Having children is a major life course event yet some disabilities could make it biologically challenging and some others could limit access to necessary socioeconomic resources. To date, there is relatively little data on disability and parental status and our study aimed to investigate this relationship.n = 440220). We performed descriptive analyses, graphical plots, logistic regression, and Cox regression analyses.This longitudinal cohort study was based on register data obtained from all people born in Sweden from 1968 to 1970 (Our findings from both logistic regression and Cox regression indicated that individuals that started to receive disability benefits at an early age had reduced chances of having children during the follow-up duration. Men with disabilities were less likely to have children when compared to women with disabilities and to men and women without disabilities.We found evidence that disability during early adulthood was associated with reduced chances of having children. Findings support policies and programmes aimed at promoting optimal health during early adulthood, as this would promote continued labour force participation, reduce early use of disability benefits, and possibly improve chances of becoming a parent.The online version contains supplementary material available at 10.1186/s12889-021-10371-1. Many societies consider having children a major life course event . In modeHaving a disability can profoundly affect one’s ability to fulfil the pivotal determinants for having a first child and might lead to postponement or in some cases to childlessness. Some disabilities make it biologically impossible to have children , while oFrom a theoretical point of view, the link between disability and parental status can be understood using Oppenheimer’s uncertainty hypothesis , 14 and Current literature suggests that people with disabilities report limited economic opportunities and high poverty rates , 19. SevCompared to the extensive body of research on parenthood in the general population, there is relatively little data on the parental status of people with disabilities. Available research can be divided into two subsets. One body of research examines the experiences of parenting with a disability and being a parent to a child with a disability –28. AnotThe aim of this study was to examine the relationship between having a disability in early adulthood and reduced chances of having children.n = 440220) from 1968 to 1970. Individuals were followed from birth until 2010 when the youngest were 39 years old and the oldest were 42 years old. The selection of this study duration was based on data availability. All data was obtained from the Longitudinal Integration Database for Health Insurance and Labour Market Studies (LISA database). Our data consisted of information on total population, disability benefits status, number of children, sex, and year of birth. All data was anonymised by Statistics Sweden and was made available for analysis through the Swedish Initiative for Research on Microdata in Social and Medical Sciences (Umeå SIMSAM Lab) [In this longitudinal cohort study, we used national register data that consisted of all people that were born in Sweden (SAM Lab) .n = 51092) were excluded from the from the regression analyses.The outcome variable was whether an individual became a parent or not from age 23 up to the end of the study duration. The variable “becoming a parent” was considered binary, which indicated whether an individual had a biological child or not during the observation time. Individuals who became parents at age 13–22 years, 12% . The 1968 birth cohort had the highest proportion with disabilities (Table Figure The bivariate and multivariable logistic regression results presented in Table The hazard ratio from the Cox regression presented in Table The results presented in the Appendix, also confirmed that disability was significantly associated with reduced chances of having children even after adjusting for marital status and assessing the interaction between disability and marriage. This association was confirmed in both the logistic regression and Cox regression models, Tables SOur register data for the birth cohorts of 1968 to 1970 showed that having a disability during early adulthood was associated with extremely low chances of having children during the observed duration. Men with disabilities were less likely to have children compared to women with disabilities and to men and women without disabilities. This study also noted that the chances of having children were reduced for younger birth cohorts compared to the birth cohort of 1968.Our finding that receiving disability benefits was associated with significant reduction in chances of having children support findings from previous studies that reported similar observations , 21. TheHaving a disability in early adulthood was associated with a significant reduction in the chances of becoming a parent later in life. Starting to receive disability benefits during the early twenties might imply prolonged ill health and socio-economic constraints, factors that might constrain the decision to become a parent. Moreover, previous data has shown that the majority of individuals who start to receive disability benefits continue to do so on a long-term basis, with an outflow rate at just about 3 % .This study also identified major sex differences in the chances of having children. The chances were much lower for men with disabilities compared to women with disabilities or to men and women without disabilities. Literature suggests that entry into a stable partnership requires a strong financial underpinning and more occupational stability for men compared to women , 14. LimWe noted that the odds of having children were reduced in the younger birth cohorts of 1969 and 1970 compared to people born in 1968. There are no known social economic changes during this time to explain these parental status differences by birth cohort. It is therefore possible that this association is due to random variation.The main strength of this study is the access to a large longitudinal dataset that gave us an opportunity to observe a total population for a long duration. Moreover, using register data ensured minimal loss to follow-up, data on the use of disability benefits and having children was available for all cohorts. In this study, we define disability status based on use of disability benefits, we consider this a reliable measure for disability status and the severity of the disability given that eligibility was based on medical evidence suggesting long-term health limitations in working capacity. Even though this study found a strong association between disability and reduced chances of having children, this should be strictly interpreted as an association and should not be used to draw causal conclusions. In addition, our findings should be interpreted within the frames of the studied type of disability. Further research using other definitions of disabilities and study designs could help clarify the observed association between disability and chances of having children. Even though our models excluded some people due to missing data, there is no reason to suspect that missing data differed by disability status.This study shows a strong association between receiving disability benefits and reduced chances of having children. Moreover, men with disabilities were at reduced chances of having children compared to women with disabilities and to men and women without disabilities. Our findings support policies and programmes aimed at promoting good health during reproductive age as this could reduce early exit from work and early use of disability benefits. Further research is needed to clarify the association between use of disability benefits and all factors related to reproductive health, marriage, and parenthood and family relationships among people with disabilities. Such evidence will help inform both public health and family policies.Additional file 1: Table S1. Odds of later having a first child for men that receive a disability benefit at 20–22 years of age in Sweden. Interaction between disability benefit and marriage. COR = Crude Odds Ratio; AOR = Adjusted Odds Ratio; CI=Confidence Interval.Additional file 2: Table S2. Odds of later having a first child for women that receive a disability benefit at 20–22 years of age in Sweden. Interaction between disability benefit and marriage. COR = Crude Odds Ratio; AOR = Adjusted Odds Ratio; CI=Confidence Interval.Additional file 3: Table S3. Hazard results of later having a first child for men that receive a disability benefit at 20–22 years of age in Sweden. Interaction between disability benefit and marriage. CHR = Crude Hazard Ratio; AOR = Adjusted Hazard Ratio; CI=Confidence Interval.Additional file 4: Table S4. Hazard results of later having a first child for women that receive a disability benefit at 20–22 years of age in Sweden. Interaction between disability benefit and marriage. CHR = Crude Hazard Ratio; AOR = Adjusted Hazard Ratio; CI=Confidence Interval.


Protein design is limited by the diversity of functional groups provided by the canonical protein „building blocks“. Incorporating noncanonical amino acids (ncAAs) into enzymes enables a dramatic expansion of their catalytic features. For this, quick identification of fully translated and correctly folded variants is decisive. Herein, we report the engineering of the enantioselectivity of an esterase utilizing several ncAAs. Key for the identification of active and soluble protein variants was the use of the split‐GFP method, which is crucial as it allows simple determination of the expression levels of enzyme variants with ncAA incorporations by fluorescence. Several identified variants led to improved enantioselectivity or even inverted enantiopreference in the kinetic resolution of ethyl 3‐phenylbutyrate. In enzyme engineering using an expanded genetical code, quick identification of fully translated and correctly folded variants is crucial. Herein, we report the engineering of the aryl esterase from Pseudomonas fluorescens utilizing a pool of ncAAs. Key for the identification of active and soluble protein variants was the use of the split‐GFP method, allowing for quick identification of interesting variants. While a diversification of the limited set of functional groups in enzymes would greatly expand the possibilities of enzyme engineering, available methods for the incorporation of chemical entities to proteins are very limited.The reason lies in the insufficient efficiency of the incorporation on the one hand (resulting in protein yields that are too low for application), and the limited flexibility on the other hand. Incorporation via SCS bears the risk of an abortion of the translation, leading to a high concentration of inactive enzyme fragments. The incomplete translation is controlled by active processes such as the recruitment of the release factor by the amber codonProtein purification using a C‐terminal affinity tag is often used to remove fragmented proteins and to detect incorporation problems. Yet, affinity purification is rather unpractical for high‐throughput screens and severely reduces the throughput of the assay. The split‐GFP technique was developed by Waldo et al.Pseudomonas fluorescence esterase (PFE)rac‐ethyl 3‐phenylbutyrate by incorporation of a set of five different ncAAs. Using the split‐GFP assay in combination with an activity test allows the quick identification of folded and active variants with interesting properties and decreases the need for time‐consuming screenings of all prepared variants . Typical purification yields were in the range of 28–72 mg L−1, generally lower than the expression yield of wild‐type PFE (105–120 mg L−1). The expression levels of purified proteins were consistent with the results from the small‐scale experiments using the split‐GFP methodology, in‐between 25–64 % in comparison to the wild type (100 %). The level of expression was strongly dependent on the ncAA itself, as well as on the position in the sequence. The incorporation of ncAAs in the proteins were confirmed with electrospray ionization mass spectrometry (ESI‐MS), at different studied positions in at least one variant per unnatural amino acid. No peaks corresponding to alternative amino acid incorporation were observed . The split‐GFP method is therefore straightforward in identifying any variants where promiscuous incorporation is a potential problem. These results, together with our negative controls for small‐scale screening suggests no  background incorporation of natural amino acids.All variants selected for further studies were produced in 3, Scheme ee) was achieved by substituting F198 by pAzF and F162 by NapA. The substitution of F198 with pAzF nearly doubled the enantiomeric ratio in the kinetic resolution of 3 showing preference for the (R)‐enantiomer. The enantioselectivity increase was even stronger when F162 was substituted by NapA. Residue F198 had already been reported in literature to be a hot‐spot for enantioselectivity of PFE.3. On the other hand, a mutation of the F162 residue, based on our knowledge, has not been reported yet. This residue is part of the alcohol‐binding pocket. The mechanism, whose consequence is improvement of enantioselectivity, is probably indirect through a rearrangement of neighboring amino acid side chains. A substitution at position I224 has already yielded a switch in enantioselectivity in a previous report.S)‐4 in the kinetic resolution of 3. In our study, the variant I224pAzF_PFE enabled almost a doubling in the enantiomeric ratio. A direct influence of I224 on the enantioselectivity was also strongly expected since its side chain is in direct contact with the acyl moiety of the substrate on the opposite side to F198. Substitution for aromatic side chains possibly enables π interaction that leads to the different binding mode and subsequent preference of the (S)‐enantiomer. This supports the previous claims that bulky and hydrophobic amino acids, which block the entrance to the active site of the PFE have effect on selectivity. Overall, our data showcases that utilizing ncAAs provides another means to redesign the active site next to standard directed evolution techniques, where a switch of enantioselectivity can also be achieved.The effect of the ncAAs on the activity and enantioselectivity were further studied using the kinetic resolution of ethyl 3‐phenylbutyrate ‐3. Substitution of I224 for pAzF swapped the enantiopreference of the enzyme for (S)‐3 and outperformed the canonical amino acid substitution of I224Y, in enantiomeric ratio by a factor of two. Our data demonstrate that the split‐GFP self‐assembly method facilitates high‐throughput screening of production levels of an ncAA‐incorporated enzyme. The speed and simplicity of the method allow for easy screening of expression levels, reliable elimination of misfolded variants and those with incomplete translation, as well as estimation of ncAA‐carrying enzyme concentration in cell‐free extracts. We expect that this method will widely extend the capacity to test ncAA‐carrying enzyme variants in a short time and thus to overcome obstacles for wide application of ncAA for enzyme engineering. Ultimately, we showcase that the power of the method expands beyond traditional directed evolution screenings to libraries of ncAA‐carrying enzymes.In summary, we report the engineering of the aryl esterase from The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


P < 0.001). The five‐microRNA signature was proved to be superior to IDH mutation in survival prediction (AUCtraining = 0.688 vs 0.607). Stratification analysis found the signature could further divide patients after radiotherapy into two risk groups. GO and KEGG analyses revealed that microRNAs from the prognostic signature were mainly enriched in cancer‐associated pathways. The newly discovered five‐microRNA signature could predict survival and radiotherapeutic response of LGG patients based on individual microRNA expression.Despite the prognostic value of IDH and other gene mutations found in diffuse glioma, markers that judge individual prognosis of patients with diffuse lower‐grade glioma (LGG) are still lacking. This study aims to develop an expression‐based microRNA signature to provide survival and radiotherapeutic response prediction for LGG patients. MicroRNA expression profiles and relevant clinical information of LGG patients were downloaded from The Cancer Genome Atlas  and the Chinese Glioma Genome Atlas . Cox regression analysis, random survival forests‐variable hunting (RSFVH) screening and receiver operating characteristic (ROC) were used to identify the prognostic microRNA signature. ROC and TimeROC curves were plotted to compare the predictive ability of IDH mutation and the signature. Stratification analysis was conducted in patients with radiotherapy information. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to explore the biological function of the signature. We identified a five‐microRNA signature that can classify patients into low‐risk or high‐risk group with significantly different survival in the training and test datasets ( According to histomorphological classification, World Health Organization (WHO) classifies gliomas into grades I to IV for diagnosis, guidance treatment and prognosis. Grade I gliomas have the lowest invasiveness and the best prognosis. Generally, patients can be cured by surgical removal of tumour tissue, and the 5‐year survival rate reaches 94%.With the introduction of IDH mutation and 1p/19g codeletion into the classification of diffuse gliomas, it is increasingly recognized that molecular features play a significant role in the evaluation of prognosis and treatment response. MicroRNAs are a group of short‐chain non‐coding RNA molecules that are involved in the regulation multiple genes expression and activation of signalling pathways. Abnormal microRNA expression occurs in a variety of tumours and is closely related to tumour invasion, metastasis and more malignant lesions. Thus, microRNA could be used to predict treatment response and prognosis of many types of cancer and become a molecular marker. In addition, the stability and detectability of microRNAs in a variety of body fluids  are more favourable for their use as prognostic markers. Therefore, microRNA signature containing multiple microRNAs has been demonstrated its promising prognostic role in various tumours including breast cancer,In the present study, LGG patients with microRNA expression data were collected from the Cancer Genome Atlas (TCGA) database and the Chinese Glioma Genome Atlas (CGGA). We aim to use these expression data and clinical data to identify a prognostic microRNA signature and validate its predictive ability for survival and treatment response.22.1http://cancergenome.nih.gov/, https://xenabrowser.net/datapages/), of which 525 LGG patients had survival time and survival status. Another dataset with 107 LGG cases was downloaded from CGGA database (http://www.cgga.org.cn/), and we found 99 cases with survival information. Then, the 525 LGG cases from TCGA and 99 LGG cases from CGGA were treated as the training and test datasets, respectively. The clinical information of all 624 patients was shown in Table One dataset with 530 LGG cases and microRNA expression data were collected from the TCGA  algorithm. In RSFVH, an iteration procedure was performed to narrow down the microRNAs set in which the 1/4 least important microRNAs were discarded at each iteration step and five hundred trees were grown at each step until without changing the error rate too much and then 9 microRNAs were selected.2.3www.r‐project.org), including packages named pROC, TimeROC, randomForestSRC and survival downloaded from Bioconductor (http://www.bioconductor.org/). MicroRNA function was analysed by DIANA‐mirPath, which is a web‐based computational tool developed to identify molecular pathways potentially for single or multiple microRNAs by performing an enrichment analysis of multiple microRNA target genes.The median risk score was used as the cut‐off value to subdivide patients with LGG into two risk groups. Kaplan‐Meier analysis was performed to assess the survival difference of two risk groups, and statistical significance was assessed using the two‐sided log‐rank test. Multivariate Cox regression analysis was performed to explore the independence of the screened signature. ROC and TimeROC were used to compare predictive performance. All analyses were performed with R program  and male patients were more than female ones. The number of grade II cases was basically the same as that of grade III, accounting for roughly half. Every patient had survival information, all but 186 of whom died. In addition, we listed the histological type, IDH mutation and radiotherapy and chemotherapy information  with microRNA expression. A total of 400 microRNAs significantly associated with OS  or low‐risk group (n = 263). Kaplan‐Meier analysis identified the low‐risk group had significantly longer survival time than those in the high‐risk group  of IDH mutation and the five‐microRNA signature to analyse their predictive power.3.5P < 0.001, Figure P < 0.001, Figure From the clinical information in Table3.6To explore the role and function of microRNAs screened in this study, we first detected the target genes of the five microRNAs and then performed functional analysis of the target genes by mirPath (see method). Figure 4Since molecular features have integrated into glioma classification, the importance of molecular features in the prognosis of glioma is self‐evident. At present, IDH mutation and 1p/19g codeletion still have some defects in the prognosis evaluation and treatment guidance of patients with LGG. This study analysed 624 LGG patients and found a good indicator for prognosis prediction and radiotherapy guidance, which is named as a five‐microRNA signature. The signature could predict the survival of patients with LGG and determine whether patients can benefit from radiation therapy.Compared with GBM patients with a median overall survival of 14‐17 months,Isocitrate dehydrogenase (IDH)1 and IDH2 are key enzymes that catalyse the conversion of isocitrate to α‐ketoglutarate. IDH mutations cause a change in enzyme activity, resulting in a large amount of 2‐hydroxyglutarate (D2HG) being synthesized and accumulated. Since the discovery of IDH mutations in diffuse lower‐grade glioma,According to the European Association for Neuro‐Oncology (EANO) guideline, the treatment of patients with LGG is mainly conservative management and radiotherapy, and a few patients with high malignancy require combination chemotherapy. However, there is no consistent conclusion as to which patient can no longer continue to ‘watch and wait' but need radiotherapy or which patient have good radiotherapeutic response and can benefit from radiation therapy. Whether patients currently receive radiotherapy depends mainly on some prognostic indicators, such as age, Karnofsky performance score.Notably, the five microRNAs in the signature are all risk factors. As for the functions of microRNAs in LGG, our GO and KEGG analysis found that the five risky microRNAs enriched in glioma related pathways. In the Pubmed database, we searched related studies to explore the role of the five microRNAs in glioma. Since the expression of miR‐10b was found to be up‐regulated and be closely related to the poor prognosis of glioma,In summary, our study findings revealed an expression‐based five‐microRNA signature can predict individual survival and radiotherapeutic response of patients with LGG. This paper highlights the promising potential of the novel five‐microRNA signature as a good prognostic biomarker for individual survival prediction and therapeutic decision making.The authors confirm that there are no conflicts of interest.Zhang JH, Hou RQ, Pan YHL, Gao YH and Yang Y involved in data collection, data analysis, interpretation and drafting; Tian WQ and Zhu YB involved in study design, study supervision and final approval of the manuscript.This article does not contain any studies with human participants or animals performed by any of the authors.Informed consent: Informed consent was obtained from all individual participants included in the study. For specific informed consent, please refer to the source of public data.Table S1Click here for additional data file.Table S2Click here for additional data file.


The twin‐arginine protein transport (Tat pathway) is found in prokaryotes and plant organelles and transports folded proteins across membranes. Targeting of substrates to the Tat system is mediated by the presence of an N‐terminal signal sequence containing a highly conserved twin‐arginine motif. The Tat machinery comprises membrane proteins from the TatA and TatC families. Assembly of the Tat translocon is dynamic and is triggered by the interaction of a Tat substrate with the Tat receptor complex. This review will summarise recent advances in our understanding of Tat transport, focusing in particular on the roles played by Tat signal peptides in protein targeting and translocation. The twin‐arginine protein transport (Tat) pathway transports folded proteins across membranes. Targeting of substrates to the Tat system is mediated by the presence of an N‐terminal signal sequence containing a highly conserved twin‐arginine motif. The Tat machinery comprises membrane proteins from the TatA and TatC families. This review will summarise recent advances in our understanding of Tat transport. In prokaryotes, the general secretory (Sec) and twin‐arginine translocation (Tat) pathways operate in parallel to transport proteins across the cytoplasmic membrane. The Sec system transports unfolded proteins through a narrow channel, in a process that can either be co‐translational or post‐translational Figure . Followibc1 and b6f respiratory complexes which is essential for bacterial photosynthesis and for many types of respiratory metabolism  when they emerge from the ribosome exit tunnel to engage in co‐translational translocation. By contrast, moderately hydrophobic Sec signals escape SRP and mediate post‐translational translocation through interaction with SecA and other chaperones  located between 12 and 17 residues distal to the twin‐arginine motif , is a Sec substrate , two functionally distinct TatA family proteins, TatA and TatB, are present  copies of TatA, TatB and TatC in a 1:1:1 ratio (Alcock et al., Tat transport is initiated by the interaction of a Tat signal peptide with the receptor, with the twin‐arginine motif recognised by a conserved surface patch on the cytoplasmic face of TatC (Alami et al., The structure of the signal peptide‐activated form of the receptor complex is not known. However, it has been shown that covalently attaching the twin‐arginine motif to its binding site on TatC does not inhibit translocation of a substrate across the membrane, indicating that the twin‐arginine residues remain at the cytoplasmic face of the membrane (Gérard & Cline, A recent study has confirmed that Tat signal peptides bind to the receptor complex in a hairpin conformation. Fluorescence quenching experiments place the C‐terminal end of the signal peptide h‐region at the tip of the hairpin, directly preceding the helix‐destabilising residue Figure . The secThis signal peptide‐induced structural rearrangement primes the receptor for the recruitment of further TatA molecules, in a process that is dependent on the protonmotive force (Alami et al., Evidence suggests that unhinging of the signal peptide hairpin may be a critical step in substrate translocation and deliberate locking of the hairpin by internal crosslinking inhibits transport (Hamsanathan et al., 5E. coli TatBF13Y; Huang et al., Significant progress towards understanding the mechanism of protein transport by the Tat pathway has been catalysed by the determination of high‐resolution structures for TatC and the helical regions of TatA and TatB (Ramasamy et al.,


Malignant pleural effusions usually manifest in the course of metastatic cancer disease. Primary pleural tumours are rare with mesothelioma being by far the most common. Primary squamous cell carcinoma of the pleura (PSCCP) is extremely rare. It is usually asymptomatic, until it invades the pleura presenting pain as the first symptom. Our knowledge about its treatment or prognosis is limited due to its rarity. We present the case of a 48‐year‐old man who presented with persistent right‐sided thoracic pain with chest computed tomography (CT) scan demonstrating a right‐sided pleural effusion and pleural mass invading the ribs. Ultrasound‐guided biopsy revealed a PSCCP. Positron emission tomography staging demonstrated metastatic lung and lymph node involvement precluding surgical therapy. We provide information about treatment, including immunotherapy as well as extended follow‐up course. Immunotherapy with nivolumab resulted in prolongation of survival with good quality of life. We report the case of a 48‐year‐old man who presented with persistent right‐sided thoracic pain with chest computed tomography scan demonstrating a right‐sided pleural effusion and pleural mass invading the ribs. Ultrasound‐guided biopsy revealed a primary squamous cell carcinoma of the pleura. Positron emission tomography staging demonstrated metastatic lung and lymph node involvement precluding surgical therapy. Immunotherapy with nivolumab resulted in prolongation of survival with good quality of life. Malignant pleural effusions are common and usually present metastatic involvement of the pleura during the course of neoplasms such as lung or breast cancer. On the contrary, primary pleural tumours are rare with mesothelioma either diffuse or localized being by far the most common. Primary squamous cell carcinoma of the pleura (PSCCP) is extremely rare with only case reports published in the literature. It is usually asymptomatic at the beginning until it invades the surrounding structures presenting pain as a symptom. Its course is to progress locally and metastasize. Our knowledge is limited regarding the treatment and long‐term prognosis of PSCCP.A 48‐year‐old man, active smoker, presented with persistent right‐sided thoracic pain lasting more than a month. Chest computed tomography (CT) demonstrated a right‐sided pleural effusion and a 6.4‐cm pleural mass at the level of the right lower lobe invading the eighth and ninth ribs Fig. A. SmalleThe patient received six cycles of platinum‐based combination with taxane (classic cis‐platinol and docetaxel), with good initial response . No side effects associated with chemotherapy were documented. However, repeat chest CT scan at the completion of treatment (six months from diagnosis) demonstrated disease progression Fig. C. The paOur patient's clinical course was complicated with pneumonitis due to nivolumab toxicity Fig. C, D resuPSCCP is an extremely rare tumour. Its cause is not known although earlier reports connected it with chronic inflammation or surgery Anti‐tumour immunotherapy with immune check point inhibitors especially targeting PD‐1 receptor or its PD‐L1 has changed the landscape in the treatment of advanced non‐small cell lung cancer (NSCLC) exhibiting improved survival and response rates combined with a less toxic profile We present here the case of a patient with metastatic PSCCP, with no history of pleural inflammation or operation. The immunohistochemistry profile of the patient was suggestive for PSCC . The combination of p40+ and TTF‐1− was highly indicative of the de novo genesis of SCCP as lung parenchyma was free of disease and no special immunochemistry markers could stain the cancer arising from lung. Moreover, positivity for both p63 and p40 differentiated it from mesothelioma as mentioned above. Apart from surgical removal, evidence on the role of systemic treatment in PSCCP is limited. To our knowledge, immunotherapy has not been previously administered in patients with PSCCP. The decision to use nivolumab was based on the established algorithm that, nowadays, squamous‐cell lung cancers responded excellently to second‐line therapy with immunotherapies molecules. The patient was informed and consented to the use of this treatment as first‐line platinum‐based therapy has failed. Immunotherapy resulted in extremely prolonged disease control.We thank National and Kapodistrian University of Athens for funding the publication of the paper.Appropriate written informed consent was obtained for publication of this case report and accompanying images.


This paper demonstrates that localized and chronic stop‐question‐and‐frisk (SQF) practices are associated with community members’ utilization of emergency department (ED) resources. To explain this relationship, we explore the empirical applicability of a legal epidemiological framework, or the study of legal institutional influences on the distribution of disease and injury.Analyses are derived from merging data from the Philadelphia Vehicle and Pedestrians Investigation, the National Historical Geographic Information System, and the Southeastern Philadelphia Community Health database to zip code identifiers common to all datasets. Weighted multilevel negative binomial regressions measure the influence that local SQF practices have on ED use for this population. Analytic methods incorporate patient demographic covariates including household size, health insurance status, and having a doctor as a usual source of care.Findings reveal that both tract‐level frisking and poor health are linked to more frequent use of hospital EDs, per respondent report. Despite their health care needs, however, reporting poor/fair health status is associated with a substantial decrease in the rate of emergency department visits as neighborhood frisk concentration increases . Moreover, more sickly people in high‐frisk neighborhoods live in tracts that have greater racial disparities in frisking—a pattern that accounts for the moderating role of neighborhood frisking in sick people's usage of the emergency room.Findings indicating the robust association reported above interrogate the chronic incompatibility of local health and human service system aims. The study also provides an interdisciplinary theoretical lens through which stakeholders can make sense of these challenges and their implications. Police violence is an unyielding public health crisis in ethnoracially marginalized and economically vulnerable American communities.Direct contact with police officers is associated with a number of poor health outcomes, including psychological distress, substance misuse and co‐morbidity, infectious disease transmission, and death.Indirect contact with police officers, via residence in a neighborhood with higher concentrations of proactive and lethal policing, is associated with poor health outcomes as well —especially, among men living in aggressively surveilled areas and women living in lethally surveilled areas.An empirical application of legal epidemiology, which examines the chronic incompatibility of local health, safety, and human service system aims.Evidence that sicker people who live in neighborhoods with high stop‐and‐frisk rates report less frequent use of the hospital ED, while ED utilization among healthier people is unrelated to their residential exposure to frisking. Agencies tasked with fostering a safe environment appear to engage practices that curtail the use of services by those facing serious health challenges.1Police violence is an unyielding public health crisis in a number of marginalized and vulnerable American communities.Emergency room admission protocols open opportunities for legal surveillance.Legal epidemiology is a framework that could enhance our theoretical understanding of how collusion between law enforcement and health services influences patients’ decisions to rely on ED care. Legal epidemiology posits that law and legal practices shape health outcomes.negative illness feedbacks where police tasked with fostering a safe environment engage practices that curtail the procurement of services for those facing health challenges. Such countervailing relationships produce new forms of systemic violence that reveal the systematic marginalization that governs the lives of the inequitably surveilled. In such communities, police behaviors weaken, and even disentangle, the relationship between self‐rated health and hospitalization. We account for within and between neighborhood variation in known sociodemographic factors associated with our measures of interest.The current study will test whether police officers’ stop‐question‐and‐frisk (SQF) practices dampen ED visitation. This association is an indicator of 22.1This study is a cross‐sectional observational study, describing the rate of ED visits due to residential exposure to frisk . The study focuses on the 18‐65 population of the Philadelphia metropolitan division  in the years surrounding 2015. Data on individual reports of health collected in 2014‐2015, police stop characteristics in 2015 and 2016, and neighborhood demographic characteristics in 2011‐2015 are linked by geographical identifiers for zip code provided in all three datasets.2.2The individual data source for this study comes from the Southeastern Pennsylvania Household Health Survey (SEPA HHS), a repeated cross‐sectional telephone survey of more than 10 000 households. SEPA HHS is one of the longest‐running household health surveys in the United States and is collected regularly at approximately biennial intervals. This study uses data from 2014 to 2015, the most recent period of data collection that has been publicly released. The data are proprietary to the Public Health Management Corporation (PHMC)’s Community Health Data Base (CHDB), which serves the information needs of health and human service agencies in the Southeastern Pennsylvania region. Information is collected about residents’ health status, use of health services, and access to care. Individual respondents lived in 44 zip codes.www.opendataphilly.org) on April 4, 2017. This data source provides x/y coordinates for all investigations pursued by the Philadelphia Police Department (PPD). Since the first day of 2014, data on police investigations of pedestrians and vehicles have been uploaded daily made available to the public through OpenDataPhilly by the PPD with a 14‐day lag for operational approval processes. The information compiled by the PPD includes details related to the location of the investigation, type of investigation, the race, gender, and age of the person stopped, the behaviors of the police officer during the investigation , and the discovery of any contraband due to the investigation. We focus on 830 077 investigations recorded by officers that occurred in either 2014 or 2015. All investigations were successfully geocoded to zip codes. From poststop information recorded after the stop was completed, we created a contextual dataset where data were aggregated to one of 52 zip codes where the PPD conducted investigations.The contextual data for this study come from two sources. First, the City of Philadelphia's Vehicle and Pedestrian Investigation dataset (PVPI) dataset was downloaded from OpenDataPhilly : 5‐Year Data [2011‐2015] through the National Health Geographic Information Survey.2.3The outcome of interest is the number of ED visits in the past year. Respondents were asked: “How many visits, if any, did you have to an emergency room during the past twelve months, that is, since (date one year ago) 2013/2014?” This is reported to SEPA HHS by the respondent as a count variable characterizing the number of times in the past year that the respondent has visited the emergency room (ED) for any reason. Higher values indicate more ED utilization.The individual‐level independent variable is a five‐category self‐rated health, an ordinal variable with Likert response options . Self‐rated health is also measured as a dichotomous indicator, where 1 = Poor/Fair and 0 = Excellent/Very Good/Good. Higher values of both outcomes indicate worse health. Self‐rated health captures lay constructions of illness and is a well‐known strong predictor of mortality.The contextual independent variable is neighborhood frisk concentration and is measured at the zip code‐level. This continuous indicator characterizes the percentage of stops in a neighborhood where police officers engage in frisking—that is, patting down a pedestrian or a driver. Unlike prior research on the illness risks of policing pedestrians,The analysis adjusts for several individual‐level confounders of the estimated relationships among poor self‐rated health, zip code frisk concentration, and past‐year ED utilization behavior, including ethnoracial status, gender, age, household income, family poverty, total number of kids in the household, respondent work status, respondent education, marital status, health insurance status, and regular source of medical care. Age and household income are continuous variables. Age is centered at 18. Total number of kids in the household is a count variable characterizing the number of children under the age of 18 are related to the respondent by blood, marriage, or adoption, including students under the age of 18 who are living away from home and related to the respondent.in = 654. 21.3 percent; Table Household income includes all sources of income from anyone living at the address who is related to the respondent by blood, marriage, or adoption and is transformed so that a one‐unit change is equivalent to $10 000. Respondents are provided 26 categories from which to choose, and these categories are midpoint recoded  or female (0). A person is indicated as having health care insurance (1) if they indicated they received health insurance through work, school, or a union; that they bought health insurance directly and paid for it in total by themselves or their family regardless of whether they did so with government assistance; that they had access to health insurance through a government program; or that they obtained health insurance through some other insurance, group, or place not including those already mentioned. All others are coded as uninsured (0). Regular source of medical care is captured by the question: “Is there one person or place you USUALLY go to when you are sick or want advice about your health?” Individuals affirming this question are coded as “yes” (1); all others are coded as “no” (0). The presence of chronic health conditions is indicated by having doctor‐diagnosed asthma, diabetes, hypertension/high blood pressure, and obesity.Ethnoracial status, family income, respondent work status, respondent education, and marital status are measured as nominal indicators. Ethnoracial status captures respondents who self‐identified as Black non‐Latino, Latino, Asian non‐Latino, Other non‐Latino, or White non‐Latino (Reference) are included in the analysis. Respondent work status references the current employment situation and is coded as either: 1) nonfull time ; (2) unemployed; or (3) full time (Reference). Respondent education is coded as the last grade of school that was completed and is coded as either: (1) less than high school graduate ; (2) high school graduate (12 years or GED certificate); (3) technical, trade, or vocational school after high school; (4) some college but no four‐year degree or Associate's degree; and (5) college graduate or four‐year degree; (6) postgraduate or professional schooling after college. Respondent marital status is coded as (1) married or living with a partner (Reference); (2) widowed, separated, and divorced; (3) other marital status; or (4) single. Table  nonfull r = −.59), and a moderate correlation exists between neighborhood frisk concentration and neighborhood socioeconomic status .Neighborhood‐level confounders derived from the 2015 ACS dataset account for covariance related to education and poverty status. Neighborhood educational attainment is measured by the percentage of the population over the age of 25 who has at least a college degree. Neighborhood poverty status is measured as the percentage of families whose income to poverty level ratio is less than one (1). A moderate negative correlation exists between neighborhood education and neighborhood poverty ; the remaining respondents lived in either Delaware (in = 2) or Montgomery (in = 65) counties.The study sample focused on people between 18 and 65 at the time of the survey administration, nested in neighborhoods surveilled by local police. Of the 9044 respondents sampled in 2014‐2015 by SEPA HHS, only 7,024 respondents (77.7 percent) met the age criteria for the study. While all SEPA HHS respondents were geocoded to a zip code by PHMC, not all these respondents lived in neighborhoods surveilled by PPD. Only 44 of the 143 geocoded zip codes have policing information (30.8 percent). Of those that meet the age criteria for this study, only 3073 respondents (43.8 percent) reside in neighborhoods where information on police behavior is available from the PPVD. The vast majority of respondents lived in Philadelphia County , we employed two missing data techniques. First, we engaged in dummy‐variable replacement, including an indicator of all cases with missing household income data. Second, to reduce bias in our estimates, we included a measure imputing family poverty status, which is based on work status and educational attainment characteristics. Among the analytical sample, there is no statistically significant difference in the distributions of missing household income data across levels of family poverty (Pearson's Chi2(2) = 3.96; P = .138).The analytical sample, meanwhile, only retained respondents with valid data on the outcome of interest, the effect modifier, and sociodemographic and neighborhood controls. Due to the substantial proportion of cases missing data on household income (2(2) = 0.29; P = .866). Our final sample size is 2920 in 44 neighborhoods (84.6 percent of eligible zip codes).Aside from household income, listwise deletion was conducted since no individual‐level covariate contributed more than 1 percent to missing data. Only 126 (4.1 percent) of the study sample were removed from the analysis due to invalid nonincome data. Among the study sample, there is no statistically significant difference in the distributions of missing nonincome data across levels of family poverty , which allows us to maintain the sample size while providing analytical estimates that represent the demographics of the Philadelphia metropolitan division. At the neighborhood level, we assume that all neighborhoods surveilled by the PPD have equal likelihood of being represented in the sample. Stata 14.1t tests were conducted to compare the averages of continuous and count measures across groups; proportion tests are conducted to compare the averages of dichotomous measures across groups; and chi‐square statistics are computed to compare the distributions of nominal measures across groups. We expect that respondents who report worse (poor or fair) health will live in neighborhoods (zip codes) where police are more likely to frisk pedestrians and drivers (Hypothesis 1).Our descriptive statistics provide a comparison of sample covariates for two key groups—those with excellent/very good/good health and those with poor/fair health. We conduct three sets of regression analyses to evaluate the role of illness and neighborhood frisk exposure on ED utilization. The first regression analysis (Model 1) evaluates the past‐year rate of ED visits to self‐rated health. We expect that respondents with worse self‐rated health will utilize the ED more in the 12 months prior to participating in the SEPA HHS survey (Hypothesis 2).The second regression analysis (Model 2) evaluates whether the rate of ED visits associated with worse self‐rated health is independent of neighborhood frisk concentration. We expect that, among those respondents with the same reported health profile, living in zip codes where police are more likely to frisk during stops will be associated with an increased rate of visiting the ED (Hypothesis 3). Essentially, self‐rated health and neighborhood frisking likelihoods are separate sources of variation in ED utilization behavior.The third regression analysis (Model 3) evaluates an effect modifier—that is, whether the number of visits to the ED in the past year is associated with exposure to police frisking behavior in the neighborhood is different according to lay reports of health. We expect that respondents of worse health who live in zip codes where police engage more frequently in frisking more often will be less likely to visit the ED (Hypothesis 4). Confirmation of Hypothesis 4 would evidence that neighborhood frisk concentration represses, or buffers against, ED utilization.Incidence rate ratios are shown, and 95% confidence intervals are provided in brackets. Estimates shown above one (1) indicate higher rates of ED visits, while estimates below one indicate lower rates of ED visits. Estimates of control covariates are omitted from tabulated results but are available upon request.3P < .001). Consequently, if a person were to decrease their health status by one‐unit , their rate of ED visits would be expected to increase by a factor of 1.367, while holding all other variables in the model constant. Hypothesis 2 is supported: People with worse health utilize the ED more often.Table Model 2 includes a covariate for zip code‐level frisk concentration to examine whether living in areas where police are more likely to pat down people is associated with the rate of ED visits. Zip code frisk concentration is not statistically significant. Supplemental analyses indicate that similar patterns are evident when not controlling for lay health. There is no association between area‐level pat downs and ED visits in Philadelphia. Hypothesis 3 is not supported—among people with the same health profile, living in areas where police are more likely to engage in frisking does not distinguish their ED utilization.P < .001). Reporting better health, however, negates the rate of ED visits associated with residential exposure to frisking . Healthfulness buffers against the rate of ED use that is associated with the prevalence of police frisking pedestrians—Hypothesis 4 is supported.Model 3 includes an interaction term between better self‐rated health and zip code frisk concentration; this regression analysis tests whether the number of ED visits for people in better health is buffered or amplified by living in areas where police pat down people more. Better health continues to deter ED utilization. Nonetheless, the main association of living in areas with high levels of surveillance via frisking is statistically significant, as is the interaction term denoting effect modification to the health care costs of police frisking. Holding all other covariates in the model constant, each percentage increase in areal exposure to police frisking is expected to decrease the rate of ED visits by a factor of 0.925 significant . Meanwhile, ED utilization for healthier people is not affected by residential exposure to frisking. For instance, after taking into consideration the interaction term assessing the relative rate of ED utilization associated with exposure to police frisking for those in excellent/very good health compared to those in poor/fair health , testing linear combination of parameters reveals there is effectively no change in the rate of ED visits among the healthiest population . Supplemental analysis reveals similar patterns for those who report “good” health.Panel B of Table Figure 4Ostensibly, emergency health care providers and local law enforcement endeavor to adhere to similar missions of treating people in crisis. However, the danger that accompanies police presence and questioning in a community context already characterized by police intrusion undermines these institutions’ alleged shared goals. While we acknowledge that this study is limited by its cross‐sectional design and its examination of geographically based contexts that are structurally under‐resourced and underserved, we believe that these findings offer important health care provision and theoretical implications for addressing this conflict.First, our findings suggest that racial discrimination perpetuates intergenerational and epigenetic adverse health. Thus, place‐based structural determinants of health should be incorporated more directly into patient‐centered care.Second, hospitals must provide deidentified emergency care to all, regardless of their race or ethnicity, the location of where injury or illness originated, or their financial capacity.into the community instead of waiting for its residents to pass through their doors.We conclude by considering the ethical and future research implications of the results for the behaviors of health care professionals and providers. Our findings highlight the health care consequences of two interspersed sources—embeddedness in a legally sanctioned highly surveilled community and reliance on the medical community for access to the sick role. However, most health care administrators and professionals do not draft intake protocols in collaboration with community members who understandably fear medical intervention and engage in self‐isolating practices in the presence of and as a result of localized police presence. Our results, then, provide support for the utility of empirical inquiry into social medicine, which calls medical professions to go Namely, explicit policy and protocols that limit police presence inside the emergency and trauma care setting could reduce hospital utilization disparities. We also recommend a committed consideration of alternatives to police presence that not only reduce the routine disruptions that are linked to criminal legal system intrusion, but allow for the cultivation of community‐based, community‐built, and community‐directed health and wellness promoting institutions.Author MatrixClick here for additional data file.Appendix S1‐S2Click here for additional data file.


Although low muscle mass is an important predictor of increased physical morbidity in older patients, information on its impact on mental health and well-being is lacking. The first aim of this report is to look for associations if any between low muscle mass and mental health of older people in clinical practice. The second aim is to study underlying mechanisms including nutritional status.In this prospective longitudinal study we randomly selected and studied 432 hospitalized older patients’ baseline demographic data, clinical characteristics and nutritional status on admission, at 6 weeks and at 6 months. Low muscle mass was diagnosed using anthropometric measures based on the European Working Group criteria. Mental health outcome measures including cognitive state, depression symptoms and quality of life were also measured.p < 0.05). Although patients with low muscle mass had lower micronutrient concentrations compared to those patients with normal muscle mass, only serum albumin showed significant correlations with quality of life at admission and depression symptoms at 6 weeks.Out of 432 patients assessed 44 (10%) were diagnosed with low muscle mass. Patients diagnosed with low muscle mass at admission and over a 6-month follow up period had significantly poor cognitive function, quality of life and increased depression symptoms compared with those with normal muscle mass. After adjustment for poor prognostic indicators, age, disability, severity of acute illness and low muscle mass were associated with poor cognitive function and quality of life and higher depression symptoms in older patients over a 6 months period (Low muscle mass is associated with poor blood-borne poor nutritional status and mental health in hospitalized older patients, however, this is partly explained by underlying co morbidity. Despite growing evidence that low muscle mass is common and associated with increasing morbidity and mortality in older people, there is a lack of good-quality data of the effect of low muscle mass diagnosis on mental health and quality of life measures and their response to treatment –3. AlthoSubjects included in this research report were acutely ill-hospitalized older patients with common diagnoses who were part of for a randomized controlled trial  All subjp-value of < 0.05 is regarded as statistically significant. A forward stepwise multiple regression analysis was performed to determine the influence blood-borne nutritional markers on mental health outcome measures including cognitive state, depression symptoms and quality of life at admission and at 6 weeks. We also used multivariate analysis to determine the influence of low muscle mass on mental health and quality of life after adjusting for a number of independent poor prognostic clinical indicators including age, gender, disability, comorbidity (previous illnesses), and severity of acute illness (inflammation) measured using CRP.The independent student-t test or the nonparametric Mann-u-Whitney (SPSS version 24) were used to test differences in nutritional micronutrient variables between patients with low muscle mass and those patients with normal muscle mass. A p < 0.05). Although tissue inflammation showed significant associations with both cognitive function and depression symptoms, chronic illness revealed significant and independent associations with cognitive function, depression symptoms and quality of life (Table p < 0.05). Ascorbic acid, zinc, lycopene, folate, and retinol were also significantly lower in patients with low muscle mass at 6 weeks (Table All 432 acutely ill older patients aged 65 to 92 years [211 (49%) female] admitted to hospital and followed up for period of 6 months were included in this analysis. Among the 432 patients recruited 42 (10%) had low muscle mass at baseline. Corresponding figures at 6 weeks and at 6 months were 15 (10%) and 9 (6%). Exclusions were due to early discharge, death or inability to provide outcome data at follow up visits. Patients with low muscle mass at admission and at 6 weeks and 6 months follow up had significantly poor cognitive function, quality of life and/or increased depression symptoms compared with patients with normal muscle mass  could be associated with cognitive impairment . AnotherPhysical inactivity in hospitalised older patients during both acute illness and recovery period is another possible reason linking muscle mass loss to poor mental health . ExercisSome important limitations of this study include the number of exclusions and small numbers of patents with low muscle mass at follow up visits. Another important limitation is error known to be associated with measurement of anthropometric and biochemical nutritional indices in hospitalised older people. The longitudinal design and training and assessing observer’s error on anthropometric measurements, of the study and the use of a number of analyses to adjust for poor prognostic clinical indicators was to overcome some of these weaknesses.The lack of direct correlations between blood borne micronutrients and mental health measures may partly be explained by small numbers. Nevertheless new evidence is emerging of a link between malnutrition and poor mental health and quality of life in older people and that improvement in nutritional status may leads to improvement in mental health and well-being . There iLow muscle mass in older patients is associated with poor nutritional status and mental health and well-being. Hitherto the evidence for the effectiveness of specific treatment or nutrient supplement is incomplete but sufficient to justify further research. Based on currently available evidence increased physical activity particularly following acute illness and a healthy diet with protein, fruits and vegetables to mitigate inflammatory responses is clearly appropriate for healthy independent ageing particularly for older patients.


They play an important role in the assessment of health services, especially in primary care, where clinics and facilities are usually near each person/family. Starfield and Shi mentioned by the authors on references #1 and #4 had developed and validated a set of questionnaires to evaluate primary healthcare facilities—the Primary Care Assessment Tool (PCAT),2“increasingly important role in the healthcare system,” we propose a leap beyond. Why not outline a national policy for primary care assessment including users’ perspective? Thinking about this issue, in early 2019, the Brazilian Ministry of Health sought Brazilian Institute of Geography and Statistics (IBGE)—the Statistics Bureau of Brazil—to include in its main National Health Survey (PNS‐2019), the set of questions that forms Brazilian Adult PCAT reduced version.The use of PCAT is widespread in health services in Brazil, in the states of São Paulo, Rio de Janeiro and especially in Rio Grande do Sul. In agreement with Ozaki et al (2019),Therefore, we encourage the authors in future studies to focus on expanding their research in community clinics in Japan using J‐PCAT for the assessment of patients’ experience, helping to foster a baseline to compare nationwide primary care facilities. It could be used not only for health service research, but for a Japanese primary care policy, as Brazilian Federal Government is innovating since 2019, considering it for Family Health Teams , to evaluate the quality of primary care throughout a part of a pay‐for‐performance program implemented.The authors declare no conflict of interests for this article.


Is there a “double standard”  in the perceived ages at which women and men reach old age, and have these judgments changed over time? We use European Social Survey data from 23 countries in 2006 and newly released data from 16 of those countries in 2018. In both 2006 and 2018, men typically assign women substantially earlier ages than women themselves do. In some places, however, men also give themselves lower ages than women give them. With respect to when women become old, the differential views of men and women are persistent. So is the fact that women differentiate less between the sexes¬–though men differentiate less in 2018 relative to 2006. We use multilevel modeling to examine variation explained by both individual characteristics and country indicators of demographic and policy contexts. Findings underscore the significance of the double standard in cultural constructions of aging.


As the older adult population grows and Federal funding remains stagnant, coordination of services at the local level becomes more critical. Building on the Federal Administration for Community Living model, California’s Master Plan for Aging creates opportunities for innovative restructuring of the way aging services are delivered through the Area Agencies on Aging (AAA). We conducted a comparative case study of California AAAs (N=5) representing different levels of integration, from standalone departments of aging , to partial integration (Los Angeles County), to full integration with aging and disability programs . We examined the impact of departmental organization and integration on the AAAs’ service delivery for older adults. Interviews with leaders of the AAAs were coded by two researchers using constant comparative analysis to identify themes within and between the AAAs. Emerging themes revealed the role that “structure,” “politics,” “funding,” and “visibility” play in service delivery for AAAs with varying levels of integration. Findings suggest that integrating the AAA with other departments  and programs  improves coordination and allows for greater visibility of the AAA. Key stakeholders in standalone AAAs, however, fear that integration would hinder their visibility and “agility” in service provision. Findings shed light on best practices for locally coordinated aging service delivery during a window of opportunity for California AAAs, yet they can also inform how aging services are provided for local governments nationwide.


E. coli that recognize quorum sensing signals from pathogens in a biofilm and secrete toxins in response. To solve the challenge of dilute signalling molecules, we propose to use nanobodies and enzymes displayed on the surface of the cells to localize them to the biofilm and degrade the extracellular polymeric substances, thus creating a solution with better ‘seek and destroy’ capabilities.This opinion piece describes a new design for the remediation of recalcitrant biofilms. It builds on previous work to develop engineered  In food and drink manufacturing settings, bacterial biofilms can contaminate plant pipelines, resulting in production losses, economic damage and the potential for infections in consumers  or implanted medical devices , where the biofilms effectively hide bacteria from the host immune system and render them up to 1000‐fold less susceptible to antibiotics than in their planktonic state   to cause E. coli to swim towards the pathogen in response to secreted QS molecules. As a result, the engineered E. coli cells were able to kill both planktonic and biofilm‐residing cells. However, this system still relies on diffusion of the QS molecules, which may limit the distance over which it is effective.With the advent of synthetic biology, which aims to develop living organisms with genetically programmed responses, there has been wide interest in engineering commensal bacteria to address biofilms. Studies have primarily relied on the detection of QS molecules because they are reliable signals of biofilm formation and a wealth of genetic parts exist that can be used for engineering. Early work demonstrated the potential use of engineered , et al.  demonstrE. coli to biofilms would be via direct detection of the EPS components themselves. These large macromolecules would be difficult to detect via genetic regulators such as activators or repressors due to their slow diffusion and inability to cross the cell membrane. However, to facilitate adhesion of engineered E. coli cells to biofilms, one possible option could be the display of recombinant antibodies (Abs) or Ab fragments such as ‘nanobodies’ (Nbs) on the surface to physically bind the cells to the EPS. Nbs are single‐domain antibodies derived from the heavy chain Abs of camelids, which, unlike classical Abs, are devoid of the light chain and the CH1 constant domains   Fig. . The intE. coli cells in order to (i) target and degrade biofilms, (ii) sense the presence of pathogenic organisms and (iii) activate the production of toxins to kills these organisms. The novelty of BeQuIK lies in first module, which aims to solve the problems of previous ‘seek‐and‐destroy’ engineered cells by aiding in the targeting and penetration of biofilms. To achieve this, cells would display one or more biofilm‐targeting Nb (to recognize and bind to components of the EPS or biofilm‐mediated proteins) , a design for battling recalcitrant biofilms. BeQuIK is composed of three genetic modules introduced into E. coli cells would also target planktonic cells for the prevention of biofilm formation leading to pathogen eradication. With accessible resources of Nbs and other materials, we envision that it is a feasible alternative for application to both biotic and abiotic surfaces, especially as a cleaning‐in‐place method for medical devices and industrial pipes. Furthermore, the sensing module and a responsive promoter in the killing module can be tailored to target any pathogens via its characteristic QS molecules for achieving an improved ‘seek‐and‐destroy’ system.Our design represents a new perspective for treating biofilm infections effectively by improving target localization based on physical linking between Nbs and specific antigens in the EPS. The engineered None declared.


Arising from the city of Wuhan, Hubei province in China, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 has been rapidly spreading since its first presentation in late 2019. The World Health Organization declared a pandemic on the 11th March 2020, and as of 29th of April 2020 more than 3 million cases have been reported worldwide with over 225 000 confirmed deaths. Where mechanical ventilation may not be enough, extracorporeal membrane oxygenation (ECMO) could play a role as a form of rescue therapy and may provide beneficial results in the hands of skilled clinicians in centers with experience of using ECMO appropriately in selected patients. Our understanding of COVID‐19 is ever‐changing and the need for intensive care beds is rising, which means that ECMO will surely play a key role in the near future. The World Health Organization (WHO) declared a pandemic on the 11th March 2020, and as of late April 2020 more than 2.7 million cases have been reported worldwide. We are in unprecedented times fighting a pathogen that is not fully understood. Those who suffer from this illness may experience a clinical course ranging from being asymptomatic to having a minor illness, and in a significant minority a severe form of viral pneumonia, which can result in respiratory failure and death.SARS‐CoV‐2 is an RNA virus and part of the family of Coronaviruses and the third of its kind to affect humans in recent decades. It is thought to gain entry into type 2 pneumocytes via the ACE2 receptor, and the cytokine storm that is created in response to this virus can result in acute respiratory distress syndrome (ARDS), which can severely impair gas exchange.2A comprehensive literature search is done through the available electronic database to identify articles that reported the use of ECMO and mechanical circulatory support in COVID‐19 patients. The keywords used were “mechanical circulatory,” “extra‐corporeal membrane oxygenation,” “SARS‐CoV‐2,” “SARS‐CoV,” “ECMO,” “VA‐ECMO OR VV‐ECMO” “COVID‐19” “mechanical support.” The search terms were used as keywords and in combination as MeSH terms to maximize the output from literature findings. References of each included article is cross‐checked for any possible relevant study.The inclusion criteria were articles that discussed the indications, outcomes, and survival benefit from using mechanical circulatory support in the form of VV‐ECMO or VA‐ECMO in patients with COVID‐19.3ECMO is a form of cardiopulmonary bypass and can be divided into venovenous (VV‐ECMO) and venoarterial (VA‐ECMO), which can be used in the setting of respiratory failure and cardiogenic shock, respectively. VV‐ECMO can provide respiratory support and can replace the gas exchange function of the lungs and minimize ventilator‐induced lung injury, barotrauma, and oxygen toxicity. VA‐ECMO can provide both respiratory and hemodynamic support and may be of use to COVID‐19 patients who sustain myocardial injury leading to refractory cardiogenic shock.Patient selection is crucial when considering ECMO and those who are inappropriately selected stand a much lower chance of survival. Extracorporeal Life Support Organization (ELSO) has provided selection criteria needed for ECMO referral. If in spite of optimal ventilation strategies, neuromuscular blockade, appropriate PEEP, prone positioning, and the use of pulmonary vasodilators, patients develop the following criteria: PaO2/FiO2 less than 60mm Hg for greater than 6 hours, PaO2/FiO2 less than 50mm Hg less than 3 hours or pH less than 7.20 + PaCO2 greater than 80mm Hg for less than 6 hours, and do not have any contraindications, they may be suitable for ECMO referral.4Alshahrani et al studied the effect of ECMO during the Middle Eastern respiratory syndrome (MERS) outbreak. Patients suffering from MERS had been known to develop ARDS. VV‐ECMO was offered to those who failed optimal ventilation strategies and were found to have lower in‐hospital mortality, better PaO2/FiO2 ratios, and fewer instances of organ failure.When considering ECMO a question of when to intervene arises: in the setting of COVID‐19, would early use of ECMO be beneficial or should patients be placed on mechanical ventilation first and then transitioned to ECMO should they continue to deteriorate? There may be two separate components to hypoxemic respiratory failure: those with normal or high compliance, and those with low compliance and severe hypoxia. ECMO may not be indicated until lung compliance worsens or hypoxemia that is deemed to be severe sets in.Combes et al placed a group of patients with non‐COVID‐related ARDS immediately on VV‐ECMO and found than after a period of 60 days there was no significant difference between the early application of ECMO and the control group, which followed conventional treatment. Twenty‐eight percent of their patients, however, needed to cross over to the ECMO group for refractory hypoxemia.5Our understanding of COVID‐19 is evolving and the role of ECMO is being studied at various specialist centers. These centers tend to save ECMO for those who are critically ill. Yang et al studied 52 critically ill patients and six of these patients were placed on ECMO. Sixty‐seven percent of these patients had ARDS and of the six on ECMO only one had survived beyond the 28‐day period. PaO2/FiO2 ratio was shown to differ between survivors and nonsurvivors being 100 mm Hg and 62.5 mm Hg, respectively, indicating the severity of the disease and prognosis.Henry et al reviewed 234 cases of COVID‐19‐related ARDS in China of which 17 (7.25%) received ECMO. The study showed a 94.1% mortality rate in ECMO patients compared with 70.9% in conventional patients, though the severity of ARDS and the timing of ECMO intervention is not mentioned, bearing in mind that those who are most ill are more likely to be provided with ECMO.Lung compliance may provide us with a useful parameter to guide us in the use of ECMO. Zochios et al state that in COVID‐related hypoxemic respiratory failure, patients can be divided into those with normal or high lung compliance and those with low lung compliance. ECMO is deemed to be suitable to those who have had prolonged mechanical ventilation (<7 days), worsening lung compliance, and failed conventional strategies.6Complications can arise from the use of ECMO with hemorrhage and coagulopathy being the most common. Hemorrhage can range from cannula site to intracranial and pulmonary bleeding. These patients are also at risk of thromboembolism paradoxically due to prolonged bed rest, comorbidities, and disease burden. DVT and PE have been identified while patients have been on ECMO. COVID‐19 has been shown to promote thrombosis and in severe cases can result in disseminated intravascular coagulation, which combined with ECMO will place the patient at greater risk of coagulopathy.7ECMO should be reserved for those who are critically ill and in these current times with the emergence of COVID‐19 we are seeing more and more critically ill patients. ECMO is resource‐intensive and requires clinical knowledge, understanding, and experience of ECMO to obtain the best results. There are few intensive care beds and even fewer ECMO machines and it is imperative that patients are selected correctly. ELSO has provided guidance on the criteria needed to refer these patients for ECMO and what cohort of patients should be deemed unsuitable for ECMO. Timing may play an important factor. Should these patients be provided ECMO immediately or soon after presentation, or should maximal ventilation strategies be trialed before ECMO is utilized as a last resort? ELSO currently recommend the latter. Previous viral illnesses in recent times such as MERS and H1N1 have shown to present good results from ECMO. There may be scope for the use of ECMO as rescue therapy and this intervention should, therefore, be strongly considered in patients with severe lung injury secondary to COVID‐19.The authors declare that there are no conflict of interests.


MMWR published “Deaths and Years of Potential Life Lost From Excessive Alcohol Use — UnitedStates, 2011–2015” (MMWR that some results were inaccurate because of a data inputerror that occurred during an update to the Alcohol-Related Disease Impact application(MMWR report accordingly and confirmed that the interpretation andthe conclusions of the original report were not affected by these corrections. Inaccordance with December 2017 guidance from the International Committee of MedicalJournal Editors (MMWR is republishing the report (On July 31, 2020,


The patient was successfully self‐regulated for 10 days and was discharged on 2 L/min nasal cannula on day 14 of his illness.Management of critically ill coronavirus disease 2019 (COVID‐19) patients remains both risky and technically challenging. A 55‐year‐old male COVID‐19‐positive patient with obstructive sleep apnoea (OSA), diabetes, and obesity presented with cough and shortness of breath, escalating to requiring high‐flow oxygen therapy by high‐velocity nasal insufflation. The patient's flow rate and oxygen fraction remained labile throughout much of the hospitalization. This lability required frequent clinician interactions and use of personal protective equipment. The patient was alert and oriented and was instructed on the operation of the high‐flow system, specifically the adjustment of both flow rate and oxygen percentage. The patient was instructed to modify oxygen to maintain an SpO 2  target range and flow rate, to address dyspnoea as well as reduction of flow, as tolerated, when other staff entered the room. This was a successful 10‐day self‐regulation of HVNI, wherein on day 14 the patient was discharged.We present a case report on a 55‐year‐old male with obstructive sleep apnoea (OSA), diabetes, and obesity requiring escalation to high‐flow oxygen by high‐velocity nasal insufflation . As this patient required frequent clinician interaction and use of personal protective equipment (PPE) to control flow rate and oxygen fraction due to lability, and the patient was alert, we instructed the patient to modify the oxygen to maintain an SpO Critically ill patients with coronavirus disease 2019 (COVID‐19) pneumonia often require oxygenation support to maintain oxygen saturation target levels . All higA 55‐year‐old man with obesity, obstructive sleep apnoea (OSA), and diabetes mellitus presented with cough and shortness of breath for seven days and oxygen saturation of 88% on room air. Laboratories were significant for lymphopenia and high neutrophil‐to‐lymphocyte ratio of 3.6. He was initiated on treatment with hydroxychloroquine, zinc, and azithromycin  but his oxygen saturation and dyspnoea worsened over the next three days. Chest computed tomography (CT) was consistent with COVID‐19  to achieve an SpO2  target value, and on adjustment of flow rate for both dyspnoea relief and to reduce exposure to staff when they entered the room (reduction in flow as tolerated by the patient). This patient activity constituted self‐regulation. This was made possible by the patient's facility using his smartphone, specifically FaceTime audio/video chat and SMS/picture messaging. The smartphone permitted high‐frequency interaction with a clinician outside the room to assess patient decision‐making regarding both FiO2 and flow rate adjustments. The patient was able to demonstrate successful decision‐making during training and in subsequent follow‐up. Self‐adjustment by the patient was endorsed by the managing clinician after assessment by message‐based interactions.The primary objective was to provide effective treatment of the patient whilst using this novel approach, allowing the patient to assist with effective self‐monitoring and adjustment, while maintaining direct contact with the attending physician, after education and understanding the disease process and training on the limited control of the equipment. The patient understood that this would also subsequently minimize patient–clinician interactions to protect clinical staff from avoidable exposure risk. The patient was instructed on the operation of the HVNI high‐flow device, on adjustment of oxygen fraction  therapy, but also for self‐regulation . The staAppropriate written informed consent was obtained for publication of this case report and accompanying images.At the time this report was accepted for publication, the authors declared that this patient had not been included in any previously published report on COVID‐19 that they had authored.


To create a novel neurological vital sign and reliably capture MS‐related limb disability in less than 5 min.Consecutive patients meeting the 2010 MS diagnostic criteria and healthy controls were offered enrollment. Participants completed finger and foot taps wearing the MYO‐band© . Signal processing was performed to extract spatiotemporal features from raw sensor data. Intraclass correlation coefficients (ICC) assessed intertest reproducibility. Spearman correlation and multivariable regression methods compared extracted features to physician‐ and patient‐reported disability outcomes. Partial least squares regression identified the most informative extracted textural features.P = 0.002). The most informative combination of extracted features from all three sensors strongly correlated with physician EDSS  and had equally strong associations with patient‐reported outcomes . Associations remained with multivariable modeling adjusted for age and sex.Baseline data for 117 participants with MS (EDSS 1.0–7.0) and 30 healthy controls were analyzed. ICCs for final selected features ranged from 0.80 to 0.87. Time‐based features distinguished cases from controls (Extracted features from the multi‐sensor demonstrate striking correlations with gold standard outcomes. Ideal for future generalizability, the assessments take only a few minutes, can be performed by nonclinical personnel, and wearing the band is nondisruptive to routine practice. This novel paradigm holds promise as a new neurological vital sign. Capturing with precision the extent of MS‐related disability is critical for effective clinical care and the development of new outcome metrics for rapid testing of therapeutic agents. To date, outcomes research in MS has centered on periodic clinical exams, which may be insensitive to changes over the short term  and only capture a single semiquantitative snapshot of the patient’s performance. Single limb progression, which may be critical to quality of life and for screening of neuroprotective agents in early stage trials, has not been used as a primary outcome in MS studies largely due to lack of reliable and accessible quantitative measures of limb function. With the advent of mass production of sensors in the gaming and computer control industry, there is an opportunity to extend the traditional neurological exam with biosensors already in use outside the realm of health applications.While accelerometers have been the most commonly studied sensor in MS research to date,Using a sophisticated signal processing approach, we sought to validate a wearable multi‐sensor device (MYO©) for detection of upper and lower limb dysfunction in MS patients. We determined if extracted features from the three sensors , individually and in combination, can be reliably measured, are associated with standard and validated measures of MS disability, and to evaluate their potential to help detect subtle dysfunction in comparison to healthy controls.Participants were recruited from the UCSF Adult MS clinic . They were offered enrollment and testing was performed at the time of their routine clinic visits. Diagnosis of MS, as defined by the International 2010 revised McDonald criteria,The Committee on Human Subjects at UCSF approved this study, which is in compliance with the principles of the Declaration of Helsinki. All MS and control participants completed written informed consent.In this cross‐sectional study, before or after the clinical visit, MS subjects completed secure RedCap questionnaires on provided tablets for clinical and treatment history, and self‐reported disability metrics , World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), described below) with supervision from the study coordinator to ensure completion. During the office visit exam, the MYO‐band was placed at the widest point of the upper forearm during routine finger tap testing. Markers on the wristband ensured the device was worn in the same orientation for all participants. The participant was asked to complete 20 taps with the right forefinger and thumb as quickly as possible with demonstration by the examiner of 4‐inch amplitude and 4‐Hz taps. Then the device was moved to the left arm and measurements repeated. The device was then placed over the widest part of the upper right calf. The participant was instructed from a sitting position to leave the heel of the foot on the ground and quickly tap the ball of the foot 20 times with large amplitude. The examiner demonstrated 4‒6‐inch amplitude and 4‐Hz taps. Measurements were repeated for the left leg. Each tapping task was repeated twice.During these assessments, accelerometer (ACC), gyroscope (GYR), and surface EMG (sEMG) data were collected from MYO through a Bluetooth connection to an encryption‐protected laptop with both immediate signal processing and postprocessing metrics extraction as described below. At the end of the clinical visit, physician‐derived EDSS scores were entered into a separate RedCap EDSS form.Patients were queried for handedness. Physician scored and patient‐reported disability measures were assessed including both physician‐derived EDSS and patient‐reported telephone EDSS score adapted for digital questionnaire use.Modification to the data acquisition software development kit  and additional proprietary C++ code was made to export all of the MYO sensor data to text files in ASCII format at varied frame rates as set by device defaults and firmware.An overview of the signal processing approach is presented in Figure Textural features  of the waveform data from all three sensors  were extracted using well‐established and published image processing methods to more richly quantify performance during the tapping tasks.The time‐based sensor‐derived metric described above measured the duration of time in seconds required for 20 taps in each limb. For the final texture‐based metric, to understand which textural features of the waveforms from the three sensors were more likely to be describing phenomena of interest (vs. noise) and best distinguished levels of function, we applied a partial least squares (PLS) method to all of the extracted features in 60% of the data (training dataset).For descriptive analysis, means, medians, or frequencies were presented as appropriate. Spearman (rho) correlations for nonparametric data were presented for comparison of sensor‐derived with patient‐reported and physician‐measured metrics. Handedness was addressed by creating a dominant limb category for metric results. Intraclass correlation coefficients (ICC) were used to assess reproducibility for repeated trials of both the time‐ and texture‐based metrics.We compared case versus control differences in the time‐based sensor‐derived metrics with logistic regression, adjusted for age and sex. Extracted time‐ and texture‐based features were compared to patient‐reported and physician‐measured disability metrics with Spearman correlation coefficients. In addition, multivariable regression methods were used to assess the association of the sensor‐derived metrics with disability metrics (physician‐ and patient‐reported EDSS and WHODAS 2.0), adjusting for age and sex. To avoid over fitting and bias, PLS‐model training data were not used in any of the final analyses; only the replication dataset was used.P‐value of less than 0.05 was considered significant.Matlab and STATA v12 were used for analyses. A two‐sided Software may be available upon request to corresponding author and approval under nonexclusive use and nondisclosure contracts.Clinical and sensor data were collected from 117 participants with MS and from 30 healthy controls. Descriptive comparisons of these groups are available in Table P < 0.001) and 0.08 sec longer 20‐foot tap duration time . Thus, age was included in all multivariable analyses below. Sex, however, was not associated with 20‐finger tap duration  or 20‐foot tap duration , but adjustment for sex was included for face validity.Surface electromyogram data were used to extract time‐based features for analysis. The total duration of time taken by participants to complete 20 finger or foot taps was calculated for all limbs using the sEMG data. Task duration times for dominant and nondominant limbs are presented in Table P = 0.002) and 1.82 sec longer 20‐foot tap duration  compared to healthy controls. Differences were still seen between cases and controls when the analysis was restricted to MS participants with no disability .In multivariable regression analysis adjusting for age and sex, participants with MS had 1.65 sec longer 20‐finger tap duration , patient self‐reported EDSS , and WHODAS total scores  were associated with 20‐finger tap duration of the dominant hand in Spearman correlation analyses  were used to generate textural features of tap performance in all limbs. Waveform textural feature extraction was performed as described in the Methods and the Supplemental Appendices. Overall, the extracted textural features demonstrated greater tap performance irregularity across 20 tap segments in those with higher versus lower EDSS scores. The strength of the approach is capturing this irregularity in high resolution, mathematical detail.To understand which of the textural features were more likely to be describing phenomena of interest (limb disability) versus fluctuation related to noise, we applied a partial least squares (PLS) based‐optimization method followed by statistical analysis to all of the textural features for all three sensors to derive a single summary textural feature value (“T‐metric”) for each participant with MS (60% of data used for training). This T‐metric single scalar value was then modeled as a predictor of physician‐ and patient‐reported EDSS as well as WHODAS scores .Neurological patients receive vital sign measurements of blood pressure and heart rate with every clinic visit. While these data give a snapshot of cardiovascular health, there historically has been no equivalent for neurological function. One could easily argue that development of a neurological vital sign would have more direct import for neurological patients than the cardiovascular measures. In the same time it takes to measure blood pressure and heart rate, we were able to use a single device to provide a discrete numerical estimate of both upper and lower limb function. The MYO‐band is smaller than a blood pressure cuff and comfortable. Testing can be administered by nonclinical personnel and could even be used remotely by patients for telemedicine visits in the future.In addition to the benefits of this new vital sign for clinical care, there is a high demand for improved outcome measures in MS for clinical trials.This type of biosensor approach also offers potential advantages over components of the MS Functional Composite (MSFC). In the MSFC, the nine‐hole peg test (9HPT) is used to assess upper limb function and the timed 25‐foot walk (T25FW) test evaluates lower limb function. These tests can be very useful in tracking progression, but use different scales of measurement for upper and lower limbs. With the MYO‐band approach, we applied the same device and analytics for upper and lower limbs; thus, the results are comparable. One can measure progression similarly in any limb. Comparing the MYO‐band to the T25FW, each leg’s performance is measured rather than a composite of walking function. With the band device we are better able to evaluate subtle changes within one leg. In this proof of concept study we were able to demonstrate differences in foot tapping function even in those with normal ambulatory function.The highest reproducibility of the MYO‐band measures for the upper limbs was for the dominant side, which is intuitive given importance of handedness for upper limb function. For textural analyses the strongest correlations with gold standard EDSS was with the fused statistic for right and left limbs.One of the advantages of the MYO multi‐sensor system is inclusion of surface EMG. This sensor has not been commonly used in MS wearable studies. While sEMG has been studied in the past as a possible diagnostic tool for neuromuscular disorders,Tapping tasks were selected for analysis for simplicity of the motion, mathematical advantages in analyzing repeated movements, and ability to use the same software for upper and lower limbs. Instructions to the patient are simple  and additional equipment is not required in the clinic. Another advantage is the eventual generalizability of the software to other neurological diseases for which tapping movements are used in diagnosis and follow‐up of patients .Regarding scalability and the long‐term utility of this algorithm, while the current work was proof of concept, it is our vision that a multi‐sensor device (these types of sensors are now widely available at low cost) and software with a commercial grade user interface that could run on any PC would be accessible to practices and eventually patients for home measurements. Both acquisition and analytical software would be available without need for any local signal processing expertise. After additional study to demonstrate sensitivity to changes over time and reproducibility within a multisite setting, there are no obvious limits to future scalability.Limitations of the current work include cross‐sectional design, and analyses are already underway to address sensitivity of the textural feature algorithm to detect within patient change over time in a real‐world clinical setting. While we anticipate this method to be more sensitive than the EDSS to deficits and change over time, in the absence of a better ground truth or gold standard, statistical approaches to prove superiority for a novel technology are challenging. Our inclusion of patient‐reported outcomes adds validity to our approach.Other strengths of our work include the sophisticated image processing approach to extracting features from the raw signal data and creation of a simplified final statistic to represent the complexity and patterns of irregularity in the data. We had consistent results across physician and two different patient‐reported outcomes. We demonstrated good to excellent intertest reliability and rigorously evaluated which metrics extracted from the sensor data performed better than others. The examinations took place in routine clinical practice and MYO tests took only a few minutes. The bracelet fits on a wide variety of body types on both upper and lower limbs. This work also demonstrates that commercially available sensors can be validated for clinical use at low development cost.This device and analytical approach holds potential as a new neurological “vital sign” that could be checked by nonclinical personnel in routine visits. Future validation of this multi‐sensor algorithm will include longitudinal study in MS patients and both cross‐sectional and longitudinal studies in other neurological diseases.Alireza Akhbardeh has no disclosures. Jennifer Arjona has no disclosures. Kristen Krysko is supported by the Sylvia Lawry Physician Fellowship from the National MS Society (FP‐1605‐08753 (Krysko)) and a Biogen Fellowship grant. Bardia Nourbakhsh has current grant support from PCORI. P.A. Gourraud is supported by the ATIP‐Avenir INSERM program and the Region Pays de Loire ConnecTalent, ARSEP Foundation (France), and the Nantes University Foundation. Jennifer Graves has received recent grant and clinical trial support from the National MS Society, Race to Erase MS, UCSF CTSI RAP program, Biogen, and Genentech. She has received honoraria from Biogen, Novartis and Genzyme for education events.Alireza Akhbardeh contributed to signal processing and statistical analysis plan, performed the signal processing and parts of the statistical analyses, and edited the manuscript. Jennifer Arjona managed the data collection for the project, contributed to the analyses and edited the manuscript. Kristen Krysko provided feedback on project design and data interpretation and edited the manuscript. Bardia Nourbakhsh contributed patient data, provided feedback on project design and edited the manuscript. P.A. Gourraud contributed to study design and edited the manuscript. Jennifer Graves designed the study, provided participants for the study and performed study evaluations, created the signal processing and statistical analysis plan, and drafted and edited the manuscript.Data S1. Methods Supplemental Appendices. Click here for additional data file.