Background and Purpose: Heart failure can reflect impaired contractile function at the myofilament level. In healthy hearts, myofilaments become more sensitive to Ca2+ as cells are stretched. This represents a fundamental property of myocardium that contributes to the Frank-Starling response, although the molecular mechanisms underlying the effect remain unclear. Mavacamten is a drug that binds to myosin, which is under investigation as a potential therapy for cardiovascular disease. We tested how mavacamten affects the sarcomere-length dependence of Ca2+-sensitive isometric contraction to determine how mavacamten might modulate the Frank-Starling mechanism. Experimental Approach: Multicellular preparations from the left ventricular free wall of hearts procured from organ donors were chemically permeabilized and Ca2+-activated in the presence or absence of 0.5 μM mavacamten at 1.9 or 2.3 µm sarcomere length (37°C). Isometric force and frequency-dependent viscoelastic myocardial stiffness measurements were made. Key Results: At both sarcomere lengths, mavacamten reduced maximal force and Ca2+-sensitivity of contraction. In the presence and absence of mavacamten, Ca2+-sensitivity of force increased as sarcomere length increased. This suggests that the length-dependent activation response was maintained in human myocardium, even though mavacamten reduced Ca2+-sensitivity. There were subtle effects of mavacamten reducing force values under relaxed conditions (pCa 8.0), as well as slowing myosin cross-bridge recruitment and speeding cross-bridge detachment under maximally activated conditions (pCa 4.5). Conclusion and Implications: Mavacamten did not eliminate sarcomere length-dependent increases in the Ca2+-sensitivity of contraction in myocardial strips from organ donors at physiological temperature. Pharmaceuticals that modulate myofilament function may be useful therapies for cardiovascular disease.

At the date of writing this editorial, there is growing agreement amongst experts that the first wave of the COVID-19 pandemic is in decline. The number of deaths reported each day is now around 1% of the cumulative total and falling. In general, the approach to predicting pandemic policy has been through a comparison of inter-country performance in managing this crisis. While all countries are paying a high price in economic slowdown and lives lost, the health consequences in terms of cases and deaths have varied considerably. Countries with lower relative mortality and infection numbers have shown a more structured logical approach to pandemic management. There is a very real urgency to learn lessons immediately given the pressure to reduce the home confinement policy as soon as possible. While this is clearly a challenging time for policy makers, public health messaging is often emotive around concepts such ‘being at war’ with the virus, and other similar statements. We propose that a more rational approach to moving forward is required to avoid a second wave. Understanding this rational approach can be found through an evaluation of not only how other countries are approaching this challenge, but also from history.

Abstract In recent years, immune checkpoint therapy to reverse NK and T cell exhaustion has emerged as a promising treatment in various cancers. Recently, the FDA has approved anti-PD-1 pembrolizumab for patients with recurrent or metastatic cervical cancer. Other checkpoint molecules, such as TIGIT and Tim-3 have yet to be fully explored in this disease. Here, we found that PD-1, TIGIT, and Tim-3 are over-expressed on some peripheral blood CD56dim and CD56bright NK cells and T cells in cervical cancer patients and women with premalignant lesions. However, we observed stronger significance and separation between groups when these three molecules were examined together. These cells, with an apparently “exhausted” phenotype, were significantly augmented in patients. Different PD-1 levels (PD1low, PD1int, PD-1hi) on T cells were used to further define checkpoint positive populations. Soluble PD-L1 was observed to be increased in cervical cancer. Within the cancer group, the highest levels of sPD-L1 and triple positive or double positive cells and tumor stage were found similarly within tumors of different stages. Our results might show an overview of what is happening in patients with precancerous lesions and cervical cancer, and may give an early clue as to whom to administer monoclonal checkpoint blocking therapies.

Full genome analysis of a young girl with deafness, dystonia, central hypomyelination, refractory seizure, and fluctuating liver function impairment revealed a heterozygous, de novo variant in the BCAP31 gene on chromosome X28q (NC_000023.11(BCAP31_v001):c.92G>A), mutations of which caused the X-linked recessive severe neurologic disorder DDCH (Deafness, Dystonia, and Cerebral Hypomyelination, OMIM#300475). Reverse transcription-PCR (RT-PCR) of the patient’s white blood cells showed the absence of wild-type BCAP31 mRNA but the presence of two novel BCAP31 mRNAs. The major alternatively-spliced mRNA is due to exon 2 skipping and the utilization of a new initiation site in exon 3 that leads to a frameshift and truncated transcript while the minor novel mRNA has a 110 nucleotide insertion to exon 2. Phasing studies showed that the de novo variant arose in the paternal X chromosome. X chromosome inactivation assay was done and confirmed that the patient’s maternal X chromosome was preferentially inactivated, providing evidence that the mutated BCAP31 gene was the predominantly expressed. According to the ACMG guideline, this variant is deemed “pathogenic” (PS2, PS3, PM2, PP3, PP4) and deleterious. This is the first reported female patient in BCAP31-related syndrome resulted from skewed X-inactivation and a de novo mutation in the active X chromosome.

Although parathyroid tissue auto-transplantation is useful for preventing hypoparathyroidism during thyroidectomy, hyperparathyroidism may occur due to proliferation of the transplanted parathyroid tissue. Hyperparathyroidism due to the autografted parathyroid gland should be suspected in patients who undergone parathyroid auto-transplantation.

Adenoid Cystic Carcinoma (AdCC) is a malignant tumor mostly occurring in the head and neck salivary glands. In this article, two rare cases of adenoid cystic carcinoma occurring in the buccal mucosa with their treatment and long-term follow-up are presented.

Premature ovulation may occur during controlled ovarian stimulation. Usually, this is noticed and treatment is canceled before ovum pick up (OPU). In this case, a 24-year-old woman naturally conceived during the stimulation and OPU was successfully performed afterwards. Despite developing severe ovarian hyperstimulation syndrome, she delivered a healthy baby.

Pregnancy provides optimal opportunities for health promotion and disease prevention. Smoking before and during pregnancy is one of the largest modifiable risk factors for a range of adverse pregnancy outcomes. Concerns over the risks of smoking motivate many pregnant smokers to quit. However, most of their partners continue to smoke throughout pregnancy. More than one-third (35%) of men in the world smoke, and just over 6% of women do (Ritchie et al. Published online at OurWorldInData.org 2020). The impact of paternal smoking, second-hand or third-hand smoking on the perinatal health is largely overlooked. Given the vast majority of studies focusing on the pregnant smokers, less is known about paternal smoking on their future children.In this paper (Zhou et al. BJOG 2020), using a large national prepregnancy registry database, Zhou et al. found that paternal smoking may be associated with birth defects such as congenital heart diseases, limb abnormalities and neural tube defects in the offspring. The result was consistent with previous retrospective studies, but a medium to large effect size was seen. All of the odd ratios exceeded 2.5, with one even over 20 (congenital heart diseases OR=2.51, 95%CI 1.04-6.05; limb abnormalities OR=20.64 95%CI 6.46-68.02; digestive tract anomalies OR=3.67 95%CI 1.44-9.37; neural tube defect OR=4.87,95%CI 1.66-14.28). Such difference might be partially explained by potential confounding factors. For example, the extent of tobacco exposure, in the National Birth Defects Prevention Study (Malik et al. Pediatrics 2008; 121: e810), compared with light smoking exposure (<14 cigarettes per day), heavy smoking women (≥25 cigarettes per day) were more likely to have infants with septal defects (OR 2.06; 95%CI: 1.20-3.54), suggesting a dose-dependent relationship between tobacco exposure and birth defects.In addition, a reduced risk of birth defects after changing smoking behaviors was found in Zhou’s paper. It is no surprise that paternal smoking cessation could improve the adverse outcomes. Limited evidences address whether there is a critical window period by which smoking must be stopped to prevent subsequent adverse perinatal outcomes. Results from a retrospective case-control study indicated that the risk of fetal congenital heart diseases increased as women smoked during the first trimester (Sullivan et al. J Pediatr; 2015; 166:978). In a prospective cohort study (McCowan et al. BMJ 2009; 338: b1081), the authors concluded that stopping smoking early in pregnancy, and certainly by 15-16 weeks’ gestation, may minimize the adverse effects of smoking on late pregnancy complications and should be an important goal for pregnant smokers. Yet, such critical time for paternal smoking cessation remains unknown.Tobacco smoke is also a human germ cell mutagen. It is estimated that with even a modest 25% increase in sperm mutation frequency caused by smoke-exposure, for each generation across the global population there will be millions of smoking-induced de novo mutations transmitted from father to offspring (Beal et al. Mutation Research;2017; 773:26).Therefore, it is strongly recommended that women and men should immediately stop smoking in advance of reproduction.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Aims: The investigation regarding the clinical significance of programmed cell death protein-1 (PD-1)-targeted immunotherapy in Chinese patients is rare. This study evaluated safety and efficacy of PD-1 with Toripalimab, Camrelizumab or Sintilimab for Chinese Hepatocellular carcinoma (HCC) patients in a real-life cohort. Methods: We retrospectively analyzed HBV associated HCC patients treated with Toripalimab, Camrelizumab or Sintilimab in a retrospective cohort from Nov 2018 to Dec 2019. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP) and overall survival (OS). Results: Seventy eight patients were finally included in the analysis: 26 for Toripalimab, 36 for Camrelizumab, and 16 for Sintilimab. Mean duration of follow-up was 22.7 ± 12.6 weeks and the mean Cycles of PD-1 at cut-off were 4.8 ± 2.7 for all patients. The ORR and DCR for the whole cohort were 17.9% and 73.1%, respectively. Overall, 21 (26.9%) patients had radiological disease progression and 6 (7.7%) patients died during follow-up. Median PFS was 40.7 (95% CI, 34.7-46.7) weeks, median TTP was 45.7 (95% CI, 40.5-60.0) weeks, and median OS was 51.1 (95% CI, 46.4-55.9) weeks. Most frequent drug-related AEs were Rash (19.2%), Hypertension (15.4%), Fatigue (12.8%), Paraesthesia (12.8%), and Diarrhoea (10.3%). Conclusions: Our findings suggest that: 1. PD-1-targeted immunotherapy with Toripalimab, Camrelizumab or Sintilimab yielded a promising outcome in Chinese HBV patients with HCC; 2. Immunotherapy was well tolerated generally and had manageable side effects, which is worth of popularization and application in clinical practice.

Retropharyngeal emphysema is a rare condition with various causes including traumatic and iatrogenic injuries, or it could occur spontaneously. Symptoms of mediastinitis and/or airway obstruction should be evaluated as indicators for surgical incision. Complications of mediastinitis are associated with poor prognosis; therefore, worsening of symptoms should be carefully monitored.

Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63-year-old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.

A patient with mucopolysaccharidosis type VI, on enzyme replacement therapy (galsulfase) for more than 6-years with good adherence. Urine glycosaminoglycans became stable, cardiopulmonary progression is slow, motor skills have improved, pain is controlled and no adverse reactions were reported. These support the benefits of galsulfase, as it slows disease progression.

Previous research has identified a relationship between climate and occurrence of SARS-CoV and MERS-CoV cases, information that can be used to reduce the risk of infection. Using COVID-19 notification and postcode data from New South Wales, Australia during the exponential phase of the epidemic in 2020, we used time-series analysis to investigate the relationship between 749 cases of locally-acquired COVID-19 and daily rainfall, 9am and 3pm temperature, and 9am and 3pm relative humidity. Lower 9am relative humidity (but not rainfall or temperature) was associated with increased case occurrence; a reduction in relative humidity of 1% was predicted to be associated with an increase of COVID-19 cases by 6.11%. During periods of low relative humidity, the public health system should anticipate an increased number of COVID-19 cases.

Scientists are increasingly using volunteer efforts of citizen scientists to classify images captured by motion-activated trail-cameras. The rising popularity of citizen science reflects its potential to engage the public in conservation science and accelerate processing of the large volume of images generated by trail-cameras. While image classification accuracy by citizen scientists can vary across species, the influence of other factors on accuracy are poorly understood. Inaccuracy diminishes the value of citizen science derived data and prompts the need for specific best practice protocols to decrease error. We compare the accuracy between three programs that use crowdsourced citizen scientists to process images online: Snapshot Serengeti, Wildwatch Kenya, and AmazonCam Tambopata. We hypothesized that habitat type and camera settings would influence accuracy. To evaluate these factors, each photo was circulated to multiple volunteers. All volunteer classifications were aggregated to a single best answer for each photo using a plurality algorithm. Subsequently, a subset of these images underwent expert review and were compared to the citizen scientist results. Classification errors were categorized by the nature of the error (e.g. false species or false empty), and reason for the false classification (e.g. misidentification). Our results show that Snapshot Serengeti had the highest accuracy (97.9%), followed by AmazonCam Tambopata (93.5%), then Wildwatch Kenya (83.4%). Error type was influenced by habitat, with false empty images more prevalent in open-grassy habitat (27%) compared to woodlands (10%). For medium to large animal surveys across all habitat types, our results suggest that to significantly improve accuracy in crowdsourced projects, researchers should use a trail-camera set up protocol with a burst of three consecutive photos, a short field of view, and consider appropriate camera sensitivity. Accuracy level comparisons such as this study can improve reliability of future citizen science projects, and subsequently encourage the increased use of such data.

Introduction: Early recurrence (ER) of atrial fibrillation (AF) is defined as the recurrence of atrial tachyarrhythmias within 3 months after AF ablation, however, this definition is based on data from the era of radiofrequency catheter ablation (RFCA), without contact force (CF) technology. We investigated the significance of ER as a risk factor for late recurrence (LR) in paroxysmal AF (PAF) patients treated with CF and non-CF-guided ablation. Methods and Results: We studied 395 patients with PAF who underwent RFCA. Of these, 97 patients underwent RFCA without CF technology (Non-CF group) and 298 underwent with CF technology (CF group). Over a 2-year post-ablation follow-up period, LR occurred in 54 of 97 (55.7%) patients in the Non-CF group, and in 105 of 298 (35.2%) patients in the CF group. ER had a more significant relationship with LR in the CF than in the Non-CF group, and all patients in the CF group with ER in the 3rd month developed LR. Conclusion: ER in PAF patients who have undergone CF-guided ablation have a greater risk of LR than those who have undergone non-CF-guided ablation. ER in the 3rd month after CF-guided ablation may indicate an absolute risk of LR. Blanking period could be defined as 2 months in the CF era.

The interesting article published on this issue by Helen Perry et al (BJOG 2020 xxxx) is an important contribution to the idea demonstrated several years ago with echocardiographic evaluation of maternal central parameters, that the blood pressure value alone is not useful to understand the degree of compromise of the maternal condition in the evaluation of gestational hypertension and Preeclampsia (Valensise H et al. BJOG. 2006 Sep;113(9):1044-52. Epub 2006 Jul 7). The authors present an elegant study in which the evaluation of the maternal cardiovascular parameters obtained through non-invasive methods (Continuous Waveform Doppler USCOM) show major differences in cardiac output, systemic vascular resistances and heart rate in those patients with the diagnosis of Preeclampsia with a reduced fetal growth.These findings open two lines of research that needs to be implemented on the future: the first is linked to the possibility to identify ‘personal targeted therapy’ according to the parameters found to ameliorate the placental perfusion and fetal growth increasing the heart rate when below the normal values, reducing the systemic vascular resistances and increasing the plasma volume so as to try to bring back to normal the cardiocirculatory conditions (Valensise H et al. Ultrasound Obstet Gynecol. 2008 Jan;31(1):55-64).The second most important research line has to concentrate to the maternal circulatory condition before pregnancy (Vasapollo B et al. Am J Obstet Gynecol. 2020 Mar 3. pii: S0002-9378(20)30234-9. doi: 10.1016/j.ajog.2020.02.043) that in high risk pregnancies might induce not only an automatic passive calculation of the risk factors, but an active therapy based on the modifications of the maternal cardiac parameters to bring them back to normal as much as possible to PREVENT the appearance of the abnormal adaptation to pregnancy.In the future maternal health control in pregnancy will not be possible without the knowledge of maternal cardiac hemodynamics before pregnancy, in the first and second trimester, and at the appearance of hypertension or signs of fetal growth restriction. For this reason the implementation of clinical research with the use of non-invasive devices accessible to any doctor need to be recommended.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Graphene quantum dots (GQDs), the latest member of graphene family, have attracted outstanding interest in the last few years, due to their outstanding physical, chemical, electrical, optical and biological properties. Their strong size-dependent photoluminescence (PL) and the presence of many reactive groups on the graphene surface allow their multimodal conjugation with therapeutic agents, targeting ligands, polymers, light responsive agents, fluorescent dyes, and functional nanoparticles, making them valuable agents for cancer diagnosis and treatment. In this review, the very recent advances covering the last three years on the applications of GQDs as drug delivery systems (DDS) and theranostic tools for anticancer therapy are discussed, highlighting the relevant factors which regulate their biocompatibility. Among these factors, the size, kind and degree of surface functionalization have shown to greatly affect their use in biological systems. Toxicity issues, which still represent an open challenge for the clinical development of GQDs based therapeutic agents, are also discussed at cellular and animal levels.

Abstract Background: Cystic fibrosis may lead to left ventricular dysfunction. This dysfunction can be documented by methods such as tissue doppler echocardiographic imaging and two-dimensional speckle tracking echocardiography in early stage. Patients and Methods: A total of 34 patients diagnosed with cystic fibrosis (mean age and SD 9.9±4.9 years) and 37 healthy control subjects with a comparable gender and age distribution (mean age 9.8±4.3) were studied. The results for the two groups were compared along with the results of published reports. Result: Control group had higher diastolic and systolic dimentions compared to the patient group in M-mode measurements of left ventricle by conventional echocardiography (p <0.05). There was no significant relationship between the groups in terms of the dimensions of systolic and diastolic measurements of interventricular septum and posterior wall of left ventricle, and ejection fraction. Pulmonary artery systolic pressure was significantly higher in the patient group (p<0.001). Myocardial performance indices of left ventricle free wall and interventricular septum were increased in the patient group compared to the control group (p<0.05). ). As measured by speckle tracking echocardiography, 7 segments in left ventricular myocardial longitudinal strain and 3 segments in left ventricular myocardial circumferential strain showed significant reductions in patients with cystic fibrosis compared to controls (p <0.05). Conclusions: Tissue doppler echocardiographic imaging and speckle tracking echocardiography may help identifying subclinical left ventricular dysfunction in cystic fibrosis patients with unremarkable conventional echocardiography. Its may be considered for the routine follow-up of cystic fibrosis patients.