardized to 2020 US Census data. RESULTS: In time-stratified analyses, BL decreased from 1.76 µg/dl in 1999-2004 to 0.93 µg/dl in 2017-2020, while the proportion of individuals with BL < 1 µg/dl increased from 19.2% to 63.0%. Total mortality was unrelated to BL (hazard ratio (HR) for a fourfold BL increment: 1.05 [95% confidence interval, CI: 0.93-1.17]). The HR for cardiovascular death was 1.44 (1.01-2.07) in the 1999-2000 cycle, but lost significance thereafter. BL was directly related to cardiovascular mortality, whereas the indirect BL pathway via BP was not significant. Low socioeconomic status (SES) was directly related to BL and cardiovascular mortality, but the indirect SES pathway via BL lost significance in 2007-2010. From 1999-2004 to 2017-2020, cardiovascular PAF decreased ( P  < 0.001) from 7.80% (0.17-14.4%) to 2.50% (0.05-4.68%) and number of lead-attributable cardiovascular deaths from 53 878 (1167-99 253) to 7539 (160-14 108). CONCLUSION: Due to implementation of strict environmental policies, lead exposure is no longer associated with total mortality, and the mildly increased cardiovascular mortality is not associated with blood lead via blood pressure in the United States.

Mortality and Cardiovascular End Points In Relation to the Aortic Pulse Wave Components: An Individual-Participant Meta-Analysis.

BACKGROUND: Wave separation analysis enables individualized evaluation of the aortic pulse wave components. Previous studies focused on the pressure height with overall positive but differing results. In the present analysis, we assessed the associations of the pressure of forward and backward (Pfor and Pref) pulse waves with prospective cardiovascular end points, with extended analysis for time to pressure peak (Tfor and Tref). METHODS: Participants in 3 IDCARS (International Database of Central Arterial Properties for Risk Stratification) cohorts (Argentina, Belgium, and Finland) aged ≥20 years with valid pulse wave analysis and follow-up data were included. Pulse wave analysis was done using the SphygmoCor device, and pulse wave separation was done using the triangular method. The primary end points consisted of cardiovascular mortality and nonfatal cardiovascular and cerebrovascular events. Multivariable-adjusted Cox regression was used to calculate hazard ratios. RESULTS: A total of 2206 participants (mean age, 57.0 years; 55.0% women) were analyzed. Mean±SDs for Pfor, Pref, Tfor, and Tfor/Tref were 31.0±9.1 mm Hg, 20.8±8.4 mm Hg, 130.8±35.5, and 0.51±0.11, respectively. Over a median follow-up of 4.4 years, 146 (6.6%) participants experienced a primary end point. Every 1 SD increment in Pfor, Tfor, and Tfor/Tref was associated with 27% (95% CI, 1.07-1.49), 25% (95% CI, 1.07-1.45), and 32% (95% CI, 1.12-1.56) higher risk, respectively. Adding Tfor and Tfor/Tref to existing risk models improved model prediction (∆Uno's C, 0.020; P<0.01). CONCLUSIONS: Pulse wave components were predictive of composite cardiovascular end points, with Tfor/Tref showing significant improvement in risk prediction. Pending further confirmation, the ratio of time to forward and backward pressure peak may be useful to evaluate increased afterload and signify increased cardiovascular risk.

OSTEO18, a novel urinary proteomic signature, associated with osteoporosis in heart transplant recipients.

Background: Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods: A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results: In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76-0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased (p < 0.0001) across OSTEO18 quartiles from 0.39 (95 % CI: 0.25-0.61) to 3.14 (2.08-4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 (p = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 (p = 0.0004) for OSTEO18 as continuously distributed classifier. Conclusion: OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic.

What characteristics of dogs help them stay shorter in shelters? Evidence from a polish animal shelter.

Staying in animal shelters can be stressful for dogs because of exposure to noise, unfamiliar environment, and social separation. Consequently, the wellbeing of sheltered dogs could be improved through reduction of length of stay in a shelter (LOS). To help inform the development of interventions aimed at LOS reduction, we analyze dogs' characteristics affecting their LOS. We use econometric modeling to identify the characteristics's influence by simultaneously controlling for multiple factors. We use data from Poland's largest animal shelter (11805 observations from the years 2000-2020). We compare two modeling approaches: a Cox survival model, commonly used in animal welfare studies, and an accelerated failure time model, theoretically better fitted to studying time-dependent factors but not yet applied in the context of LOS. We conclude that the latter approach is preferable for studying factors affecting LOS. Male sex, mixed-breed, dark fur, large size, and older age appear to be associated with longer time to adoption for dogs. To our knowledge, this is the first econometric examination of factors affecting LOS in a country in Central and Eastern Europe.

Angiotensin-converting enzyme inhibitors and angiotensin-II-receptor antagonists modulate sodium handling based on endogenous lithium clearance.

BACKGROUND: Numerous studies based on assessment of lithium clearance demonstrated higher sodium reabsorption in renal proximal tubules in individuals with hypertension, overweight, obesity, metabolic syndrome, or diabetes. AIMS: We aimed to assess the influence of angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin-II-receptor antagonists (ARB) treatment on sodium handling. METHODS: In a sample of 351Caucasian subjects without diuretic treatment with prevailing sodium consumption, we studied associations between renal sodium reabsorption in proximal (FPRNa) and distal (FDRNa) tubules assessed by endogenous lithium clearance and daily sodium intake measured by 24-hour excretion of sodium (UNaV), in the context of obesity and long-term treatment with ACE-I or ARB. RESULTS: In the entire study population, we found a strong negative association between FPRNa and ACE-I/ARB treatment (b = -19.5; SE = 4.9; P <0.001). Subjects with FPRNa above the median value showed a significant adverse association between FPRNa and age (b = -0.06; SE = 0.02; P = 0.003), with no association with ACE-I/ARB treatment (P = 0.68). In contrast, in subjects with FPRNa below the median value, we found a strongly significant adverse relationship between FPRNa and ACE-I/ARB treatment (b = -30.4; SE = 8.60; P <0.001), with no association with age (P = 0.32). CONCLUSIONS: ACE-I/ARB long-term treatment modulates FPRNa in the group with lower reabsorption, but not in that with higher than median value for the entire study population.

The sodium-chloride difference: A marker of prognosis in patients with acute myocardial infarction.

BACKGROUND: The difference between serum sodium and chloride ion concentrations (SCD) may be considered as a surrogate of a strong ion difference and may help to identify patients with a worse prognosis. We aimed to assess SCD as an early prognostic marker among patients with myocardial infarction. METHODS: Data of 594 consecutive patients with acute myocardial infarction treated with PCI (44.9% STEMI patients; 70.7% males) was analysed for SCD in relation to their 30-day mortality. A restricted cubic spline regression model was used to study the relationship between mortality and SCD. Cox regression models were used to assess the association between SCD and the mortality risk. RESULTS: Patients with Killip class ≥3 had lower SCD values in comparison to patients with Killip class ≤2: (32.0 [30.0-34.0] vs. 33.0 [31.0-36.0], p = .006). The overall 30-day mortality was 7.7% (n = 46). There was a significant difference in SCD values between survivors and non-survivors groups of patients (median (IQR): (33.0 [31.0-36.0] vs. 31.5 [28.0-34.0] (mmol/L), p = .002). The restricted cubic splines model confirmed a non-linear association between SCD and mortality. Patients with SCD <30 mmol/L (in comparison to SCD ≥30 mmol/L) had an increased mortality risk (unadjusted HR 2.92, 95% CI 1.59-5.36, p = .001; and an adjusted HR 2.30, 95% CI 1.02-5.19, p = .04). CONCLUSIONS: Low SCD on admission is associated with an increased risk of 30-day mortality in patients with acute myocardial infarction treated with PCI and may serve as a useful prognostic marker for these patients.

Association of Air Pollution with a Urinary Biomarker of Biological Aging and Effect Modification by Vitamin K in the FLEMENGHO Prospective Population Study.

BACKGROUND: A recently developed urinary peptidomics biological aging clock can be used to study accelerated human aging. From 1990 to 2019, exposure to airborne particulate matter (PM) became the leading environmental risk factor worldwide. OBJECTIVES: This study investigated whether air pollution exposure is associated with accelerated urinary peptidomic aging, independent of calendar age, and whether this association is modified by other risk factors. METHODS: In a Flemish population, the urinary peptidomic profile (UPP) age (UPP-age) was derived from the urinary peptidomic profile measured by capillary electrophoresis coupled with mass spectrometry. UPP-age-R was calculated as the residual of the regression of UPP-age on chronological age, which reflects accelerated aging predicted by UPP-age, independent of chronological age. A high-resolution spatial-temporal interpolation method was used to assess each individual's exposure to PM10, PM2.5, black carbon (BC), and nitrogen dioxide (NO2). Associations of UPP-age-R with these pollutants were investigated by mixed models, accounting for clustering by residential address and confounders. Effect modifiers of the associations between UPP-age-R and air pollutants that included 18 factors reflecting vascular function, renal function, insulin resistance, lipid metabolism, or inflammation were evaluated. Direct and indirect (via UPP-age-R) effects of air pollution on mortality were evaluated by multivariable-adjusted Cox models. RESULTS: Among 660 participants (50.2% women; mean age: 50.7 y), higher exposure to PM10, PM2.5, BC, and NO2 was associated with a higher UPP-age-R. Studying effect modifiers showed that higher plasma levels of desphospho-uncarboxylated matrix Gla protein (dpucMGP), signifying poorer vitamin K status, steepened the slopes of UPP-age-R on the air pollutants. In further analyses among participants with dpucMGP ≥4.26µg/L (median), an interquartile range (IQR) higher level in PM10, PM2.5, BC, and NO2 was associated with a higher UPP-age-R of 2.03 [95% confidence interval (CI): 0.60, 3.46], 2.22 (95% CI: 0.71, 3.74), 2.00 (95% CI: 0.56, 3.43), and 2.09 (95% CI: 0.77, 3.41) y, respectively. UPP-age-R was an indirect mediator of the associations of mortality with the air pollutants [multivariable-adjusted hazard ratios from 1.094 (95% CI: 1.000, 1.196) to 1.110 (95% CI: 1.007, 1.224)] in participants with a high dpucMGP, whereas no direct associations were observed. DISCUSSION: Ambient air pollution was associated with accelerated urinary peptidomics aging, and high vitamin K status showed a potential protective effect in this population. Current guidelines are insufficient to decrease the adverse health effects of airborne pollutants, including healthy aging trajectories. https://doi.org/10.1289/EHP13414.

Resistant hypertension: challenges in everyday practice.

Resistant hypertension is defined as not achieving sufficient control of blood pressure (BP), that is, maintaining BP values equal to or above 140/90 mm Hg when using 3 antihypertensive drugs, including diuretics, properly combined and at maximum doses. The uncontrolled treated hypertension should be confirmed in out­of­office BP measurements, preferably with 24­hour ambulatory BP monitoring. Demographic and clinical characteristics indicate that patients with resistant hypertension are older than the general population of patients with arterial hypertension and more often suffer from comorbidities. When resistant hypertension is suspected, it is necessary to assess whether optimal pharmacotherapy has been prescribed, including appropriate combinations of antihypertensive drugs and diuretics at appropriate doses. It is also important to exclude parallel use of drugs that may have unfavorable interactions leading to an increase in BP. A common cause of pseudoresistant hypertension is a patient's failure to comply with therapeutic recommendations, including a lack of lifestyle changes and nonadherence to the prescribed medication regimen. An important step in management of resistant hypertension is targeted screening with diagnostic tests for secondary hypertension. Expanding of the drug therapy beyond a 3­drug regimen should include a mineralocorticoid receptor antagonist, in particular spironolactone. In selected patients, device­based hypertension treatment might be considered.

Pathomechanism of Pruritus in Psoriasis and Atopic Dermatitis: Novel Approaches, Similarities and Differences.

Pruritus is defined as an unpleasant sensation that elicits a desire to scratch. Nearly a third of the world's population may suffer from pruritus during their lifetime. This symptom is widely observed in numerous inflammatory skin diseases-e.g., approximately 70-90% of patients with psoriasis and almost every patient with atopic dermatitis suffer from pruritus. Although the pathogenesis of atopic dermatitis and psoriasis is different, the complex intricacies between several biochemical mediators, enzymes, and pathways seem to play a crucial role in both conditions. Despite the high prevalence of pruritus in the general population, the pathogenesis of this symptom in various conditions remains elusive. This review aims to summarize current knowledge about the pathogenesis of pruritus in psoriasis and atopic dermatitis. Each molecule involved in the pruritic pathway would merit a separate chapter or even an entire book, however, in the current review we have concentrated on some reports which we found crucial in the understanding of pruritus. However, the pathomechanism of pruritus is an extremely complex and intricate process. Moreover, many of these signaling pathways are currently undergoing detailed analysis or are still unexplained. As a result, it is currently difficult to take an objective view of how far we have come in elucidating the pathogenesis of pruritus in the described diseases. Nevertheless, considerable progress has been made in recent years.

Serial echocardiographic evaluation of COVID-19 patients without prior history of structural heart disease: a 1-year follow-up CRACoV-HHS study.

Background: It is a well-known fact that COVID-19 affects the cardiovascular system by exacerbating heart failure in patients with preexisting conditions. However, there is a poor insight into the cardiovascular involvement and sequelae in patients without preexisting conditions. The aim of the study is to analyse the influence of COVID-19 on cardiac performance in patients without prior history of structural heart disease. The study is part of the CRACoV project, which includes a prospective design and a 12-month follow-up period. Material and methods: The study included 229 patients hospitalised with a diagnosis of COVID-19 (median age of 59 years, 81 were women). A standard clinical assessment and laboratory tests were performed in all participants. An extended echocardiographic image acquisition was performed at baseline and at a 3-, 6-, and 12-month follow-up. All analyses were performed off-line. A series of echocardiographic parameters was compared using repeated measures or Friedman analysis of variance. Results: In all subjects, the left ventricular (LV) ejection fraction at baseline was preserved [63.0%; Q1:Q3 (60.0-66.0)]. Elevated levels of high-sensitivity cardiac troponin T were detected in 21.3% of the patients, and elevated NT-proBNP levels were detected in 55.8%. At the 1-year follow-up, no significant changes were observed in the LV diameter and volume (LV 48.0 ± 5.2 vs. 47.8 ± 4.8 mm, p = 0.08), while a significant improvement of the parameters in the biventricular strain was observed (LV -19.1 ± 3.3% vs. -19.7 ± 2.5%, p = 0.01, and right ventricular -19.9 ± 4.5% vs. -23.2 ± 4.9%, p = 0.002). In addition, a decrease in the LV wall thickness was also observed (interventricular septum 10.4 ± 1.6 vs. 9.7 ± 2.0 mm, p < 0.001; LV posterior wall 9.8 ± 1.4 vs. 9.1 ± 1.5 mm, p < 0.001). Conclusions: In an acute phase of COVID-19, the elevation of cardiac biomarkers in patients with normal left ventricular ejection fraction is a frequent occurrence; however, it does not translate into clinically significant cardiac dysfunction after 1 year. The serial echocardiographic evaluations conducted in patients without preexisting structural heart disease demonstrate an overall trend towards an improved cardiac function and a reduced myocardial thickening at 1-year follow-up. This suggests that the acute cardiac consequences of COVID-19 are associated with systemic inflammation and haemodynamic stress in patients without preexisting conditions.

Derivation of an Outcome-Driven Threshold for Aortic Pulse Wave Velocity: An Individual-Participant Meta-Analysis.

BACKGROUND: Aortic pulse wave velocity (PWV) predicts cardiovascular events (CVEs) and total mortality (TM), but previous studies proposing actionable PWV thresholds have limited generalizability. This individual-participant meta-analysis is aimed at defining, testing calibration, and validating an outcome-driven threshold for PWV, using 2 populations studies, respectively, for derivation IDCARS (International Database of Central Arterial Properties for Risk Stratification) and replication MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease Health Survey - Copenhagen). METHODS: A risk-carrying PWV threshold for CVE and TM was defined by multivariable Cox regression, using stepwise increasing PWV thresholds and by determining the threshold yielding a 5-year risk equivalent with systolic blood pressure of 140 mm Hg. The predictive performance of the PWV threshold was assessed by computing the integrated discrimination improvement and the net reclassification improvement. RESULTS: In well-calibrated models in IDCARS, the risk-carrying PWV thresholds converged at 9 m/s (10 m/s considering the anatomic pulse wave travel distance). With full adjustments applied, the threshold predicted CVE (hazard ratio [CI]: 1.68 [1.15-2.45]) and TM (1.61 [1.01-2.55]) in IDCARS and in MONICA (1.40 [1.09-1.79] and 1.55 [1.23-1.95]). In IDCARS and MONICA, the predictive accuracy of the threshold for both end points was ≈0.75. Integrated discrimination improvement was significant for TM in IDCARS and for both TM and CVE in MONICA, whereas net reclassification improvement was not for any outcome. CONCLUSIONS: PWV integrates multiple risk factors into a single variable and might replace a large panel of traditional risk factors. Exceeding the outcome-driven PWV threshold should motivate clinicians to stringent management of risk factors, in particular hypertension, which over a person's lifetime causes stiffening of the elastic arteries as waypoint to CVE and death.

The role of stress hyperglycemia and hyperlactatemia in non-diabetic patients with myocardial infarction treated with percutaneous coronary intervention.

BACKGROUND: Stress hyperglycemia and lactates have been used separately as markers of a severe clinical condition and poor outcomes in patients with myocardial infarction (MI). However, the interplay between glucose and lactate metabolism in patients with MI have not been sufficiently studied. The aim in the present study was to examine the relationship of glycemia on admission (AG) and lactate levels and their impact on the outcome in non-diabetic MI patients treated with percutaneous coronary intervention (PCI). METHODS: A total of 405 consecutive, non-diabetic, MI patients were enrolled in this retrospective, observational, single-center study. Clinical characteristic including glucose and lactate levels on admission and at 30-day mortality were assessed. RESULTS: Patients with stress hyperglycemia (AG ≥ 7.8 mmol/L, n = 103) had higher GRACE score (median [interquartile range]: 143.4 (115.4-178.9) vs. 129.4 (105.7-154.5), p = 0.002) than normoglycemic patients (AG level < 7.8 mmol/L, n = 302). A positive correlation of AG with lactate level (R = 0.520, p < 0.001) was observed. The coexistence of both hyperglycemia and hyperlactatemia (lactate level ≥ 2.0 mmol/L) was associated with lower survival rate in the Kaplan-Meier estimates (p < 0.001). In multivariable analysis both hyperglycemia and hyperlactatemia were related to a higher risk of death at 30-day follow-up (hazard ratio [HR] 3.21, 95%, confidence interval [CI] 1.04-9.93; p = 0.043 and HR 7.08; 95% CI 1.44-34.93; p = 0.016, respectively) CONCLUSIONS: There is a relationship between hyperglycemia and hyperlactatemia in non-diabetic MI patients treated with PCI. The coexistence of both hyperglycemia and hyperlactatemia is associated with lower survival rate and are independent predictors of 30-day mortality in MI patients and these markers should be evaluated simultaneously.