Adaptive genetic divergence occurs when selection imposed by the environment causes the genomic component of the phenotype to differentiate. However, genomic signatures of natural selection are usually identified without information on which trait is responding to selection by which selective agent(s). Here, we integrate whole-genome-sequencing with phenomics and measures of putative selective agents to assess the extent of adaptive divergence in threespine stickleback occupying the highly heterogeneous lake Mývatn, NE Iceland. We find negligible genome wide divergence, yet multiple traits (body size, gill raker structure and defense traits) were divergent along known ecological gradients (temperature, predatory bird densities and water depth). SNP based heritability of all measured traits was high (h2 = 0.42 – 0.65), indicating adaptive potential for all traits. Whilst environment-association analyses identified thousands of loci putatively involved in selection, related to genes linked to neuron development and protein phosphorylation, only allelic variation linked to pelvic spine length was concurrently linked to environmental variation (water depth) - supporting the conclusion that divergence in pelvic spine length occurred in face of gene flow. Our results suggest that whilst there is substantial genetic variation in the traits measured, phenotypic divergence of Mývatn stickleback is mostly weakly associated with environmental gradients, potentially as a result of substantial gene flow. Our study illustrates the value of integrative studies that combine genomic assays of multivariate trait variation with landscape genomics.

Article type: Editorial

Abstract Objective: To determine whether Betahistine dihydrochloride is effective in treating primary tinnitus in adults. Design: Intention-to-treat, randomized, triple-blinding, monocentric clinical trial Setting: Botucatu Medical School – State University of São Paulo (Unesp) in Brazil. Participants: 62 adults with primary tinnitus for at least six months (both sexes), and a Tinnitus Handicap Inventory score above 18 were randomized in two equal study groups: betahistine (24 mg of oral betahistine 12/12hs for 90 days), control group (a matched placebo). Main outcomes measures: Primary outcome measure - change in Tinnitus Handicap Inventory score; secondary outcome - Clinical Global Impression Improvement and participants’ perceived improvement after the intervention. Results: Participants had a median age (interquartile range) of 54 (48 to 60) years, with a balanced number of men and women. There was no significant difference in Tinnitus Handicap Inventory change before and after treatment between the study group and control (median difference of -2 points; 95% CI, -8 to 6 points); the Tinnitus Handicap Inventory after intervention was a median (interquartile range) of 4 (-4 to 14) lower in the betahistine group, and a median (interquartile range) of 2 (-6 to 10) lower in the placebo group. The secondary endpoint, covariate adjustment, and per-protocol analysis provided similar results, and side effects were without difference between both groups. Conclusion: Betahistine was ineffective when compared to the placebo in the treatment of the primary tinnitus .

Interferon-beta, the most widely prescribed medication for multiple sclerosis, is generally considered safe. Nevertheless, rarely serious and/or life-threatening side effects have been reported such as thrombotic microangiopathy. A few mechanisms have been proposed to explain how interferon causes thrombotic microangiopathy, but insufficient immunological studies have been unable to pin this phenomenon down to a single pathophysiologic pathway. We report thrombotic microangiopathy due to acquired complement factor I deficiency in a male receiving interferon-beta treatment for multiple sclerosis. After three years of starting the therapy, the 28-year-old patient presented with malignant hypertension causing seizures, rapidly progressive renal failure requiring hemodialysis, and hemolytic anemia. Corticosteroid and plasma exchange sessions permitted hemolysis control. Nonetheless, the patient remained hemodialysis-dependent. Exploration of the complement system found a complement factor I deficiency whose activity normalized at the control carried out after two years. We concluded that IFNβ treatment may cause complement factor I deficit, which can lead to thrombotic microangiopathy and severe renal failure.

Background: Desmoid tumor (DT) is rare and challenging, often affects head neck (HN) region in children, and its appropriate treatments are under discussed. This study aimed to retrospectively evaluate long-term effectiveness and safety of 125I seed brachytherapy for pediatric DT in HN. Procedure: Seven pediatric patients with median age of 3 years old suffered from DT in HN treated with 125I brachytherapy from January 2008 to June 2018 were included. Among which, 5 underwent sole brachytherapy and the others combined with surgery under a prescription doses ranging from 10 000 cGy to 12 000 cGy. The rate of local control (LC), complete response (CR) and partial response (PR) were calculated after evaluation by radiological and pathological means. The radiation-associated toxicities were also evaluated Results: The LC rate was 7/7 during the follow-up time ranging from 43 to 135 months and with a mean of 57 months. No recurrent lesion was found in the patients receiving surgery combined with brachytherapy. In patients treated with sole brachytherapy, the radiological PR rate and CR rate were 4/5 and 1/5, respectively. In those reaching radiological PR, 3/4 were pathological CR. Slight acute radiation-associated toxicities were observed in all patients, and no late or severe acute toxicity was observed. Conclusion: 125I brachytherapy is effective and safe in the management of pediatric DT in HN as sole modality or combined with surgery in long term.

Title pageTitle : Letter to the editor: Septal myectomy in the era of genetic testingArticle type : Letter to the editor

Primula, well known for its heterostyly, is the largest genus in the family Primulaceae with more than 500 species. The considerable species number has introduced a huge challenge for taxonomy. Although several phylogenetic constructions have been carried out thoroughly, the relationships between Primula species were remained incompletely understood, especially for the relationship among sections within Chinese species. P. wilsonii Dunn is a PSESP (plant species with extremely small populations) with very limited genetic information to explore its endangered mechanism and conservation. In this study, we sequenced and assembled the complete chloroplast genomes of P. wilsonii using Illumina sequencing and compared its genomic sequences with those of four related Primula species. The chloroplast genomes of Primula species were similar in the basic structure, gene order and GC content. The detected 38 SSRs loci and 17 hyper-variable regions had many similarities in P. wilsonii, P. anisodora, P. miyabeana and P. poissonii, but showed a significant difference compared with those in P. secundiflora. Slight variations were observed among Primula chloroplast genomes, in consideration of the relatively stable patterns of IR contraction and expansion. Phylogenetic analysis based on chloroplast genomes confirmed three major clades in Chinese Primula, but the infrageneric sections were not in accordance with morphological traits. The P. poissonii complex was confirmed here and P. anisodora was the species that was most closely related to P. wilsonii. Overall, the chloroplast genome sequences provided useful genetic and evolutionary information for phylogeny, population genetics and conservation studies on Chinese Primula species.

Progressive familial intrahepatic cholestasis (PFIC) is an abnormality in the formation and secretion of bile components and bile acids.We present a case of a 6-years-old female with Type 3 of PFIC which was confirmed via detecting pathogenic variants in the ABCB4 gene.

The analytic signal is a useful mathematical tool. It separates qualitative and quantitative information of a signal in form of the local phase and local amplitude. The Clifford Fourier transform (CFT) plays a vital role in the representation of multidimensional signals. By generalizing the CFT to the Clifford linear canonical transform (CLCT), we present a new type of Clifford biquaternionic analytic signal. Due to the advantages of more freedom, the envelop detection problems of 3D images, with the help of this new analytic signal, can get a better visual appearance. Synthesis examples are presented to demonstrate these advantages.

Most researches interested in finding the bounds of the cumulative standard normal distribution Φ(x) are not tight for all positive values of the argument x. This paper mainly proposes new simple lower and upper bounds for Φ(x). Over the whole range of the positive argument x, the maximum absolute difference between the proposed lower bound and Φ(x) is less than 3×〖10〗^(-4), while it is less than 4.8×〖10〗^(-4) between the proposed upper bound and Φ(x). Numerical comparisons have been made between the proposed bounds and some of the other existing bounds, which showed that the proposed bounds are more compact than most alternative bounds found in the literature.

Despite the growing number of dam removals, very few have been studied to understand their impacts on stream fish communities. An even smaller proportion of dam removal studies focus on the impacts of low-head dam removals, although they are the most common type of dam. Instead, the majority of removal studies focus on the impacts of larger dams. In this study, two previously impounded Illinois rivers were monitored to assess the impacts of low-head dam removal on the functional assemblage of stream fishes. Study sites were sampled each fall from 2012-2015 (pre-dam removal) and 2018-2020 (post-dam removal) in three habitat types: downstream of the dam, impounded areas, and runs of rivers. Fishes were aggregated into habitat and reproductive guilds, relating community changes to habitat, environmental metrics, and stream quality. Prior to removal, the slackwater guild was the most prevalent habitat guild throughout both rivers, while nest builders and benthic spawners were the most abundant reproductive guilds. During the two years following removal, habitat conditions and fish assemblages improved throughout both rivers, with improvements in QHEI, IBI, water temperature, and dissolved oxygen, as well as a shift to more evenly distributed representation of habitat and reproductive guilds. The improvements in environmental metrics and overall stream quality, particularly in the formerly impounded habitats, indicate diminished habitat homogeneity, and a shift towards natural habitat diversity. This habitat diversification likely led to the restoration of a range of potential niches, thereby increasing the array of guild types inhabiting these rivers, while simultaneously preventing single-guild dominance.

Purpose: Left ventricular diastolic dysfunction (LVDD) is associated with poor outcomes in intensive care unit (ICU). Nonetheless, precise reporting of LVDD in COVID-19 patients is currently lacking and assessment could be challenging. Methods: We performed an echocardiography study in COVID-19 patients admitted to ICU with the aim to describe the feasibility of full or simplified LVDD assessment and its incidence. We also evaluated the association of LVDD or of single echocardiographic parameters with hospital mortality. Results: Between 06.10.2020 and 18.02.2021, full diastolic assessment was feasible in 74% (n=26/35) of patients receiving full echocardiogram study. LVDD incidence was 46% (n=12/26), whilst the assessment produced different results (incidence 81%, n=21/26). Nine patients were hospital-survivors (39%); incidence of LVDD (full assessment) was not different between survivors (n=2/9, 22%) and non-survivors (n=10/17, 59%; p=0.11). Also, the E/e’ ratio lateral was lower in survivors (7.4 [3.6] vs non-survivors 10.5 [6.3], p=0.03). We also found that s’ wave was higher in survivors (average, p=0.01). Conclusion: In a small single-center study, assessment of LVDD according to latest guidelines was feasible in three quarter of COVID-19 patients. Non-survivors showed a trend towards greater LVDD incidence; moreover, they had significantly worse s’ values (all) and higher E/e’ ratio (lateral).

Harlequin ichthyosis is a rare autosomal recessive congenital ichthyosis with a distinct phenotypic appearance. We report a male baby with harlequin ichthyosis who was born to consanguineous parents that have a previous female baby who was diagnosed with harlequin ichthyosis.

Background. The COVID-19 pandemic has spread across the world, leading to government measures associated with a negative impact on mental health. The aim of this study was to evaluate the impact of COVID-19 on depression, anxiety and resilience in Dutch people with cystic fibrosis (PwCF) or primary ciliary dyskinesia (PwPCD) and their caregivers during the pandemic. Methods. Adolescents (12-17 years), adults and caregivers of children (0-17 years) with CF or PCD completed questionnaires on depression (PHQ-9), anxiety (GAD-7) and resilience (BRS) between September 2020 and February 2021. The psychosocial impact of COVID-19 was measured by the Exposure and Family Impact Survey (CEFIS) Part 2. Mixed model analyses compared PHQ-9 and GAD-7 results to participants’ pre-pandemic scores. Results. 110 participants (10 PwCF, 31 PwPCD, 52 CF caregivers, 17 PCD caregivers) completed questionnaires during the pandemic. Pre-pandemic outcomes were available for 87 participants. The prevalence of symptoms of depression and anxiety (PHQ-9 or GAD-7 scores ≥5) in PwCF and PwPCD and their caregivers before and during the pandemic was high, with an increase in depression in PwCF (2.75; 95%-CI: 0.82 to 4.68) and increase in anxiety in CF caregivers (1.03; 0.09 to 1.96) during the pandemic. Resilience was within the normal range for all groups, CEFIS scores corresponded to a low to normal impact. Conclusion. PwCF and PwPCD and their caregivers were at high risk of increased depression and anxiety symptoms both before and during the pandemic, which emphasizes the importance of mental health screening and psychological care in CF and PCD.

This case report describes of a pharmacokinetic drug–drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic non-small cell lung cancer with MET exon-14 deletion and hepatitis C virus infection genotype 1A, received both crizotinib and sofosbuvir/velpatasvir. Crizotinib was well tolerated, but 1 week after sofosbuvir/velpatasvir initiation, the patient experienced bilateral lower-limb edema and class III NYHA dyspnea. We assumed that increased exposure to crizotinib could account for this cardiac toxicity. Drug causality was probable according to the Naranjo scale. We hypothesized a reciprocal interaction between crizotinib and velpatasvir, mediated by both cytochrome 3A4 (CYP3A4) and P-glycoprotein (P-gp). Clinicians should be aware of the risk of drug–drug interactions between direct-acting antiviral agents that inhibit CYP3A4 (glecaprevir) and/or P-gp (voxilaprevir) and anticancer tyrosine kinase inhibitors that are mostly CYP3A4 and/or P-gp substrates (gefitinib, afatinib, erlotinib, crizotinib, ceritinib, lorlatinib, brigatinib, capmatinib etc.).

Objective: To investigate reliable biomarkers for predicting histological chorioamnionitis (HCA). Design: In this retrospective study, PPROM mothers were treated with a course of dexamethasone. Blood tests for serum indictors were conducted continuously after first injection. Setting: One Shanghai hospital Population: PPROM mothers before 34 0/7 weeks of gestation Methods: Data were compared by General Linear Model analysis. The diagnostic accuracy in predicting HCA were evaluated with ROC curve. Main Outcome Measures: The response of infectious indictors to dexamethasone treatment; the diagnostic accuracy for CRP and PCT in predicting HCA. Results： We found 98 HCA women (62.42%) and 59 CON women (37.58%) in 157 PPROM mothers. WBC and neutrophil significantly increased 24 hours after the first injection in both groups, followed by a decrease at 72 hours post first injection (P<0.05). No significances were found between two groups in WBC, neutrophil and lymphocyte. Both CRP and PCT were significantly higher in the HCA group after first injection. PCT had both high specificity and sensitivity, especially at the baseline (cutoff, 0.031 ng/ml). Furthermore, the positive predictive values (PPV) of PCT were respectively 0.946 and 0.960 at 48 (cutoff, 0.049 ng/ml) and 72 (cutoff, 0.051 ng/ml) hours, which were better than the corresponding PPV of CRP. Conclusion: The response of WBC, neutrophil and lymphocyte to dexamethasone could be differentiated from uterine infection; PCT could be a reliable biomarker for early diagnosis of HCA. Funding: Shanghai Municipal Commission of Health and Family Planning (GWIV-26, 202040128); Pudong Commission of Health and Family Planning (PW2019D-13).

Herein, we propose a novel method to enhance the photoreactivity of an MOF catalyst by grafting isocyanate bonds (−N=C=O) and sulfhydryl-complexed copper (−SCu) onto ZIF-8 (NIF-SCu). The grafting process intercalated interlayer bands between the conduction and valence bands of ZIF-8, thereby providing a “ladder” for facile electron transition. The extreme improvement in the photoreactivity of NIF-SCu could be attributed to the enhancement in light responses in the range of 350–450 nm by −N=C=O groups and the widening of the visible light range of the MOF by −SCu groups. The formation of staggered energy levels in NIF-SCu could also narrow the band gap, lower the resistance, and facilitate the transfer of photogenerated carriers, thereby generating electrons with strong reduction potential in the −SCu conduction band. This study provides a new strategy for improving or even endowing the photoactivity of environmental functional materials with wide bandgaps.

George and colleagues report their experience with a non-transplant left ventricular assist device program (1). This manuscript spans a decade’s experience with LVADs and clearly demonstrates that LVAD therapy is possible in centers without a heart transplant program. 100 LVADs were placed during this period. The positive findings from this report include that as volume increased, the complications of right heart dysfunction and bleeding decreased. Noteworthy is that 85 of the 100 patients were implanted with a fully magnetically levitated ventricular assist device. Given the superior performance of a fully magnetically levitated device to a rotary pump (2) these findings are relevant for all contemporary centers with LVAD programs.The authors importantly sought the resources of a transplant center to ensure that patients who were offered LVAD in their non-transplant center were indeed not candidates for cardiac transplantation. In addition to this fundamental necessity, three features are necessary for a successful non-transplant LVAD program. Firstly, the institution must offer robust infrastructure and support. Secondly there must be a strong surgeon-leader dedicated to overseeing the program. Lastly, cardiologists who are dedicated to heart failure are essential to guide patients to this therapy.The extension of LVAD therapy to patients in non-transplant centers is essential for durable mechanical circulatory support to remain as a vital part of advanced therapies for heart failure. VADs will continue to play an important role in the management of end-stage heart failure for patients who are not eligible for cardiac transplantation. The 2020 Society of Thoracic Surgeons INTERMACs report now offers patients a 5-year survival of 45%(3). The survival of patients with LVADs continues to increase. The data in this current report offer a new perspective and increased access to LVAD therapy for patients with end stage heart failure.ReferencesGeorge TJ, Aldrich A, Smith III RL, et al. Development of a Non-Transplant Left Ventricular Assist Device Program. J Card SurgMehra MR, Uriel Y, Naka Y, et al. A Fully Magnetically Levitated Left Ventricular Assist Device – Final report. N Engl J Med 2019:380:1618-27.Molina EJ, Shah P, Kierman MS, et al. The Society of Thoracic Surgeons Intermacs 202 Annual Report. Ann Thorac Surg 2021;111:778-92.