Survivorship care is a major area of focus in the holistic management of childhood cancer with current knowledge and information almost exclusively from high-income countries. In this review, we summarize the state of scientific knowledge, service delivery, advocacy initiatives and research efforts in this field in India. 21 single centre studies published till date (20 in the last decade) confirm some of the well-documented issues in childhood cancer survivors and also highlight the high prevalence of hepatitis B and hepatitis C infection in our survivors. Heterogeneity in methodology, outcome metrics and quality precludes drawing further conclusions and the ongoing multicenter Indian Pediatric Oncology Group study would address this. Besides the usual model of follow-up clinics in hospital settings, innovative models of service delivery led by not-for-profit organisations are being developed. Advocacy initiatives driven by survivors and support groups are also underway. All of these portend a promising future.

We suggest PLAID,APLAID and FCAS3 have to be considered as same diseases,because of our long-term clinical experiences and genetic results in six patients.Small proportion of CVID patients are also PLAID/APLAID/FCAS3 patients and all these have disease-causing-mutations in PLCG2-genes,so it may be better to define all of them as “PLCG2 deficiency”.

Introduction There is currently a lack of available data clearly addressing whether the proportion of young patients diagnosed with head and neck cancer (HNC) within the U.S. has increased over the last several decades in comparison to other age cohorts. This study attempts to elucidate any trends in oral cavity, oropharynx, larynx and hypopharynx cancer age distribution in the United States population from 1975-2016. Unlike previous studies, this paper does not track incidence, but rather reports proportional changes of prevalence within age cohorts over time. Methods This is a retrospective chart review centered on data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI). Each decade interval from 1975-2016 displays the proportion of HNC patients, classified by primary tumor subsite, within each age cohort. Results Mean age at diagnosis increased for three of the four HNC evaluated. Oropharyngeal cancer was the only subsite to demonstrate an overall proportional increase, mainly in middle age (40-59 years) patients. Cancers of the oral cavity were the only subset to show a true increase in the proportion of young (0-39 years) patients. When stratifying by gender, the proportion of young patients in female HNC cases is higher than the proportion of young male HNC cases. Conclusion Overall, this study demonstrates an increased proportion of older HNC patients that is consistent with the aging population. Oral cavity is the only cancer to demonstrate a true increase in the proportion of young patients, likely from the increased incidence of young women diagnosed with this cancer. Case reports citing more young patients becoming diagnosed with other types of HNC are not currently supported by the data. Lastly, the increased proportion of middle-age patients with oropharyngeal cancer likely reflects the increase in HPV-related cancers.

To the Editor:We enjoyed reading the case, authored by Janus and Hoit, of a 67-year-old woman with a subarachnoid hemorrhage (SAH) who presented with three different variants of takotsubo (TT).[i] We congratulate the authors on their interesting contribution to the literature. We would like to share some comments and questions on the chronology and management of the events between the first two episodes, which occurred a few days apart. Although fascinating, this is not the first case of TT with a rapidly evolving pattern. We previously described a case of mid-ventricular takotsubo which replaced apical ballooning in 6 hours.[ii] A recent meta-analysis showed that almost 80% of TT recurrences exhibit a ballooning pattern different from the first presentation.[iii] In this regard, regional cardiac sympathetic innervation remodeling or denervation could hypothetically justify why the same territory is usually spared from further relapses. Even though images were not provided, the authors stated that “echocardiographic wall motion abnormalities quickly resolved after each acute stressor”. One could therefore argue that this was not a case of multiple TT variants during the same episode, as noted by Madias,iii but rather an example of early recurrences. Additionally, if cardiac innervation remodeling were responsible for the different locations of the ballooning, we believe that the change in pattern would have taken longer to manifest. This would not support the observation of two distinct ballooning patterns emerging within days, let alone hours.i, ii In this case, a short-term change from the mid-ventricular to apical pattern could be reasonably explained by different β adrenergic-receptor (β-AR) subtype downregulation. We know that norepinephrine can downregulate β1-AR after a few hours. Beta1-ARs are markedly lower on biopsied patients with acute TT compared to healthy controls,[iv] whilst in the same study β2-ARs expression—which is predominant in the apical and mid-ventricular segments and thought to be involved in typical takotsubo pathogenesis[v]—was equivalent to normal. Thus, the sequence of events could be interpreted as a relative local β2 prevalence due to dynamic β1 downregulation (β1:β2 mismatch), following a base:mid-ventricle, and ultimately a mid-ventricle:apex progression. What do the authors think about this theory? Is it possible that multi-faceted presentations might simply be under-recognized? Should this be the case, how do they think we could better understand this phenomenon in a noninvasive fashion? Could dobutamine stress echocardiography have utility to identify areas of β-AR downregulation and sympathetic denervation? It would also be interesting to know more about the patient’s medical therapy. Did she receive nonselective β-blockers, such as labetalol or carvedilol, usually prescribed after SAH? If so, this might indicate that β-blockers do not prevent recurrences,[vi] but rather create a maladaptive imbalance in regional β1:β2 distribution favoring early relapse(s), as this case suggests.References[i] Janus SE, Hoit BD. The three faces of takotsubo cardiomyopathy in a single patient. Echocardiography. 2020 Jan;37(1):135-138. doi: 10.1111/echo.14560. Epub 2019 Dec 16.[ii] Casavecchia G, Zicchino S, Gravina M, et al. Fast 'wandering' Takotsubo syndrome: atypical mixed evolution from apical to mid-ventricular ballooning. Future Cardiol. 2017 Nov;13(6):529-532. doi: 10.2217/fca-2017-0018. Epub 2017 Oct 12.[iii] Madias JE. Comparison of the first episode with the first recurrent episode of takotsubo syndrome in 128 patients from the world literature: Pathophysiologic connotations. Int J Cardiol. 2020 Mar 3. pii: S0167-5273(20)30215-1. doi: 10.1016/j.ijcard.2020.03.003.[iv] Nakano T, Onoue K, Nakada Y, et al. Alteration of β-Adrenoceptor Signaling in Left Ventricle of Acute Phase Takotsubo Syndrome: a Human Study. Sci Rep 8, 12731 (2018). https://doi.org/10.1038/s41598-018-31034-z.[v] Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012 Aug 7;126(6):697-706. doi: 10.1161/CIRCULATIONAHA.112.111591. Epub 2012 Jun 25.[vi] Santoro F, Ieva R, Musaico F, et al. Lack of efficacy of drug therapy in preventing takotsubo cardiomyopathy recurrence: a meta-analysis. Clin Cardiol. 2014 Jul;37(7):434-9. doi: 10.1002/clc.22280. Epub 2014 Apr 3.

Aims The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the non-clinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by species-specificity. The elements of the non-clinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013-2018 to identify the approach followed for non-clinical development of these products. Methods The purpose of the in vivo studies was designated to be (a combination of) pharmacology/proof-of-concept, safety, biodistribution and/or tumourigenicity. For biodistribution and tumourigenicity also the need for, type and design of in vitro and in vivo studies were recorded. Results In vivo studies for cell-based therapies were primarily aimed at proof-of-concept (75/86), followed by addressing safety (64/86), biodistribution (49/86) or tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for six (out of 86) products, which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. In vivo tumourigenicity studies were regarded of limited value. Conclusions Compared to more conventional medicinal products, the non-clinical development program for cell-based products was more tailored and focussing on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience.

Despite their therapeutic potential, many protein drugs remain inaccessible to patients since they are difficult to secrete. Each recombinant protein has unique physicochemical properties and requires different machinery for proper folding, assembly, and post-translational modifications (PTMs). Here we aimed to identify the machinery supporting recombinant protein secretion by measuring the protein-protein interaction (PPI) networks of four different recombinant proteins (SERPINA1, SERPINC1, SERPING1 and SeAP) with various PTMs and structural motifs using the proximity-dependent biotin identification (BioID) method. We identified PPIs associated with specific features of the secreted proteins using a Bayesian statistical model, and found proteins involved in protein folding, disulfide bond formation and N-glycosylation were positively correlated with the corresponding features of the four model proteins. Among others, oxidative folding enzymes showed the strongest association with disulfide bond formation, supporting their critical roles in proper folding and maintaining the ER stability. Knock down of ERP44, a measured interactor with the highest fold change, led to the decreased secretion of SERPINC1, which relies on its extensive disulfide bonds. Proximity-dependent labeling successfully identified the transient interactions supporting synthesis of secreted recombinant proteins and refined our understanding of key molecular mechanisms of the secretory pathway during recombinant protein production.

The present investigation is concerned with high-cycle axial fatigue testing of a 2 mm AA6060-T6 HYB butt weld produced in the solid state using AA6082 filler metal addition. The results complement the three-point bend testing and the tensile testing done in two previous studies. In this study, optical microscope and scanning electron microscope examinations have been carried out to reveal the joint macro/microstructure and document possible surface and root defects deemed to affect fatigue life. In the as-welded condition, the HYB weld suffers from surface irregularities at the weld face and “kissing” bond formation in the root region. Despite of this, the subsequent testing shows that the fatigue properties exceed those reported for comparable AA6082-T6 gas metal arc butt welds and matching those reported for corresponding high-strength laser beam and friction stir weldments.

A document by Francesco Zanon. Click on the document to view its contents.

Cardiac pacing is the only effective therapy for patients with symptomatic brady-arrhythmia. Traditional right ventricular apical pacing causes electrical and mechanical dyssynchrony resulting in left ventricular dysfunction, recurrent heart failure and atrial arrhythmias. Physiological pacing activates the normal cardiac conduction thereby providing synchronized contraction of ventricles. Though His bundle pacing (HBP) acts as an ideal physiological pacing modality, it is technically challenging and associated with troubleshooting issues during follow up. Left bundle branch pacing (LBBP) has been suggested as an effective alternative to overcome the limitations of HBP as it provides low and stable pacing threshold, lead stability and correction of distal conduction system disease. This paper will focus on the implantation technique, troubleshooting, clinical implications and a review of published literature of LBBP

Multiple functional and hard-to-quantify sensorial product attributes that can be satisfied by a large number of cosmetic ingredients are required in the design of cosmetics. To overcome this challenge, a new optimization-based approach for expediting cosmetic formulation is presented. It exploits the use of a hierarchy of models in an iterative manner to refine the search for creating the highest-quality cosmetic product. First, a systematic procedure is proposed for optimization problem formulation, where the cosmetic formulation problem is defined, design variables are specified, and a set of models for sensorial perception and desired product properties are identified. Then, a solution strategy that involves iterative model adoption and two numerical techniques (i.e., generalized disjunctive programming reformulation and model substitution) is applied to improve the efficiency of solving the optimization problem and to find better solutions. The applicability of the proposed procedure and solution strategy is illustrated with a perfume formulation example.

“Atrial Fibrillation and Premature Ventricular Complexes” – is there a unifying diagnosis?

Low-field nuclear magnetic resonance (NMR) relaxometry is an attractive approach for point-of-care testing medical diagnosis, industrial food science, and in situ oil-gas exploration. However, one of the problems is the inherently long relaxation time of the (liquid) sample (and hence low signal-to-noise ratio) which causes unnecessarily long repetition time. In this work, a new methodology is presented for a rapid and accurate object classification using NMR relaxometry with the aid of machine learning techniques. It is demonstrated that the sensitivity and specificity of the classification are substantially improved with a higher order of (pseudo)-dimensionality (e.g., 2D or multidimensional). This new methodology (the so-called Clustering NMR) may be extremely useful for rapid and accurate object classification (in less than a minute) using the low-field NMR.

We present, by using previous results on extended Petri Nets, the relations of various hydrological dynamical systems ($\mathtt{HDSys}$) derived from the water budget ($\mathtt{DynWB}$). Once $\mathtt{DynWB}$ has been implemented, there exist a consistent way to get the equations for backward travel time distributions ($\mathtt{DynTT}$), for the forward response time distribution ($\mathtt{DynRTD}$) and for the concentration for a solute or a tracer ($\mathtt{DynC}$). We show that the $\mathtt{DynWB}$ has a correspondence one to many with the $\mathtt{DynTT}$. In fact to any one of the $\mathtt{DynWB}$ equation correspond as many equation as the input precipitation events times. The $\mathtt{DynTT}$ is related to $\mathtt{DynRTD}$ by the Niemi’s relationship and, in presence of multiple, $n$ outputs, by the specification of $n-1$ partition functions, which determine which fraction of water volume, injected in the control volume at a specific time $t_{in}$, goes asymptotically into a specific output. The $\mathtt{DynC}$, given $\mathtt{DynTT}$, depends further on the solute/tracer concentration in inputs. The paper clarifies the complicate set of relations above by using an example from literature. Upon the introduction of the appropriate information, it is also shown how these ($\mathtt{HDSys}$) can be solved simultaneously without duplicating calculations. It is also shown that these systems can be solved exactly, under the hypothesis of uniform mixing of water ages inside each reservoir within the system.

During the later stages of seed maturation, two key adaptive traits are acquired that contribute to seed lifespan and dispersal, longevity and dormancy. The seed-specific heat shock transcription factor A9 is an important hub gene in the transcriptional network of late seed maturation. Here we demonstrate that HSFA9 plays a role in thermotolerance rather than in ex situ seed conservation. Storage of hsfa9 seeds of Medicago truncatula and Arabidopsis had comparable lifespan at moderate storage relative humidity (RH), whereas at high RH, hsfa9 seeds lost their viability much faster than wild type seeds. Furthermore, we show that in M. truncatula, Mthsfa9 seeds acquired more dormancy during late maturation than wild type. Transient expression of MtHSFA9 in hairy roots and transcriptome analysis of Mthsfa9 Tnt1 insertion mutants identified a deregulation of genes involved in ABA biosynthesis, catabolism and signalling. Consistent with these results, Mthsfa9 seeds exhibited increased ABA levels and higher sensitivity to ABA. These data suggest that in legumes, HSFA9 acts as a negative regulator of the depth of seed dormancy during seed development via the modulation of hormonal balance.

Summary. Objectives: After corrective for scoliosis, postoperative pulmonary complications lead to increases in morbidity, length of hospital stay and mortality. This study aimed to identify associations with such respiratory complications. Methods: This retrospective cohort study included all children aged ≤17 years who underwent spinal surgery for scoliosis between January 2009 and January 2012 at a quaternary paediatric hospital. Factors associated with severely compromised pulmonary function (SCPF) were established and correlations with the occurrence of postoperative pulmonary complications and length of hospital stay (LOS) were identified. Rresults: Altogether, 133 children had corrective surgery for scoliosis, aged 12.7 (range 2-17) years at operation. Scoliosis causes were identified as: idiopathic (39.8%), neuromuscular disease (32.2%), syndrome (15.7%) and congenital (12%). Correlates with SCPF (FVC<40% predicted, n=10) included markers of sleep hypoventilation, including serum bicarbonate ≥29 mmol/L, morning pCO2 >50 mmHg (P=0.003), and overnight, episodic CO2 retention of >7 mmHg, thus an additional 8 children with SCPF were identified. Post-operative pulmonary complications were seen in 24 children (18%) and their occurrence correlated with higher Cobb angle (>90°), lower pulmonary function (FVC), higher serum bicarbonate and underlying neuromuscular disease. Amongst 18 children with SCPF, regular use of NIV pre-operatively was associated with reduced rate of post-operative pulmonary complications (P =0.02) and reduced LOS by 6.4 days (P =0.01). Conclusion: Nocturnal hypoventilation identifies children with SCPF. Use of NIV in children with SCPF was linked to fewer post-operative pulmonary complications and reduced duration of hospital stay. Keywords: Ventilation ; Pulmonary complications ; Scoliosis ; Polysomnography.

Internal mammary harvesting: the long-lasting history and harvesting techniquesRunning Head: Internal mammary artery

Abstract Objective: Total laryngectomy (TL) is a life-saving procedure for individuals with advanced laryngeal cancer or those suffering from recurrence after initial treatment. The present study aims to evaluate the differences between stapler closure (SC) and manual closure (MC) of the pharynx during TL for patients with laryngeal cancer. Design/Setting: A systematic literature search was performed using the PubMed, Embase and Cochrane Library. The data were analyzed using Comprehensive Meta-Analysis software (Version 3; Biostat, Englewood, NJ). Dichotomous data were calculated by odds ratio (OR) and continuous data were calculated by mean difference (MD) with 95% confidence intervals (CI). Main outcome/Results: A total of 7 studies (535 patients) were included in this meta‐analysis. Pooled analysis showed that the operative time of TL was significantly reduced in the SC group (MD, -63.2; 95% CI, -106.0 to -20.4). Moreover, the SC group had a lower incidence of pharyngocutaneous fistula (OR = 0.38; 95% CI, 0.18-0.83; P = 0.016) and hospital stay (MD, -2.9; 95% CI, -5.6 to -0.1). The incidence of postoperative surgical site infection (OR = 0.41; 95% CI, 0.02-8.73; P = 0.565) was comparable between the two groups. Conclusion: Based on these results, SC may be a useful option for patients who need TL.

COVID-19 causes significant hypoxia along with an inflammatory milieu, which may lead to secondary myocardial infarction and also atherosclerotic plaque rupture. Here we present a case of COVID-19 presented with ACS followed by PTE and CVA.