Prodromes predict attacks of Hereditary Angioedema: results of a prospective StudyTo the Editor,Hereditary Angioedema (HAE) is a lifetime disease characterized by repetitive bouts of tissue edema.1 Early signs, symptoms and perceptions (prodromes) are manifested by subjective and objective signals, preceding attacks by several hours.2-3 Using an new HAE-specific instrument, we have recently shown that patients can identify prodromes and able to predict oncoming attacks.4 However, that study was retrospective, which might have been affected by recall bias.In the present study a cohort of 48 HAE patients prospectively reported four events of prodromes followed by attack, attacks not preceded by a prodrome and incidents with only a prodrome. Pre-defined domains (clusters of body locations) and scalable dimensions (pain, severity, impairment and functionality), time of onset and termination were assessed in each episode.3-4 (Statistical methods are described in the supplementary data ). The study was approved by the ethics committees of Tel-Aviv University, Sheba Medical Center and Barzilai Medical center. All patients signed an informed-consent form. Mean age was 35.25 years (SD ±16.4), Median 30.0 (age range 10-70) and 27 (56.25%) were females. Mean age of onset was 8.3 years and age at diagnosis 10.9 years (2.7 years diagnostic gap) (Table S1 ).We received reports on 119 prodromes and 192 attacks. The majority experienced a prodrome before at least one of their attacks, and 64% affirmed that they can predict an oncoming attack by having a prodrome.(Table S1) .Significant differences were found between prodromes and attacks across all dimensions of the predefined clusters of body locations. Statistical analysis verified that prodromes could be discriminated from attacks for all parameters. (Table 1) Positive correlations were found between the same attributes of prodromes and attacks, most notably in the abdominal and extremity clusters (Table S2, Fig S1A-E) . Mean duration of prodromes was significantly shorter than attacks, and prodromes overlapped the attack in 24.3% of cases. The predictive power analysis indicates that individuals who experience a prodrome had higher risk for having an attack in the same region. Sensitivity of the prodrome as a predictor of attack was 95% to 99%, and specificity 18% to 64%. (Table 2).HAE prodromes represents a continuity of pathophysiologic events, initiated by the activation of the bradykinin-forming cascade and ending with a breach in vascular endothelial integrity.2, 5(Fig S2 ) In this study we aimed to capture the critical elements of prodromes and their association with consequent attacks and evaluate their predictive power as an early warning sign.2-4 The HAE-EPA instrument reliably captures patient’s experience by using the same metrics, and the prospective design better reflects patients’ experience in real-time, which may have been missed in our previous study.The study shades light on the predictive value of prodromes as forecasters of attacks.2-4 It affirms that patients can clearly distinguish prodromes from attacks. The positive correlations support our basic assumption that prodromes could predict attack location and severity, which is particularly germane in the abdomen. In most cases a high intensity attack was predated by a high intensity prodrome. This substantiate our observation on inter-personal differences between subjects4 Mean disease duration of the cohort (27 years) may surmise that the study subjects were experienced patients, who could recognize early pre-attack cues.Treating oncoming attack at the prodromal stage may enhance resolution of attacks.6, 7 Therefore; experienced patients can use prodromes as an efficient strategy in managing attacks by employing early interventions. Such approach can apply in other diseases with relapsing-remitting pattern and advance the concept of prodrome-triggered intervention.8In conclusion , the study ascertained that HAE patients can distinguish prodromes from attacks and a prodrome may predict attack in the same location. Having a prodrome increase the likelihood of subsequent attack, alerting the patients and assisting in early initiation of therapy.Table 1: Within-subject differences between prodrome and attacks

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Background: Type A aortic dissection (TAAD) involves a tear in the intimal layer of the thoracic aorta proximal to the left subclavian artery, and hence, carries a high risk of mortality and morbidity and requires urgent intervention. This dissection can extend into the main coronary arteries. Coronary artery involvement in TAAD can either be due to retrograde extension of the dissection flap into the coronaries or compression and/or blockage of these vessels by the dissection flap, possibly causing myocardial ischaemia. Due to the emergent nature of TAAD, coronary involvement is often missed during diagnosis, thereby delaying the required intervention. Aims: The main scope of this review is to summarise the literature on the incidence, mechanism, diagnosis, and treatment of coronary artery involvement in TAAD. Methods: A comprehensive literature search was performed using multiple electronic databases, including PubMed, Ovid, Scopus and Embase, to identify and extract relevant studies. Results: Incidence of coronary artery involvement in TAAD was seldom reported in the literature, however, some studies have described patients diagnosed either preoperatively, intraoperatively following aortic clamping, or even during autopsy. Among the few studies that reported on this matter, the treatment choice for coronary involvement in TAAD was varied, with the majority revascularizing the coronary arteries using coronary artery bypass grafting or direct local repair of the vessels. It is well-established that coronary artery involvement in TAAD adds to the already high mortality and morbidity associated with this disease. Lastly, the right main coronary artery was often more implicated than the left. Conclusion: This review reiterates the significance of an accurate diagnosis and timely and effective interventions to improve prognosis. Finally, further large cohort studies and longer trials are needed to reach a definitive consensus on the best approach for coronary involvement in TAAD.

Despite advances in technologies and clinical experience, conduction disorders, after TAVR or SAVR, represent the weak point of these procedures, requiring permanent pacemaker implantation (PPI) till 37.7% of patients in TAVR recipients. The role of PPI in TAVR and SAVR remains controversial in mid- and long-term outcomes. Indeed, many studies have been published with contradictory results, leaving doubts rather than certainties.

A previously healthy 68-year-old woman presented to the outpatient clinic with a 2-month history of palpitation. Physical examination and laboratory findings were unremarkable. Her electrocardiogram showed sinus tachycardia with a heart rate of 115 beats/m. Transthoracic echocardiography (TTE) showed a normal ejection fraction with a huge mass in the left atrium (Figure 1a). Transesophageal echocardiography (TEE) and cardiac magnetic resonance imaging (MRI) were performed for further evaluation. TEE revealed a hyperechogenic, well-demarcated mass in the left atrium, that was attached to the interatrial septum and adjacent to the left pulmonary veins (Figure 1b, 1c,1d). Cardiac MRI revealed a heterogeneous left atrial mass located on the fossa ovalis, 58x52x54 mm in size and markedly hyperintense on a STIR sequence (Figure 1e). These findings were suggestive of a benign cardiac tumour such as myxoma or hemangioma. A decision for surgery was made and coronary angiography was performed which showed that the branch of the circumflex artery supplied and surrounded the mass in the form of a net (Figure 1e). The patient underwent complete excision of the mass (Figure 2a, 2b). Histopathological examination revealed a nested architecture of epitelioid cells, the nests are round or oval in shape and invested by an fibrovascular stroma. Tumor cells had centrally and eccentrically located round nuclei and cytoplasm ranging from finely granular to eosiniphilic. At immunohistochemical staining, the nests were positive for chromogranin A, negative for cytokeratin (Figure 2c, 2d, 2e, 2f). A diagnosis of paraganglioma was made. After an uneventful postoperative course, she was discharged home on postoperative day 6. Cardiac paraganglioma is a very rare neuroendocrine tumour and accounts for less than 1% of primary cardiac tumours (1,2). Approximately 10% of paragangliomas may be malignant, complete surgical resection remains the first-line treatment (3).

A larger use of mitral valve repair is recommended in case of mitral regurgitation. Anterior leaflet repair is generally more difficult than posterior. Presence of atrial fibrillation or dysfunction of left ventricle appears to be independent preoperative factors of failure in case of involvement of the anterior leaflet. In experienced hands anterior leaflet repair can be effective and safe and should theoretically not limit a conservative technique instead of a replacement. This would therefore lead to being more aggressive in the treatment of this pathological condition in the earlier stages of the disease.

Background: Influenza-associated pulmonary aspergillosis (IAPA) is an important complication of severe influenza with high morbidity and mortality. Methods: We conducted a retrospective multicenter study in tertiary hospitals in Switzerland during 2017/18 and 2019/20 influenza seasons. All adults with PCR-confirmed influenza infection and treatment on intensive-care unit (ICU) for >24h were included. IAPA was diagnosed according to previously published clinical, radiological and microbiological criteria. We assessed risk factors for IAPA and predictors for poor outcome which was a composite of in-hospital mortality, ICU length of stay ≥7d, mechanical ventilation ≥7d or extracorporeal membrane oxygenation. Results: 158 patients (median age 64 years, 45% females) with influenza were included, of which 17 (10.8%) had IAPA. Asthma was more common in IAPA patients (17% vs. 4% in non-IAPA, p=0.05). Asthma (OR 12.0 (95% CI 2.1-67.2)) and days of mechanical ventilation (OR 1.1 (1.1 – 1.2)) were associated with IAPA. IAPA patients frequently required organ supportive therapies including mechanical ventilation (88% in IAPA vs. 53% in non-IAPA, p=0.001) and vasoactive support (75% vs. 45%, p=0.03) and had more complications including ARDS (53% vs. 26%, p=0.04), respiratory bacterial infections (65% vs. 37%, p=0.04) and higher ICU-mortality (35% vs. 16.4%, p=0.05). IAPA (OR 28.8 (3.3–253.4)), influenza A (OR 3.3 (1.4-7.8)) and higher SAPS II score (OR 1.07 (1.05—1.10)) were independent predictors of poor outcome. Interpretation: High clinical suspicion, early diagnostics and therapy are indicated in IAPA because of high morbidity and mortality. Asthma is likely an underappreciated risk factor for IAPA.

A quinoline derivative, 4-(quinolin-2-ylmethylene)aminophenol was synthesized and structurally characterized by single crystal X-ray diffraction. The crystal packing behaviour and intermolecular interactions were examined by Hirshfeld surface analyses, 2D fingerprint plots and QTAIM analysis. The second order nonlinear response of 4-(quinolin-2-ylmethylene)aminophenol molecule immersed in DMSO was investigated at PCM/DFT/CAM-B3LYP/6-311++G(d,p) level. Theoretical calculations of the Hyper-Rayleigh scattering first hyperpolarizability were performed using two different procedures, the Sum-over-states scheme and the energy derivative method from Gaussian16. The HRS first hyperpolarizability results were compared with obtained for other organic compounds and shown that the 4-(quinolin-2-ylmethylene)aminophenol presents a good nonlinear optical response.

The forest-floor litter layer can retain substantial volumes of water, thus affecting evaporation and soil-moisture dynamics. However, litter layer wetting/drying dynamics are often overlooked when estimating forest water budgets. Here, we present field and laboratory experiments characterizing water cycling in the forest-floor litter layer and outline its implications for subcanopy microclimatic conditions and for estimates of transpiration and recharge. Storage capacities of spruce needle litter and beech broadleaf litter averaged 3.1 and 1.9 mm, respectively, with drainage/evaporation timescales exceeding 2 days. Litter-removal experiments showed that litter reduced soil water recharge, reduced soil evaporation rates, and insulated against ground heat fluxes that impacted snowmelt. Deadwood stored ~0.7 mm of water, increasing with more advanced states of decomposition, and retained water for >7 days. Observed daily cycles in deadwood weight revealed decreasing water storage during daytime as evaporation progressed and increasing storage at night from condensation or absorption. Water evaporating from the forest-floor litter layer modulates the subcanopy microclimate by increasing humidity, decreasing temperature, and reducing VPD. Despite the relatively small litter storage capacity (<3.1 mm in comparison to ~102 mm for typical forest soil rooting zones), the litter layer alone retained and cycled 18% of annual precipitation, or 1/3 of annual evapotranspiration. These results suggest that overlooking litter interception may lead to substantial overestimates of recharge and transpiration in many forest ecosystems.

In this paper, we propose a new nonuniform mesh method to simulate acoustic scattering problems in two dimensional periodic structures with non-periodic incident fields numerically. As existing methods are difficult to extend to higher dimensions, we have designed the new method with such extensions in mind. With the help of the Floquet-Bloch transform, the solution to the original scattering problem is written as an integral of a family of quasi-periodic problems. These are defined in bounded domains for each value of the Floquet parameter which varies in a bounded interval. The key step in our method is the numerical approximation of the integral by a quadrature rule adapted to the regularity of the family of quasi-periodic solutions. We design a nonuniform mesh with a Gaussian quadrature rule applied on each subinterval. We prove that the numerical method converges exponentially with respect to both the number of subintervals and the number of Gaussian quadrature points. Some numerical experiments are provided to illustrate the results.

Birds of prey frequently feature in reintroductions and the hacking technique is typically used. Hacking involves removing large nestlings from donor populations, transferring them to captivity, feeding them ad libitum. Potentially, via the hacking method, stress of captivity and disruption of parental feeding may be detrimental. Alternatively, provision of ad libitum food may be advantageous. Although hacking has underpinned reintroduction project successes there has been no research on how the method may affect the health and nutritional status of translocated birds during captivity. We compared blood chemistry data from 55 young White-tailed Eagles, translocated from Norway as part of the species’ reintroduction to Scotland, from sampling soon after arriving in captivity and again (≈ 42 d later) before their release. Numerous significant differences between first and second samples were found, but no significant interactions showed that sexes responded similarly to captivity. According to hematological and biochemical metrics, individuals showed several changes during captivity, including in red blood cell parameters, plasma proteins and white cellular parameters related to the immune system, that indicated improved health status. Captivity with ad libitum food was associated with decreased urea and uric acid values: high values can indicate nutritional stress. Urea values became more normally distributed before release, indicating that ad libitum food had reduced nutritional differences between early nestlings in the season and later ones. Despite plentiful food, both sexes lost body mass before release, suggesting an inherent physiological mechanism to improve flight performance in fledglings. We conclude that hacking improved the health and nutritional status of released eagles which is likely to enable birds to cope with greater costs of exploratory behavior which they may require in reintroduction projects. In this context, we note the absence of survival differences between hacked and wild raptors in previous research.

Studies of natural hybrid zones can provide documentation of range shifts in response to climate change and identify loci important to reproductive isolation. Using a deep temporal (36-38 years) comparison of the black-capped (Poecile atricapillus) and Carolina (P. carolinensis) chickadee hybrid zone, we investigated movement of the western portion of the zone (western Missouri) and assessed whether loci and pathways underpinning reproductive isolation were similar to those in the eastern portion of the hybrid zone. Using 92 birds sampled along the hybrid zone transect in 2016 and 68 birds sampled between 1978 and 1980, we generated 11,669 SNPs via ddRADseq. These SNPs were used to assess movement of the hybrid zone through time and to evaluate variation in introgression among loci. We demonstrate that the interface has moved ~5 km to the northwest over the last 36-38 years, i.e., at only one-fifth the rate at which the eastern portion (e.g., Pennsylvania, Ohio) of the hybrid zone has moved. Temperature trends over the last 38 years reveal that eastern areas have warmed 50% more than western areas in terms of annual mean temperature, possibly providing an explanation for the slower movement of the hybrid zone in Missouri. Our results suggest hybrid zone movement in broadly distributed species, such as chickadees, will vary between areas in response to local differences in the impacts of climate change.

Heart failure and atrial fibrillation are often associated. Both conditions share pathophysiology and risk factor; as an example, atrial fibrillation may be regarded as either the ‘cause’ or the ‘consequence’ of heart failure. If coexistent, they are associated to very poor outcome. With this in mind, finding effective therapy for patients presenting with both heart failure and atrial fibrillation remains of paramount importance. There are also little evidence of the role and benefit of surgical atrial fibrillation ablation concomitant to heart surgery (i.e., coronary or valve surgery).

A patient was referred to the oral medicine department with symptoms of redness and swelling of the lips and cheek, and intra-oral lesion. Biopsy was taken and laboratory factors were higher than normal, suggesting diagnosis of sarcoidosis. In this study we analyze the oral findings associated with sarcoidosis.

Terminal 11q deletion syndrome, also known as Jacobsen syndrome, is a rare genetic disorder. Children with Jacobsen syndrome have multiple risk factors for recurrent pneumonia. This is a case of recurrent pneumonia in a child with Jacobsen syndrome secondary to common variable immune deficiency.

A 78-year-old woman underwent surgical intervention for severe atrial functional mitral regurgitation and left ventricular apical aneurysm secondary to apical hypertrophic cardiomyopathy. Apical hypertrophic cardiomyopathy can cause atrial fibrillation and atrial functional mitral regurgitation. Left ventricular apical aneurysms can cause fatal arrhythmias, which may require surgical intervention.

Background. Cystic fibrosis (CF) is an autosomal recessive disorder associated with an increased susceptibility to respiratory infections that cause progressive decline in lung function and lead to lung damage and chronic respiratory failure. To analyze the CF-related mortality trends in the Mexican population during a 22-year period.  We conducted a mortality trend analysis using death certificates data. Trends in CF-specific and in age-specific mortality rates were evaluated using Joinpoint regression analysis. Among subjects ≤40 years, 1184 CF-related deaths were identified. In 1999–2009 median age at death was 7 years compared to 10 years in 2010–2020. Overall mortality rate increased from 0.03 per 100,000 in 1999 to 0.06 per 100,000 in 2020. A decline in mortality rate for patients ≤28 days and an increase in mortality rate in older age groups was observed. Conclusion. The increasing trend in overall mortality, associated with a downward trend in neonatal mortality and an increase in median age at death is conceivably due to enhanced diagnosis, as well as major advances in treatment modalities, leading to higher survival rates. Key words: age at death, cystic fibrosis, epidemiology, low- and middle-income countries, mortality, survival rate.

Differences in gut microbiome composition are linked with health, disease and ultimately host fitness; however, the molecular mechanisms underlying that relationship are not well characterized. Here, we modified the fish gut microbiota using antibiotic and probiotic feed treatments to address the effect of host microbiome on gene expression patterns. Chinook salmon (Oncorhynchus tshawytscha) gut gene expression was evaluated using whole transcriptome sequencing (RNA-Seq) on hindgut mucosa samples from individuals treated with antibiotic, probiotic and control diets to determine differentially expressed (DE) host genes. Fifty DE host genes were selected for further characterization using nanofluidic qPCR chips. We used 16S rRNA gene metabarcoding to characterize the rearing water and host gut microbiome bacterial communities. Daily administration of antibiotics and probiotics resulted in significant changes in fish gut and aquatic microbiota as well as more than 100 DE genes in the antibiotic and probiotic treatment fish, relative to healthy controls. Normal microbiota depletion by antibiotics mostly led to downregulation of different aspects of immunity and upregulation of apoptotic process. In the probiotic treatment, genes related to post-translation modification and inflammatory responses were up-regulated relative to controls. Our qPCR results revealed significant effects of treatment (antibiotic and probiotic) on rabep2, aifm3, manf, prmt3 gene transcription. Moreover, we found significant associations between members of Lactobacillaceae and Aeromonadaceae with host gene expression patterns. Overall, our analysis showed that the microbiota had significant impacts on many host signaling pathways, specifically targeting immune, developmental, and metabolic processes. Our characterization of some of the molecular mechanisms involved in microbiome-host interactions will help develop new strategies for preventing/ treating microbiome disruption-related diseases.