Search

Morphogenesis, the process through which genes generate form, establishes tissue-scale order as a template for constructing the complex shapes of the body plan. The extensive growth required to build these ordered substrates is fuelled by cell proliferation, which, naively, should destroy order. Understanding how active morphogenetic mechanisms couple cellular and mechanical processes to generate order-rather than annihilate it-remains an outstanding question in animal development. We show that cell divisions are the primary drivers of tissue flow, leading to a fourfold orientationally ordered phase. Waves of anisotropic cell proliferation propagate across the embryo with precise patterning. Defects introduced into the nascent lattice by cell divisions are moved out of the tissue bulk towards the boundary by subsequent divisions. Specific cell proliferation rates and orientations enable cell divisions to organize rather than fluidize the tissue. We observe this using live imaging and tissue cartography to analyse the dynamics of fourfold tissue ordering in the trunk segmental ectoderm of the crustacean Parhyale hawaiensis beginning 72 h after egg lay. The result is a robust, active mechanism for generating global orientational order in a non-equilibrium system that sets the stage for the subsequent development of shape and form.

Clinician generated segmentation of tumor and healthy tissue regions of interest (ROIs) on medical images is crucial for radiotherapy. However, interobserver segmentation variability has long been considered a significant detriment to the implementation of high-quality and consistent radiotherapy dose delivery. This has prompted the increasing development of automated segmentation approaches. However, extant segmentation datasets typically only provide segmentations generated by a limited number of annotators with varying, and often unspecified, levels of expertise. In this data descriptor, numerous clinician annotators manually generated segmentations for ROIs on computed tomography images across a variety of cancer sites (breast, sarcoma, head and neck, gynecologic, gastrointestinal; one patient per cancer site) for the Contouring Collaborative for Consensus in Radiation Oncology challenge. In total, over 200 annotators (experts and non-experts) contributed using a standardized annotation platform (ProKnow). Subsequently, we converted Digital Imaging and Communications in Medicine data into Neuroimaging Informatics Technology Initiative format with standardized nomenclature for ease of use. In addition, we generated consensus segmentations for experts and non-experts using the Simultaneous Truth and Performance Level Estimation method. These standardized, structured, and easily accessible data are a valuable resource for systematically studying variability in segmentation applications.

Organ architecture is often composed of multiple laminar tissues arranged in concentric layers. During morphogenesis, the initial geometry of visceral organs undergoes a sequence of folding, adopting a complex shape that is vital for function. Genetic signals are known to impact form, yet the dynamic and mechanical interplay of tissue layers giving rise to organs' complex shapes remains elusive. Here, we trace the dynamics and mechanical interactions of a developing visceral organ across tissue layers, from subcellular to organ scale in vivo. Combining deep tissue light-sheet microscopy for in toto live visualization with a novel computational framework for multilayer analysis of evolving complex shapes, we find a dynamic mechanism for organ folding using the embryonic midgut of Drosophila as a model visceral organ. Hox genes, known regulators of organ shape, control the emergence of high-frequency calcium pulses. Spatiotemporally patterned calcium pulses trigger muscle contractions via myosin light chain kinase. Muscle contractions, in turn, induce cell shape change in the adjacent tissue layer. This cell shape change collectively drives a convergent extension pattern. Through tissue incompressibility and initial organ geometry, this in-plane shape change is linked to out-of-plane organ folding. Our analysis follows tissue dynamics during organ shape change in vivo, tracing organ-scale folding to a high-frequency molecular mechanism. These findings offer a mechanical route for gene expression to induce organ shape change: genetic patterning in one layer triggers a physical process in the adjacent layer - revealing post-translational mechanisms that govern shape change.

Abstract Clinician generated segmentation of tumor and healthy tissue regions of interest (ROIs) on medical images is crucial for radiotherapy. However, interobserver segmentation variability has long been considered a significant detriment to the implementation of high-quality and consistent radiotherapy dose delivery. This has prompted the increasing development of automated segmentation approaches. However, extant segmentation datasets typically only provide segmentations generated by a limited number of annotators with varying, and often unspecified, levels of expertise. In this data descriptor, numerous clinician annotators manually generated segmentations for ROIs on computed tomography images across a variety of cancer sites (breast, sarcoma, head and neck, gynecologic, gastrointestinal; one patient per cancer site) for the Contouring Collaborative for Consensus in Radiation Oncology challenge. In total, over 200 annotators (experts and non-experts) contributed using a standardized annotation platform (ProKnow). Subsequently, we converted Digital Imaging and Communications in Medicine data into Neuroimaging Informatics Technology Initiative format with standardized nomenclature for ease of use. In addition, we generated consensus segmentations for experts and non-experts using the Simultaneous Truth and Performance Level Estimation method. These standardized, structured, and easily accessible data are a valuable resource for systematically studying variability in segmentation applications.

Abstract Objectives To have confidence in one's interpretation of treatment effects assessed by comparing trial results to external controls, minimizing bias is a critical step. We sought to investigate different methods for causal inference in simulated data sets with measured and unmeasured confounders. Methods The simulated data included three types of outcomes (continuous, binary, and time-to-event), treatment assignment, two measured baseline confounders, and one unmeasured confounding factor. Three scenarios were set to create different intensities of confounding effect (e.g., small and blocked confounding paths, medium and blocked confounding paths, and one large unblocked confounding path for scenario 1 to 3, respectively) caused by the unmeasured confounder. The methods of g-computation (GC), inverse probability of treatment weighting (IPTW), overlap weighting (OW), standardized mortality/morbidity ratio (SMR), and targeted maximum likelihood estimation (TMLE) were used to estimate average treatment effects and reduce potential biases. Results The results with the greatest extent of biases were from the raw model that ignored all the potential confounders. In scenario 2, the unmeasured factor indirectly influenced the treatment assignment through a measured controlling factor and led to medium confounding. The methods of GC, IPTW, OW, SMR, and TMLE removed most of bias observed in average treatment effects for all three types of outcomes from the raw model. Similar results were found in scenario 1, but the results tended to be biased in scenario 3. GC had the best performance followed by OW. Conclusions The aforesaid methods can be used for causal inference in externally controlled studies when there is no large, unblockable confounding path for an unmeasured confounder. GC and OW are the preferable approaches.

Abstract Background To evaluate the impact of tanezumab on health status, non-work activities, and work productivity in a pooled analysis of two large phase 3 osteoarthritis (OA) studies. Methods Subcutaneous tanezumab (2.5 mg and 5 mg) was tested in double-blind, placebo-controlled, 16-week (NCT02697773) and 24-week (NCT02709486) clinical trials in patients with moderate-to-severe OA of the hip or knee. At baseline and week 16, all patients completed EQ-5D-5L and the Work Productivity and Activity Impairment-OA (WPAI-OA) activity impairment item. Those currently employed also completed WPAI-OA work time missed, impairment while working, and overall work impairment items. Between-group differences in least squares (LS) mean changes from baseline at week 16 were tested using analysis of covariance. Results Of 1545 pooled patients, 576 were employed at baseline. Improvements in EQ-5D-5L index value at week 16 were significantly greater for the tanezumab 2.5-mg group (difference in LS means [95% confidence interval (CI), 0.03 [0.01, 0.05]; p = 0.0083) versus placebo. Percent improvements (95% CI) in activity impairment (− 5.92 [− 8.87, − 2.98]; p

Organ architecture is often composed of multiple laminar tissues arranged in concentric layers. During morphogenesis, the initial geometry of visceral organs undergoes a sequence of folding, adopting a complex shape that is vital for function. Genetic signals are known to impact form, yet the dynamic and mechanical interplay of tissue layers giving rise to organs' complex shapes remains elusive. Here, we trace the dynamics and mechanical interactions of a developing visceral organ across tissue layers, from subcellular to organ scale in vivo. Combining deep tissue light-sheet microscopy for in toto live visualization with a novel computational framework for multilayer analysis of evolving complex shapes, we find a dynamic mechanism for organ folding using the embryonic midgut of Drosophila as a model visceral organ. Hox genes, known regulators of organ shape, control the emergence of high-frequency calcium pulses. Spatiotemporally patterned calcium pulses trigger muscle contractions via myosin light chain kinase. Muscle contractions, in turn, induce cell shape change in the adjacent tissue layer. This cell shape change collectively drives a convergent extension pattern. Through tissue incompressibility and initial organ geometry, this in-plane shape change is linked to out-of-plane organ folding. Our analysis follows tissue dynamics during organ shape change in vivo, tracing organ-scale folding to a high-frequency molecular mechanism. These findings offer a mechanical route for gene expression to induce organ shape change: genetic patterning in one layer triggers a physical process in the adjacent layer – revealing post-translational mechanisms that govern shape change.

Gurjyot K Doshi,1 Abhijeet Bhanegaonkar,2 Mairead Kearney,3 Murtuza Bharmal,2 Paul Cislo,4 Ruth Kim,4 Marley Boyd,5 Kathleen M Aguilar,5 Hemant Phatak2 1Texas Oncology, Houston, TX, USA; 2EMD Serono Research & Development Institute, Inc., Rockland, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany; 3Merck KGaA, Darmstadt, Germany; 4Pfizer Inc., New York, NY, USA; 5Data, Evidence and Insights, McKesson Life Sciences, The US Oncology Network, The Woodlands, TX, USACorrespondence: Abhijeet BhanegaonkarDirector, US Health Economics and Outcomes Research – Oncology, North America Medical Affairs, EMD Serono, Inc., One Technology Place, Rockland, MA 02370, USATel +1 781-681-2483Email abhijeet.bhanegaonkar@emdserono.comPurpose: Clinical trial evidence has affirmed the role for immuno-oncology (IO) treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). This Study informing treatment Pathway dEcision in bladder cAnceR (SPEAR-Bladder) aimed to provide insight into the optimal sequencing of IO treatments among la/mUC patients treated in the US Oncology Network.Patients and Methods: This was a retrospective analysis of adult patients with la/mUC who initiated first-line chemotherapy followed by either IO therapy (C-IO subgroup) or chemotherapy (C-C subgroup) between 01/01/2015 and 04/30/2017 and included a potential follow-up period through 06/30/2017. Data were sourced from iKnowMed electronic health records. Patient and treatment characteristics were assessed descriptively, with Kaplan–Meier methods used to evaluate time-to-event outcomes, including overall survival (OS).Results: A total of 117 patients were included in this analysis (median age 69 years, 74.4% male, 88.0% Caucasian): 79 and 38 patients were in the C-IO and C-C subgroups, respectively. The median OS was 19.2 months among patients who received the C-IO sequence and 11.9 months among those who received the C-C treatment sequence.Conclusion: These results suggest that patients who received the C-IO treatment sequence had notable improvement in OS compared with those who received the C-C sequence. In light of the rapidly evolving therapeutic landscape, further investigation will be required to determine how best to select the optimal therapeutic regimen and sequencing for patients with la/mUC.Keywords: urothelial carcinoma, SPEAR-Bladder, real-world clinical outcomes, treatment sequencing, retrospective, community oncology setting

Abstract Background This paper reports the significant prevalence of a presumed hereditary cataract in the Bengal cat breed in Poland. The nuclear part of the lens is affected and previous reports from Sweden and France for this type of feline cataract suggest that a recessive mode of inheritance is probably involved. Results Presumed congenital or neonatal cataract involving the posterior nuclear part of each lens was initially diagnosed in a 12 month old male Bengal cat. As both parents and a sibling were also affected with cataract, a group of 18 related and 11 non-related cats was then subsequently examined. Eight related cats and one non-related cat were found to be similarly affected. A breed survey was then completed using an additional five centres across Poland and a further 190 related cats were examined. A total of 223 cats have been involved in this study, with 75 (33%) being affected with several types of cataract and 67 (30%) being specifically affected with the same or similar nuclear lesions. Eight cats (3.6%) presented with other cataract types and a prominence of the posterior lens suture lines was recorded in 65 cats unaffected with cataract (29%). There were no demonstrable vision problems. Neither age nor coat colour was significantly associated with the nuclear cataract, but the nuclear cataract group had a higher proportion of females than the unaffected group. Pedigree analysis has indicated probable inheritance as a recessive trait. Conclusions These findings suggest that a presumably inherited nuclear cataract is present in the Bengal cat breed in Poland. It is considered to be either congenital or of very early onset, probably being inherited as a recessive trait. Although the lesion has no noticeable effect on vision, breeders in Poland and worldwide should be aware of the disease and clinical examination of young breeding stock prior to reproduction is advisable.

BackgroundThe COVID-19 pandemic triggered a seismic shift in education to web-based learning. With nearly 20 million students enrolled in colleges across the United States, the long-simmering mental health crisis in college students was likely further exacerbated by the pandemic. ObjectiveThis study leveraged mobile health (mHealth) technology and sought to (1) characterize self-reported outcomes of physical, mental, and social health by COVID-19 status; (2) assess physical activity through consumer-grade wearable sensors (Fitbit); and (3) identify risk factors associated with COVID-19 positivity in a population of college students prior to release of the vaccine. MethodsAfter completing a baseline assessment (ie, at Time 0 [T0]) of demographics, mental, and social health constructs through the Roadmap 2.0 app, participants were instructed to use the app freely, wear the Fitbit, and complete subsequent assessments at T1, T2, and T3, followed by a COVID-19 assessment of history and timing of COVID-19 testing and diagnosis (T4: ~14 days after T3). Continuous measures were described using mean (SD) values, while categorical measures were summarized as n (%) values. Formal comparisons were made on the basis of COVID-19 status. The multivariate model was determined by entering all statistically significant variables (P

BackgroundThe COVID-19 pandemic has significantly impacted lives and greatly affected the mental health and public safety of an already vulnerable population—college students. Social distancing and isolation measures have presented challenges to students’ mental health. mHealth apps and wearable sensors may help monitor students at risk of COVID-19 and support their mental well-being. ObjectiveThis study aimed to monitor students at risk of COVID-19 by using a wearable sensor and a smartphone-based survey. MethodsWe conducted a prospective study on undergraduate and graduate students at a public university in the Midwest United States. Students were instructed to download the Fitbit, Social Rhythms, and Roadmap 2.0 apps onto their personal smartphone devices (Android or iOS). Subjects consented to provide up to 10 saliva samples during the study period. Surveys were administered through the Roadmap 2.0 app at five timepoints: at baseline, 1 month later, 2 months later, 3 months later, and at study completion. The surveys gathered information regarding demographics, COVID-19 diagnoses and symptoms, and mental health resilience, with the aim of documenting the impact of COVID-19 on the college student population. ResultsThis study enrolled 2158 college students between September 2020 and January 2021. Subjects are currently being followed-up for 1 academic year. Data collection and analysis are currently underway. ConclusionsThis study examined student health and well-being during the COVID-19 pandemic and assessed the feasibility of using a wearable sensor and a survey in a college student population, which may inform the role of our mHealth tools in assessing student health and well-being. Finally, using data derived from a wearable sensor, biospecimen collection, and self-reported COVID-19 diagnosis, our results may provide key data toward the development of a model for the early prediction and detection of COVID-19. Trial RegistrationClinicalTrials.gov NCT04766788; https://clinicaltrials.gov/ct2/show/NCT04766788 International Registered Report Identifier (IRRID)DERR1-10.2196/29561

Abstract Background To report the occurrence of choroidal hypoplasia in the Australian Kelpie breed in Poland, the affected dogs testing positive for the Collie Eye Anomaly NHEJ1 gene mutation. Case presentations Choroidal hypoplasia (CH) was initially diagnosed in a young female Australian Kelpie presented for routine ophthalmological examination prior to breeding. Indirect ophthalmoscopy revealed tigroid fundi bilaterally with areas of abnormally arranged choroidal vasculature temporal to the optic disc. These lesions had the appearance of the choroidal hypoplasia diagnostic for Collie Eye Anomaly, a genetically determined disease seen most commonly in Collie types. The DNA based test for the NHEJ1 gene mutation that is confirmatory for Collie Eye Anomaly proved the dog to be homozygous for this mutation. Twenty one other related dogs were subsequently examined genetically, the dam proving to be affected and eight others were shown to be carriers. Conclusions This report demonstrates that Collie Eye Anomaly is present in a Polish bred Australian Kelpie line and as such breeders in this country and those importing dogs or semen internationally should be aware of other possible cases.

BackgroundHealth care workers (HCWs) have been working on the front lines of the COVID-19 pandemic with high risks of viral exposure, infection, and transmission. Standard COVID-19 testing is insufficient to protect HCWs from these risks and prevent the spread of disease. Continuous monitoring of physiological data with wearable sensors, self-monitoring of symptoms, and asymptomatic COVID-19 testing may aid in the early detection of COVID-19 in HCWs and may help reduce further transmission among HCWs, patients, and families. ObjectiveBy using wearable sensors, smartphone-based symptom logging, and biospecimens, this project aims to assist HCWs in self-monitoring COVID-19. MethodsWe conducted a prospective, longitudinal study of HCWs at a single institution. The study duration was 1 year, wherein participants were instructed on the continuous use of two wearable sensors (Fitbit Charge 3 smartwatch and TempTraq temperature patches) for up to 30 days. Participants consented to provide biospecimens (ie, nasal swabs, saliva swabs, and blood) for up to 1 year from study entry. Using a smartphone app called Roadmap 2.0, participants entered a daily mood score, submitted daily COVID-19 symptoms, and completed demographic and health-related quality of life surveys at study entry and 30 days later. Semistructured qualitative interviews were also conducted at the end of the 30-day period, following completion of daily mood and symptoms reporting as well as continuous wearable sensor use. ResultsA total of 226 HCWs were enrolled between April 28 and December 7, 2020. The last participant completed the 30-day study procedures on January 16, 2021. Data collection will continue through January 2023, and data analyses are ongoing. ConclusionsUsing wearable sensors, smartphone-based symptom logging and survey completion, and biospecimen collections, this study will potentially provide data on the prevalence of COVID-19 infection among HCWs at a single institution. The study will also assess the feasibility of leveraging wearable sensors and self-monitoring of symptoms in an HCW population. Trial RegistrationClinicalTrials.gov NCT04756869; https://clinicaltrials.gov/ct2/show/NCT04756869 International Registered Report Identifier (IRRID)DERR1-10.2196/29562

Abstract Background State health agencies (SHA) and local health agencies (LHA) face several challenges with the dissemination of local health data using Web-Based Data Query Systems (WDQS). To help guide future research, this study aimed to utilize expert consensus to identify the most relevant items that contribute to these challenges. Methods A total of 17 researchers and public health professionals agreed to participate in a three-round Delphi process. In round 1, four topics were represented on a 42-item questionnaire using a 5-point Likert scale, along with free-text responses. Free-text responses were analyzed leading to a series of items for a second Delphi round. Participants were given an opportunity to revise results in round 3 for items that did not meet consensus in round 1 or round 2. Consensus on expert opinions was defined at interquartile range (IQR) ≤ 1. Results The experts reached consensus on a total of 21 (50%) of the 42 items presented in the initial questionnaire. Eleven of the 15 (73%) of the items extracted from the free-text responses met consensus. Items in consensus from this pilot study were used to develop an instrument for a broader survey across Behavioral Risk Factor Surveillance System (BRFSS) coordinators across all 50 US states. Conclusion Experts confirmed that software development costs, inadequate human resources, data sharing gaps, a lack of political support, and poor data quality contribute significantly to challenges in their data implementation. The findings from this pilot study inform us of items of public health significance that will help guide future research.

Based on high energy demand of the primary production and losses during secondary production, alternative recycling of aluminum becomes a popular research topic. Compared to both primary and secondary production of aluminum, solid state recycling offers energy savings and reduced material losses during processing by surpassing an inefficient melting step. In this work, a direct recycling route for machining chips via pulsed electric current sintering (PECS) is evaluated. Therefore, necessary processing steps for a complete recycling route are briefly outlined. After cleansing, EN AW 6082 chips, provided by Neuman Aluminium GmbH, Marktl, Austria, are compacted with variable loads and consolidated via PECS on two separate systems to enable a comparison. Produced specimens are examined with density measurements, optical microscopy and the bonding quality is evaluated by Vickers micro-hardness measurements. In combination with elevated temperature and deformation, applied current promotes consolidation amongst chips and improvements in density, hardness and microstructure are achieved. The results of this work clearly show a positive effect of PECS on the bonding amongst chips, but further research will be necessary to separate and understand influences of single processing parameters. Additionally, all processing steps from collection to consolidation have to be taken into account to achieve industrial implementation.

Although several proteins have been implicated in secretory vesicle tethering, the identity and mechanical properties of the components forming the physical vesicle-plasma membrane link remain unknown. Here we present the first experimental measurements of nanomechanical properties of secretory vesicle-plasma membrane tethers using combined AFM force clamp and TIRF microscopy on membrane sheets from PC12 cells expressing the vesicle marker ANF-eGFP. Application of pulling forces generated tether extensions composed of multiple steps with variable length. The frequency of short (

Although the protective role of social support is well established in the health literature, antecedents of perceived social support are not well understood. Research on family experiential factors during early adolescence, an important psychosocial developmental period in the life course, represents a promising line of inquiry. Using a sample of young adults in Miami-Dade County, Florida (N = 1,267) involving longitudinal data spanning 8 years, we evaluated the importance of early adolescent family experiences (socioeconomic status, family structure, family support, family pride, parent derogation) on perceived family and friend support in young adulthood. Results indicated that early family experiences, especially negative experiences, were associated with lower perceived family and friend support in young adulthood. Moreover, these associations were independent of early childhood-adolescent behavioral disorders (attention deficit hyperactivity disorder, conduct), psychological disorders (major depression, anxiety), substance use disorders, and lifetime social adversity. The importance of family experiences during early adolescence for later perceived social support is discussed. (Contains 3 tables.)

A growing literature suggests that stronger ethnic identity is associated with higher levels of self-esteem among Hispanic Americans. However, most studies employ a panethnic "Hispanic" category or focus on one ethnic group, leaving open the question of how different Hispanic groups compare in this association. In the framework of social identity theory, the author provides ordinary least squares (OLS) estimates of the relationship between ethnic identity and later self-esteem in a sample of Nicaraguan and Cuban young adults in South Florida (N = 291). Results indicate that stronger ethnic identity is salutary for Cubans' self-esteem though detrimental for Nicaraguans'. Additionally, Nicaraguans report significantly weaker ethnic identification and lower self-esteem than do Cubans on average. Also, higher perceived ethnic discrimination is associated with stronger ethnic identity for Cubans. (Contains 3 tables and 5 notes.)