Digital Smoking Cessation With a Comprehensive Guideline-Based App-Results of a Nationwide, Multicentric, Parallel, Randomized Controlled Trial in Germany.

BACKGROUND: Smoking tobacco implies significant health hazards. Digital cessation support can get more smokers in contact with guideline-based cessation. The objective was to test the efficacy of a guideline-based smoking cessation app (NichtraucherHelden®). The hypothesis was a significantly higher cessation rate in the intervention group. METHODS: The study was a nationwide, multicentric, prospective, parallel, randomized controlled trial in Germany from November 2021 to March 2023. Recruitment took place in medical practices and by telephone via study centers. Eligible participants were adult tobacco-dependent smokers according to ICD-10 (F17.2). Randomization (1:1) was operated by a computer-generated stratified 1:1 block procedure. Intervention (IG; n = 336) and control group (CG; n = 325) were briefly advised with regard to stop smoking, IG was additionally treated with the cessation app. The primary endpoint was the self-reported 7-day-point abstinence after 6 months with an intention to treat analysis. Secondary endpoints comprised prolonged abstinence and biochemically verified abstinence. The study was registered at the German Registry of Clinical Trials (DRKS00025933, UTN U1111-1268-2181) and was approved by the competent ethics committees (leading ethic committee Berlin #Eth-52/20). RESULTS: Three hundred thirty six participants (IG) and 325 (CG) were analyzed. Seven-day point prevalence was significantly higher in the app group (IG) (20% vs. 10%, OR 2.2 (1.4-3.4)). Additionally, the prolonged abstinence and the objective abstinence rates were significantly higher in the app group. CONCLUSIONS: The NichtraucherHelden app doubles the abstinence rate. Apps can bridge the gap between the small number of therapeutic offers and the need for modern evidence-based cessation support. IMPLICATIONS: The study is the first to provide evidence for the feasibility and efficacy of guideline-based digital smoking cessation provided by a smartphone app for the German statutory health insurance (SHI) system. Smoking cessation support by smartphone apps could be broadly distributed and thus bring more smokers in contact with guideline-based cessation support than to date and increase the number of successful quitters substantially.

Rigor and reproducibility in analysis of rodent behavior utilizing the forelimb reaching task following a cervical spinal cord injury.

Spinal cord injury (SCI) research with animals aims to understand the neurophysiological responses resultant of injury and to identify effective interventions that can translate into clinical treatments in the future. Consistent and reliable assessments to properly measure outcomes are essential to achieve this aim and avoid issues with reproducibility. The objective of this study was to establish a baseline for implementing the forelimb reaching task (FRT) assessment and analysis that increased reproducibility of our studies. For this study, we implemented a weekly FRT training program for six weeks. During this time the language of the scoring rubric for movement elements that comprise a reaching task was simplified and expanded. We calculated intra- and inter-rater variability among participants of the study both before and after training to determine the effect changes made had on rigor and reproducibility of this behavioral assessment in a cervical SCI rodent model. All animals (n = 19) utilized for FRT behavioral assessments received moderate contusion injuries using the Ohio State University device and were tested for a period of 5 weeks post-SCI. Videos used for scoring were edited and shared with all participants of this study to test FRT score variability and the effect simplification of the scoring rubric had on overall inter-rater reliability. From our results we determined training for a minimum of three weeks in FRT analysis is necessary for rigor and reproducibility of our behavioral studies, as well as the need for two raters to be assigned per animal to ensure accuracy of results.

Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort.

BACKGROUND: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. METHODS: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. RESULTS: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). CONCLUSION: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

Myocardial edema in paroxysmal permeability disorders: The paradigm of Clarkson's disease.

PURPOSE: Paroxysmal Permeability Disorders (PPDs) comprise a variety of diseases characterized by recurrent and transitory increase of endothelial permeability. Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a rare PPD that leads to an abrupt massive shift of fluids and proteins from the intravascular to the interstitial compartment. In some cases, tissue edema may involve the myocardium, but its role in the development of shock has not been elucidated so far. MATERIALS AND METHODS: Assessment of cardiac involvement during ten life-threatening ISCLS episodes admitted to ICU. RESULTS: Transthoracic echocardiographic examination was performed in eight episodes, whereas a poor acoustic window prevented cardiac ultrasound assessment in two episodes. Myocardial edema was detected by echocardiography in eight episodes and marked pericardial effusion in one-episode. Cardiac magnetic resonance showed diffuse myocardial edema in another episode. In one case, myocardial edema caused fulminant left ventricular dysfunction, which required extracorporeal life support. The mean septum thickness was higher during the shock phase compared to the recovery phase [15.5 mm (13.1-21 mm) vs. 9.9 mm (9-11.3 mm), p = .0003]. Myocardial edema resolved within 72 h. CONCLUSIONS: During early phases of ISCLS, myocardial edema commonly occurs and can induce transient myocardial dysfunction, potentially contributing to the pathogenesis of shock.

Current and emerging biologics for the treatment of hereditary angioedema.

INTRODUCTION: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients. AREAS COVERED: This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed. EXPERT OPINION: The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.

Hereditary angioedema: Assessing the hypothesis for underlying autonomic dysfunction.

BACKGROUND: Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes. OBJECTIVE: Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation. METHODS: Twenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10') and 75-degrees-head-up tilt (10'). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively. RESULTS: HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01). CONCLUSIONS: Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.

Relevance of body size and shell colouration for thermal absorption and heat loss in white garden snails, Theba pisana (Helicidae), from Northern France.

The internal temperature of land snails depends on environmental factors, such as exposure to electromagnetic radiation and airflow as well as biotic factors including shell size, shell colouration and thickness or the resting position of the snail. In controlled field experiments, we quantified heating by thermal absorption of light and airflow-induced heat loss in the white garden snail, Theba pisana, from Normandy, France. Heating experiments revealed a significant positive relation of the internal body temperature with illumination period, shell temperature and air temperature at different times of day. The size of the snails was negatively related with both of the given illumination times: smaller animals heated up stronger than larger ones. The temperature at the surface of the shell significantly depended on the illumination period and the time of day. An AIC-based quality assessment of multiple linear modelling showed that, for explaining both shell surface and internal temperature of the soft body, several factors, i.e., exposure time, daytime, shell size and colouration contributed to the best models, respectively. Similarly, heat loss of the soft body after and during exposure of the snails to sunlight by a constant airflow depended on the initial body temperature, shell size, colouration and ambient air temperature. Our study revealed also the importance of both shell size and colouration for the loss of body temperature under natural conditions: small and banded animals that had heated up to temperatures above 30°C cooled down faster than large and un-banded ones.

Primary PCI is associated with different cardiac autonomic patterns in relation to the site of myocardial infarction.

AIM: Reflex alterations of cardiac autonomic modulation have been described after acute myocardial infarction (AMI). The non-homogeneous autonomic innervation of the heart gives reason of different patterns of autonomic modulation depending upon the site of AMI. Conflicting data are available on cardiac autonomic modifications after primary percutaneous coronary intervention (pPCI). We evaluated cardiac autonomic changes in patients with ST-elevation myocardial infarction (STEMI) after pPCI, either within 24h after revascularization (T0) and at clinical stability (T1, 6±2days), taking into account the site of infarction. METHODS AND RESULTS: We enrolled 33 consecutive patients with STEMI treated with pPCI (25 males, mean age 61±12.1yr); 15 had an anterior wall STEMI (ANT) and 18 had an inferior wall STEMI (INF). ECG and respiration were recorded at T0 and at T1. Cardiac autonomic modulation was evaluated by means of symbolic analysis of heart rate variability. At T0, At T0, 0V% (marker of sympathetic modulation) was higher in INF compared to ANT [31% (18-43) vs 18% (7-32), p=0.014]. Moreover, ANT had a higher 2LV%, index of vagal modulation, compared to INF [8% (7-15) vs 5% (2-8), p=0.006]. CONCLUSION: After pPCI, these preliminary results suggest that patients with INF were characterized by a sympathetic predominance, while ANT by a predominant vagal modulation. Our data suggest that pPCI can be associated with specific autonomic patterns, which are different for ANT and INF STEMI, according to the different autonomic innervation. Future ad hoc studies are needed to confirm these preliminary observations.

Salvage therapy with bortezomib and dexamethasone in elderly patients with relapsed/refractory multiple myeloma.

Bortezomib-dexamethasone (bort-dex) is effective for relapsed/refractory (R/R) multiple myeloma, but few data are available for elderly patients. The aim of this study was to evaluate efficacy and toxicity of bort-dex in elderly R/R MM patients. We evaluated 81 R/R MM patients treated with bort-dex. Eight of them had light-chain disease. The median age of the patients was 73 years (range 65-89 years). All patients were R/R MM patients and had been treated with melphalan and prednisone with or without thalidomide or bortezomib in the first line or with lenalidomide and dexamethasone in the second line. The median number of previous lines was 2. Thirty-nine (48%) patients received bortezomib intravenously and 42 (52%) patients received bortezomib subcutaneously. The median number of bort-dex cycles was 6 (range 1-11). Fifty-three (65.4%) patients achieved at least a partial response, including eight (11%) patients with complete response and nine (12.5%) patients with very good partial responses. The median duration of response, time to next therapy and treatment-free intervals were 8, 11 and 5 months. Duration of response was significantly longer for patients achieving complete response/very good partial response than for those achieving partial response (7.3 vs. 3.8 months, P=0.03). After a median follow-up of 24 months, 78 patients showed disease progression and 70 died. The median time to progression, progression-free survival and overall survival were 8.9, 8.7 and 22 months, respectively. Peripheral neuropathy occurred in 38 (47%) patients. Our data highlight that bort-dex is effective and tolerable in fit elderly patients, thus justifying the efforts for deeper responses. However, awareness of short-lived responses to bort-dex should lead to a thorough evaluation of the need for maintenance.

Modulation of sympathetic activity and heart rate variability by ivabradine.

AIMS: Bradycardic agents are currently used in the treatment of angina and heart failure; direct information on their effects on cardiac sympathetic nerve activity (SNA) may be relevant to their chronic use. The present study evaluates the effect of pacemaker inhibition on SNA; direct nerve recordings and indirect autonomic indexes are compared. METHODS AND RESULTS: Experiments were performed in 18 anaesthetized rats. SNA (direct nerve recording) and heart rate variability (HRV) indexes were evaluated in parallel. All parameters were recorded 10 min before to 60 min after administration of the If blocker ivabradine (IVA; 2 mg/kg, i.v.; n = 8) or vehicle (VEH; n = 5). IVA-induced RR interval (RR) prolongation (at 60 min +15.0 ± 7.1%, P < 0.01) was associated with decreased diastolic arterial pressure (DAP; -17.3 ± 8.4%, P < 0.05) and increased SNA (+51.1 ± 12.3%, P < 0.05). These effects were accompanied by increased RR variance (RRσ(2)), which showed strong positive correlation with RR. Frequency-domain HRV indexes (in normalized units) were unchanged by IVA. After baroreceptor reflexes had been eliminated by sino-aortic denervation (n = 5), similar IVA-induced RR prolongation (at 60 min +14.3 ± 5.9%, NS vs. intact) was associated with a larger DAP reduction (-30.9 ± 4.1%, P < 0.05 vs. intact), but failed to affect SNA. CONCLUSIONS: (i) IVA-induced bradycardia was associated with increased SNA, resulting from baroreceptor unloading; if this applied to chronic IVA use in humans, it would be of relevance for therapeutic use of the drug. (ii) Whenever mean HR is concomitantly changed, time-domain HRV indexes should not be unequivocally interpreted in terms of autonomic balance.

Differential Diagnosis and Management Issues of Idiopathic Angiooedema and their Resolution.

Angiooedema is a local and self-limiting swelling of the subcutaneous and sub mucosal tissues, produced by vasoactive peptides that temporary increase the vascular permeability. It is recognized that recurrent angiooedema exposes patients to the risk of fatalities and reduced quality of life, being in some circumstances associated with a critical condition. Angiooedema can occur with or without wheals. The first symptom is urticaria, the second is a distinct nosologic entity. In absence of an identifiable cause, recurrent angiooedema without wheals can be defined as idiopathic and marked"idiopathic histaminergic angiooedema" when it is responsive to anti histamine treatment, and "idiopathic non-histaminergic angiooedema" when it is not. Furthermore, idiopathic non-histaminergic angiooedema can be diagnosed as hereditary or sporadic by family history. In this review, we summarize the approaches to diagnose and treat different forms of idiopathic angiooedema.

Phenotypic diversity, population structure and stress protein-based capacitoring in populations of Xeropicta derbentina, a heat-tolerant land snail species.

The shell colour of many pulmonate land snail species is highly diverse. Besides a genetic basis, environmentally triggered epigenetic mechanisms including stress proteins as evolutionary capacitors are thought to influence such phenotypic diversity. In this study, we investigated the relationship of stress protein (Hsp70) levels with temperature stress tolerance, population structure and phenotypic diversity within and among different populations of a xerophilic Mediterranean snail species (Xeropicta derbentina). Hsp70 levels varied considerably among populations, and were significantly associated with shell colour diversity: individuals in populations exhibiting low diversity expressed higher Hsp70 levels both constitutively and under heat stress than those of phenotypically diverse populations. In contrast, population structure (cytochrome c oxidase subunit I gene) did not correlate with phenotypic diversity. However, genetic parameters (both within and among population differences) were able to explain variation in Hsp70 induction at elevated but non-pathologic temperatures. Our observation that (1) population structure had a high explanatory potential for Hsp70 induction and that (2) Hsp70 levels, in turn, correlated with phenotypic diversity while (3) population structure and phenotypic diversity failed to correlate provides empirical evidence for Hsp70 to act as a mediator between genotypic variation and phenotype and thus for chaperone-driven evolutionary capacitance in natural populations.

Intraspecific variation in cellular and biochemical heat response strategies of Mediterranean Xeropicta derbentina [Pulmonata, Hygromiidae].

Dry and hot environments challenge the survival of terrestrial snails. To minimize overheating and desiccation, physiological and biochemical adaptations are of high importance for these animals. In the present study, seven populations of the Mediterranean land snail species Xeropicta derbentina were sampled from their natural habitat in order to investigate the intraspecific variation of cellular and biochemical mechanisms, which are assigned to contribute to heat resistance. Furthermore, we tested whether genetic parameters are correlated with these physiological heat stress response patterns. Specimens of each population were individually exposed to elevated temperatures (25 to 52°C) for 8 h in the laboratory. After exposure, the health condition of the snails' hepatopancreas was examined by means of qualitative description and semi-quantitative assessment of histopathological effects. In addition, the heat-shock protein 70 level (Hsp70) was determined. Generally, calcium cells of the hepatopancreas were more heat resistant than digestive cells - this phenomenon was associated with elevated Hsp70 levels at 40°C.We observed considerable variation in the snails' heat response strategy: Individuals from three populations invested much energy in producing a highly elevated Hsp70 level, whereas three other populations invested energy in moderate stress protein levels - both strategies were in association with cellular functionality. Furthermore, one population kept cellular condition stable despite a low Hsp70 level until 40°C exposure, whereas prominent cellular reactions were observed above this thermal limit. Genetic diversity (mitochondrial cytochrome c oxidase subunit I gene) within populations was low. Nevertheless, when using genetic indices as explanatory variables in a multivariate regression tree (MRT) analysis, population structure explained mean differences in cellular and biochemical heat stress responses, especially in the group exposed to 40°C. Our study showed that, even in similar habitats within a close range, populations of the same species use different stress response strategies that all rendered survival possible.

Contralateral implantation in children affected by postimplant meningitis.

This study was designed to investigate the indication and advantages of contralateral implantation after postimplant meningitis (piM). Speech perception assessment, most comfortable levels and high-resolution computer tomography were used to monitor cochlear fibrosis/ossification and clinical changes in outcomes in 5 children affected by meningitis after a variable-time post-cochlear implantation. Ipsilateral ossification was found in 3 children, 1 of whom developed delayed contralateral ossification. These children were implanted on the contralateral side as they all showed deterioration of hearing performance. Results from the present paper and literature analysis suggest that, (1) piM can induce ipsilateral and contralateral ossification, (2) meningitis-induced cochlear ossification is more prone to develop in the presence of a normal cochlear structure and (3) contralateral implantation after piM has proven to be effective in restoring performance when a full electrode insertion is accomplished.

One night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians.

BACKGROUND: Sleep loss is associated with increased cardiovascular morbidity and mortality. It is known that chronic sleep restriction affects autonomic cardiovascular control and inflammatory response. However, scanty data are available on the effects of acute sleep deprivation (ASD) due to night shifts on the cardiovascular system and its capability to respond to stressor stimuli. The aim of our study was to investigate whether a real life model of ASD, such as "one night on-call", might alter the autonomic dynamic response to orthostatic challenge and modify the immune response in young physicians. METHODS: Fifteen healthy residents in Internal Medicine were studied before and after one night on-call at Rest and during a gravitational stimulus (head up-tilt test, HUT). Heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were analyzed during Rest and HUT before and after ASD. Plasmatic hormones (epinephrine, norepinephrine, cortisol, renin, aldosterone, ACTH) and tissue inflammatory cytokines were measured at baseline and after ASD. RESULT: HRV analysis revealed a predominant sympathetic modulation and a parasympathetic withdrawal after ASD. During HUT, the sympathovagal balance shifted towards a sympathetic predominance before and after ASD. However, the magnitude of the autonomic response was lower after ASD. BPV and BRS remained unchanged before and after ASD as the hormone levels, while IFN-γ increased after ASD compared to baseline. CONCLUSION: In summary, one night of sleep deprivation, at least in this real-life model, seems to affect cardiovascular autonomic response and immune modulation, independently by the activation of the hypothalamic-pituitary axis.

Solar radiation stress in climbing snails: behavioural and intrinsic features define the Hsp70 level in natural populations of Xeropicta derbentina (Pulmonata).

Ectotherms from sunny and hot environments need to cope with solar radiation. Mediterranean land snails of the superfamily Helicoidea feature a behavioural strategy to escape from solar radiation-induced excessive soil heating by climbing up vertical objects. The height of climbing, and also other parameters like shell colouration pattern, shell orientation, shell size, body mass, actual internal and shell surface temperature, and the interactions between those factors may be expected to modulate proteotoxic effects in snails exposed to solar radiation and, thus, their stress response. Focussing on natural populations of Xeropicta derbentina, we conducted a 'snapshot' field study using the individual Hsp70 level as a proxy for proteotoxic stress. In addition to correlation analyses, an IT-model selection approach based on Akaike's Information Criterion was applied to evaluate a set of models with respect to their explanatory power and to assess the relevance of each of the above-mentioned parameters for individual stress, by model averaging and parameter estimation. The analysis revealed particular importance of the individuals' shell size, height above ground, the shell colouration pattern and the interaction height × orientation. Our study showed that a distinct set of behavioural traits and intrinsic characters define the Hsp70 level and that environmental factors and individual features strongly interact.

Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome.

To identify gene loci associated with steroid-resistant nephrotic syndrome (SRNS), we utilized homozygosity mapping and exome sequencing in a consanguineous pedigree with three affected siblings. High-density genotyping identified three segments of homozygosity spanning 33.6 Mb on chromosomes 5, 10, and 15 containing 296 candidate genes. Exome sequencing identified two homozygous missense variants within the chromosome 15 segment; an A159P substitution in myosin 1E (MYO1E), encoding a podocyte cytoskeletal protein; and an E181K substitution in nei endonuclease VIII-like 1 (NEIL1), encoding a base-excision DNA repair enzyme. Both variants disrupt highly conserved protein sequences and were absent in public databases, 247 healthy controls, and 286 patients with nephrotic syndrome. The MYO1E A159P variant is noteworthy, as it is expected to impair ligand binding and actin interaction in the MYO1E motor domain. The predicted loss of function is consistent with the previous demonstration that Myo1e inactivation produces nephrotic syndrome in mice. Screening 71 additional patients with SRNS, however, did not identify independent NEIL1 or MYO1E mutations, suggesting larger sequencing efforts are needed to uncover which mutation is responsible for the phenotype. Our findings demonstrate the utility of exome sequencing for rapidly identifying candidate genes for human SRNS.