bluuebunny/crossref_metadata_2025 huggingface dataset:
Gastrointestinal bleeding due to jejunal metastasis of pleomorphic lung carcinoma: a case report
Authors: Beji Hazem , Laamiri Ghazi , Chtourou Mohamed F. , Zribi Slim , Sbaihi Siwar , Nechi Salwa , Bouassida Mahdi , Touinsi Hassen
Published: March 2023

Introduction and importance:

Gastrointestinal metastasis of pleomorphic lung cancer presents with nonspecific manifestations, leading to delayed diagnosis. Herein, the authors report the case of a 56-year-old patient who presented with gastrointestinal bleeding due to pleomorphic lung carcinoma.

Case presentation:

A 56-year-old patient presented to the emergency department with melena. On examination, he was hemodynamically stable. He had a sensitive and mobile mass in the periumbilical region. A thoracoabdominal computed tomography scan showed a mass of the right apical superior lobe measuring 4 cm and a lobulated jejunal mass measuring 10 cm. A percutaneous biopsy of the lung tumor revealed primary pleomorphic lung carcinoma. The authors performed a midline laparotomy and made a bowel resection with an end-to-end anastomosis. The postoperative course was marked by severe nosocomial pneumonia, leading to septic shock and death. The histopathologic examination concluded with a metastatic lesion of pleomorphic lung carcinoma.

Clinical discussion:

The authors reported a rare case of jejunal metastasis of pleomorphic lung cancer. Pleomorphic carcinoma of the lung is a rare pathology that accounts for 0.1–0.4% of nonsmall-cell lung cancer. The prognosis is poor. In the presence of gastrointestinal bleeding caused by small bowel metastases of pleomorphic lung cancer, surgery is the treatment of choice.

Conclusions:

Small bowel metastasis of pleomorphic lung cancer is rare. Surgical treatment is the treatment of choice. The authors highlight the importance of suspecting gastrointestinal metastases in patients with pleomorphic lung cancer in the presence of nonspecific digestive symptoms.
Mitral valvar anomalies causing subaortic stenosis: two rare case reports
Authors: Faraj Raid , Dib Hassan , Belhoussine Houda , Sarsari Mohamed , Lahjouji Reda , Bargach Inesse , Zarzur Jamila , Cherti Mohamed
Published: March 2023

Introduction and importance:

Subaortic stenosis (SubAS) is a common cause of left ventricular outflow tract obstruction. It may be focal or diffuse, leading to the development of a subaortic tunnel. Considered for a long time as a congenital anomaly, SubAS has been established lately as an acquired anomaly and secondary to a pre-existing anatomic alteration in the interventricular septum and mitral valve apparatus. It is a progressive disease that is often confused with obstructive hypertrophic cardiomyopathy, which can lead to several complications.

Case presentation:

In this paper, the authors report two cases of SubAS secondary to different mitral valvar anomalies. The analysis of echocardiographic data was a milestone in raising this diagnosis and identifying its mechanisms.

Conclusion:

This work highlights a rare situation, often underdiagnosed, in which the evolution can be marked by an important risk of recurrence even after surgical cure.
Anti-photoaging Effect of Micronized Fat in Ultraviolet B-Induced Human Dermal Fibroblasts
Authors: He Anqi , Zheng Shaoluan , Luan Wenjie , Wang Lu , Qian Leqi , Qi Fazhi , Feng Zihao
Published: March 2023

Background:

Adipose-derived stromal vascular fraction and mesenchymal stem cells have been proven to reduce the effects of skin photoaging. However, there is no standardized protocol for their preparation. This study aimed to investigate the skin rejuvenation potential of micronized fat, obtained using a novel device attached with a trifoliate blade, in the ultraviolet B-induced human dermal fibroblasts model.

Materials and Methods:

Micronized fat was prepared to obtain adipose-derived stromal vascular fraction and the adipose-derived mesenchymal stem cells to stromal vascular fraction ratio was determined by flow cytometry. The ultraviolet B-induced human dermal fibroblasts model was constructed to identify the characteristic of the human dermal fibroblasts using Vamiten and S-100 immunostaining, observe their morphology, and measure the levels of photoaging related factors. After the previous steps were completed, different cell groups were co-cultured with ultraviolet B-induced human dermal fibroblasts and the extent of improvement of photoaging was evaluated.

Results:

Micronized fat had a higher adipose-derived mesenchymal stem cells to stromal vascular fraction ratio than the control fat preparations. The ultraviolet B-induced human dermal fibroblasts model showed lowered levels of type I collagen and transforming growth factor-βand increased expression of matrix metalloproteinases, which are the characteristics of photoaging in normal human dermal fibroblasts. Compared to different cell groups co-cultured with ultraviolet B-induced human dermal fibroblasts, micronized fat could lower the expression of matrix metalloproteinases and increase the level of type I collagen but lower the level of transforming growth factor-β

Conclusions:

Obtaining micronized fat is more effortless and clinically safer. Micronized fat has an anti-photoaging effect by inhibiting the expression of MMPs via MAPK signaling pathway.
Autologous Fat Grafting is not Superior to Placebo as Treatment of Postherpetic Neuralgia A Double-Blinded Randomized Clinical Trial.
Authors: Sollie Martin , Thomsen Jørn B. , Sørensen Jens A.
Published: March 2023

Background:

Postherpetic neuralgia (PHN) is a chronic pain syndrome occurring after a herpes zoster (HZ) outbreak, also known as shingles. Treatment is complex, and no effective treatment exists today. Autologous fat grafting (AFG) has previously shown promise in treating PHN, but no randomised controlled trial has been performed.

This RCT aimed to investigate the effect of autologous fat grafting on postherpetic neuralgia compared to a sham treatment.

Methods:

We included forty-six participants suffering from PHN in our double-blinded, two-armed RCT. Participants were randomly assigned either the intervention group or control group. All participants had liposuction performed under general anaesthesia. The intervention group received AFG to the area of pain, and the control group received a sham treatment of saline injection. The primary outcomes were the average and maximum degree of pain measured on an 11-point numerical rating scale (NRS). Secondary outcomes were quality and degree of neuropathic pain (NPSI) and Quality of Life (SF-36).

Results:

Forty-two participants completed follow-up. In the maximal degree of pain, we observed a reduction of -1.1(0.6) and -1.0(0.5) Δ mean(SE) on the NRS in the intervention and control groups, respectively. In the average degree of pain, the reduction was -1.2(0.5) and -1.3(0.4) in the intervention and control groups. We observed stationary or minor improvements in neuropathic pain, with similar changes in both groups. We observed small reductions in QoL in all parameters and in both groups. The exceptions were pain and social functioning, where the control group reported minor improvements. For all the measured outcomes, the differences between the groups were not statistically significant.

Conclusions:

We did not find autologous fat grafting superior to a placebo when treating postherpetic neuralgia of the skin. Based on our results, we cannot recommend the routine use of this method to treat these pains.
Anatomical proposal for botulinum neurotoxin injection for horizontal forehead lines
Authors: Yi Kyu-Ho , Lee Ji-Hyun , Seo Kyle K. , Kim Hee-Jin
Published: March 2023

The frontalis muscle is situated across the forehead and is a representative target muscle for botulinum neurotoxin injections aimed at treating horizontal wrinkles in this region. However, a lack of anatomical information regarding the shape and thickness of the frontalis may lead to unexpected adverse effects, such as ptosis and samurai eyebrows, due to the lack of detail on anatomical variation. Achieving the maximum effect using the minimal amount of botulinum neurotoxin requires a precise injection into the frontalis muscle. The anatomical factors associated with botulinum neurotoxin injection into the frontalis muscle have been reviewed in the current study. Up-to-date understanding of the localization of the botulinum neurotoxin injection point according to an updated understanding of the anatomy leads to more accurate localization of the injection point into the frontalis muscle. Optimal injection sites have been provided for the frontalis muscle, and the injection method has been recommended. We suggest optimal injection sites according to the external anatomical landmarks of the forehead. Furthermore, these proposals could aid in a more precise procedure that avoids the deleterious effects of botulinum neurotoxin.

Key Contribution: The research proposes a guide for effective botulinum neurotoxin injection for frontalis muscle.
Dorsal Preservation Rhinoplasty in Asian Hump Noses
Authors: Jin Hong Ryul , Kim Yonjae , Jeon Yung Jin
Published: March 2023

Dorsal preservation rhinoplasty, which preserves the bony-cartilaginous junction and the keystone, has been gaining popularity in Western countries for hump nose correction. We aimed to report the feasibility, surgical outcome, and technical considerations of dorsal preservation rhinoplasty in Asian hump nose correction. A retrospective case series study was performed on nine patients who had undergone primary dorsal preservation rhinoplasty for hump nose correction. Rhinoplasty was performed by the senior author (HRJ) from March 2019 to December 2021. Clinical charts, graphic operation records, and standardized photographs of the patients were retrospectively reviewed and analyzed. Surgeries were performed through an open approach in all patients. Either the push-down (n = 3) or let-down technique (n = 6) was used for dorsal preservation. All patients underwent tip modification with or without radix graft together with DPR. Bony step-off camouflage at the transverse osteotomy site was required in three patients. After surgery, both the nasofacial and rhinion angles exhibited significant changes (p = 0.008). In all cases, hump reduction was successful without recurrence or saddle nose, and no major complications occurred. All patients were satisfied with the aesthetic and functional results. Dorsal preservation rhinoplasty seems to be a viable option for correcting Asian hump noses. Technical considerations include a preference for the open approach, camouflage of bony step-off deformity, and strategic management of the septal cartilage considering tip modification.
Impact of COVID-19 on HIV Adolescent Programming in 16 Countries With USAID-Supported PEPFAR Programs
Authors: Okegbe Tishina , Williams Jessica , Plourde Kate F. , Oliver Kelsey , Ddamulira Barbara , Caparrelli Kristina ,   USAID/PEPFAR Adolescent Group
Published: March 2023

Introduction:

The COVID-19 pandemic has disrupted access to critical health services, resulting in diminished gains in HIV epidemic control. This review assesses the magnitude of the impact that the COVID-19 pandemic has had on HIV services for adolescents.

Methods:

PEPFAR Monitoring, Evaluation, and Reporting programmatic data were analyzed from across 16 USAID-supported adolescent care and treatment programs for fiscal year 2020 (FY20; October 2019–September 2020). Descriptive statistics were used to calculate absolute number and percent change between the pre-COVID-19 (Quarters 1–2; October 2019–March 2020) and COVID-19 periods (Quarters 3–4; April 2020–September 2020) for clinical cascade indicators. All analyses were conducted in Microsoft Excel.

Results:

The number of HIV tests conducted during COVID-19 decreased by 21.4% compared with pre-COVID-19, with a subsequent 28% decrease in adolescents identified living with HIV. The rate of proxy linkage to antiretroviral therapy increased between periods, from 86.9% to 90.4%. There was a 25.9% decrease in treatment initiations among adolescents during COVID-19. During FY20, viral load coverage rates for adolescents dropped from 81.6% in FY20Q1 to 76.5% in FY20Q4, whereas the rates of viral load suppression for adolescents increased from 76.1% in FY20Q1 to 80.5% in FY20Q4.

Conclusion:

There was a substantial decrease in case-finding, treatment initiations, and viral load coverage rates for adolescents supported in USAID/PEPFAR programs during the COVID-19 pandemic. Additional health systems adaptations and strategies are required to ensure adolescents have continued access to HIV services during pandemic disruptions.
Standardization of the One-anastomosis Gastric Bypass Procedure for Morbid Obesity: Technical Aspects and Early Outcomes
Authors: Sakran Nasser , Haj Bassel , Pouwels Sjaak , Buchwald Jane N. , Abo Foul Salma , Parmar Chetan , Awad Ali , Arraf Jabra , Omari Abdallah , Hamoud Mohamad
Published: March 2023

Background:

One-anastomosis gastric bypass (OAGB) has become an accepted metabolic/bariatric surgery procedure. This study aimed to describe our center’s standardized OAGB operative technique and report early (≤30 d) safety outcomes in patients with severe obesity.

Methods:

The medical records of patients who had undergone either primary (n=681, 88.0%) or revisional OAGB (n=93, 12.0%) were retrospectively evaluated. Patient demographics, operative time, length of hospital stay, readmissions, reoperations, and ≤30-day morbidity and mortality rates were analyzed.

Results:

A total of 774 consecutive patients with severe obesity (647 female, 83.6%) underwent OAGB between January 2016 and December 2021. Their mean age was 36.2±10.8 years (range: 18 to 70 y) and mean body mass index was 42.7±4.2 kg/m2 (range: 17.2 to 61 kg/m2). Mean operating time was 52.6±19.9 minutes (range: 25 to 295 min) and length of hospital stay was 1.6±0.9 days (range: 1 to 9 d). Early postoperative complications occurred in 16 cases (2.1%), including 2 leaks with an intra-abdominal abscess (0.3%), bleeding (n=3, 0.4%), acute kidney failure (n=1, 0.15%), urinary tract infection (n=2, 0.3%), and intensive care unit stay (n=4, 0.5%). Seventy patients (9.1%) were readmitted, and re-laparoscopy was performed in 1 patient (0.1%). There was no mortality.

Conclusions:

In the very early term, OAGB was a safe primary and revisional metabolic/bariatric surgery operation. Consistent performance of a standardized OAGB procedure contributed to low rates of morbidity and mortality in the hands of metabolic/bariatric surgeons with good laparoscopic skills at a high-volume center.
A Novel Robotic Approach for the Repair of Abdominal Wall Hernias With Concomitant Diastasis Recti: Outcomes and Long-term Follow-up
Authors: Aitken Gabriela , Gallego Eckstein Jeremy
Published: March 2023

Background:

Diastasis recti (DR) is defined as the separation of the rectus muscles as a result of the linea alba thinning and stretching. The purpose of this study was to evaluate the long-term outcomes of a new technique, robotic rectus abdominis medialization (rRAM), for DR repair with a concomitant ventral hernia.

Methods:

Patients who underwent rRAM for repair of DR and a concomitant ventral hernia were identified between January 2015 and December 2020. The results are from a single surgeon at a single institution.

Results:

A total of 40 patients were identified, 29 of which were female. The mean age was 43 years, the mean body mass index was 27 kg/m2, and the mean inter-rectus distance was 6 cm based on available preoperative imaging. The median postoperative length of stay was 1 day, and the median follow-up time was 1 month. Within 30 postoperative days, 3 patients were re-admitted and 5 developed complications, of which 1 required operative re-intervention for seroma. Beyond 30 days, 3 patients required operative re-intervention most commonly for persistent pain from suture material. On the basis of computed tomography scans performed at a mean of 30 months after the date of service, the mean postoperative inter-rectus distance was 1 cm; 1 patient had DR recurrence, and 1 patient developed a new incisional hernia without DR recurrence. There was no hernia recurrence.

Conclusions:

rRAM is a safe and effective technique for DR repair with a concomitant ventral hernia. Further studies are needed to determine how outcomes from this robotic approach compare with those from different robotic, laparoscopic, and open techniques.
The Impact of Episodes of Lucidity on People Living With Dementia and Their Caregivers
Authors: Benson Clark , Fehland Jess , Botsch Meghan , Block Laura , Gilmore-Bykovskyi Andrea
Published: March 2023

People living with dementia (PLWD) may experience the episodes of lucidity (ELs), defined as a sudden return of abilities presumed to have been lost and presenting as meaningful communication and connection. Early research on ELs in advanced disease stages suggests these are predominantly positive events. This case report draws from 1 outlier case from a descriptive qualitative study on caregivers of PLWDs’ experiences with ELs. The caregiver-reported events perceived as an EL being accompanied with unexpected self-awareness, leading to a negative emotional reaction and feelings of loss. This case report contributes insights to the current understandings of ELs as exclusively relevant in advanced stages of dementia, as similar events may present in earlier disease stages, and may be associated with the negative emotional experiences among PLWD. Future research is needed to consider the ethical implications surrounding ELs and to support the caregivers in anticipating and responding to ELs.
Frog hatchlings use early environmental cues to produce an anticipatory resource-use phenotype
Authors: Harmon Emily A. , Evans Boyce , Pfennig David W.
Published: March 2023

Developmental plasticity can occur at any life stage, but plasticity that acts early in development may give individuals a competitive edge later in life. Here, we asked if early (pre-feeding) exposure to a nutrient-rich resource impacts hatchling morphology in Mexican spadefoot toad tadpoles,
Spea multiplicata
. A distinctive carnivore morph can be induced when tadpoles eat live fairy shrimp. We investigated whether cues from shrimp––detected before individuals are capable of feeding––alter hatchling morphology such that individuals could potentially take advantage of this nutritious resource once they begin feeding. We found that hatchlings with early developmental exposure to shrimp were larger and had larger jaw muscles––traits that, at later stages, increase a tadpole's competitive ability for shrimp. These results suggest that early developmental stages can assess and respond to environmental cues by producing resource-use phenotypes appropriate for future conditions. Such anticipatory plasticity may be an important but understudied form of developmental plasticity.
Reinforced diffusions as models of memory-mediated animal movement
Authors: Fagan William F. , McBride Frank , Koralov Leonid
Published: March 2023

How memory shapes animals' movement paths is a topic of growing interest in ecology, with connections to planning for conservation and climate change. Empirical studies suggest that memory has both temporal and spatial components, and can include both attractive and aversive elements. Here, we introduce reinforced diffusions (the continuous time counterpart of reinforced random walks) as a modelling framework for understanding the role that memory plays in determining animal movements. This framework includes reinforcement via functions of time before present and of distance away from a current location. Focusing on the interplay between memory and central place attraction (a component of home ranging behaviour), we explore patterns of space usage that result from the reinforced diffusion. Our efforts identify three qualitatively different behaviours: bounded wandering behaviour that does not collapse spatially, collapse to a very small area, and, most intriguingly, convergence to a cycle. Subsequent applications show how reinforced diffusion can create movement trajectories emulating the learning of movement routes by homing pigeons and consolidation of ant travel paths. The mathematically explicit manner with which assumptions about the structure of memory can be stated and subsequently explored provides linkages to biological concepts like an animal's ‘immediate surroundings' and memory decay.
Mechanisms of gill-clogging by hagfish slime
Authors: Taylor Luke , Chaudhary Gaurav , Jain Gaurav , Lowe Andrew , Hupe Andre , Negishi Atsuko , Zeng Yu , Ewoldt Randy H. , Fudge Douglas S.
Published: March 2023

Hagfishes defend themselves from gill-breathing predators by producing large volumes of fibrous slime when attacked. The slime's effectiveness comes from its ability to clog predators' gills, but the mechanisms by which hagfish slime clogs are uncertain, especially given its remarkably dilute concentration of solids. We quantified the clogging performance of hagfish slime over a range of concentrations, measured the contributions of its mucous and thread components, and measured the effect of turbulent mixing on clogging. To assess the porous structure of hagfish slime, we used a custom device to measure its Darcy permeability. We show that hagfish slime clogs at extremely dilute concentrations like those found in native hagfish slime and displays clogging performance that is superior to three thickening agents. We report an extremely low Darcy permeability for hagfish slime, and an effective pore size of 10–300 nm. We also show that the mucous and thread components play distinct yet crucial roles, with mucus being responsible for effective clogging and low permeability and the threads imparting mechanical strength and retaining clogging function over time. Our results provide new insights into the mechanisms by which hagfish slime clogs gills and may inspire the development of ultra-soft materials with novel properties.
An environmental DNA metabarcoding survey reveals generic-level occurrence of scleractinian corals at reef slopes of Okinawa Island
Authors: Nishitsuji Koki , Nagata Tomofumi , Narisoko Haruhi , Kanai Megumi , Hisata Kanako , Shinzato Chuya , Satoh Noriyuki
Published: March 2023

Coral reefs have the highest biodiversity of all marine ecosystems in tropical and subtropical oceans. However, scleractinian corals, keystone organisms of reef productivity, are facing a crisis due to climate change and anthropogenic activities. A broad survey of reef-building corals is essential for worldwide reef preservation. To this end, direct observations made by coral-specialist divers might be supported by another robust method. We improved a recently devised environmental DNA (eDNA) metabarcoding method to identify more than 43 scleractinian genera by sampling 2 l of surface seawater above reefs. Together with direct observations by divers, we assessed the utility of eDNA at 63 locations spanning approximately 250 km near Okinawa Island. Slopes of these islands are populated by diverse coral genera, whereas shallow ‘moats’ sustain fewer and less varied coral taxa. Major genera recorded by divers included
Acropora
,
Pocillopora
,
Porites
and
Montipora,
the presence of which was confirmed by eDNA analyses. In addition, eDNA identified more genera than direct observations and documented the presence of previously unrecorded species. This scleractinian coral-specific eDNA method promises to be a powerful tool to survey coral reefs broadly, deeply and robustly.
Death is overrated: the potential role of detection in driving virulence evolution
Authors: Kennedy David A.
Published: March 2023

A common assumption in the evolution of virulence theory literature is that pathogens transmit better when they exploit their host more heavily, but by doing so, they impose a greater risk of killing their host, thus truncating infectious periods and reducing their own opportunities for transmission. Here, I derive an equation for the magnitude of this cost in terms of the infection fatality rate, and in doing so, I show that there are many cases where mortality costs are too small to plausibly constrain increases in host exploitation by pathogens. I propose that pathogen evolution may often be constrained by detection costs, whereby hosts alter their behaviour when infection is detectable, and thus reduce pathogen opportunities for onward transmission. I then derive an inequality to illustrate when mortality costs or detection costs impose stronger constraints on pathogen evolution, and I use empirical data from the literature to demonstrate that detection costs are frequently large in both human and animal populations. Finally, I give examples of how evolutionary predictions can change depending on whether costs of host exploitation are borne out through mortality or detection.
When origin, reproduction ability and diet define the role of birds in invasions
Authors: Marino Clara , Bellard Céline
Published: March 2023

The ecological impacts of invasive alien species (IAS) are increasingly documented; however, they are usually studied through the lens of either the IAS or the affected species (IAS-threatened species). A clear understanding of how both protagonists of biological invasions are characterized is still lacking. We investigated the morphology, life history and ecology of birds involved in biological invasions. Evaluating the distribution of 450 IAS-threatened birds and 400 alien birds in a functional space, we found that both groups retained various strategies. Aliens had larger clutches and were more likely to be herbivores than IAS-threatened and worldwide birds, while IAS-threatened birds were more insular endemic from the Australia region than alien and worldwide birds. IAS-threatened species showed opposite strategies to aliens regarding traits related to diet, origin and reproduction. Further comparing traits associated with impact magnitude, we found that even if aliens were mostly herbivorous, those with high impact had more a generalist behaviour and an animal-based diet compared to aliens with low impact. By emphasizing differences relating to the distribution of bird groups in a functional space, we opened new opportunities to identify the role of birds in biological invasions.
Sperm competition increases sperm production and quality inCataglyphisdesert ants
Authors: Degueldre Félicien , Aron Serge
Published: March 2023

Sperm competition is a pervasive evolutionary force that shapes sperm traits to maximize fertilization success. Indeed, it has been shown to increase sperm production in both vertebrates and invertebrates. However, sperm production is energetically costly, which may result in trade-offs among sperm traits. In eusocial hymenopterans, such as ants, mating dynamics impose unique selective pressures on ejaculate. Males are sperm limited: they enter adulthood with a fixed amount of sperm that will not be renewed. We explored whether sperm competition intensity was associated with sperm quantity and quality (i.e. sperm viability and DNA fragmentation) in nineCataglyphisdesert ants. Our results provide phylogenetically robust evidence that sperm competition is positively correlated with sperm production and sperm viability. However, it was unrelated to sperm DNA integrity, indicating the absence of a trade-off involving this trait. These findings underscore that sperm competition may strongly mould sperm traits and drive reproductive performance in eusocial Hymenoptera.
Computational Phenotypes for Patients with Opioid-Related Disorders Presenting to the Emergency Department
Authors: Taylor Richard Andrew , Gilson Aidan , Schulz Wade , Lopez Kevin , Young Patrick , Pandya Sameer , Coppi Andreas , Chartash David , Fiellin David , D’Onofria Gail
Published: March 2023

Objective

We aimed to discover computationally-derived phenotypes of opioid-related patient presentations to the emergency department (ED) via clinical notes and structured electronic health record (EHR) data.

Methods

This was a retrospective study of ED visits from 2013-2020 across ten sites within a regional healthcare network. We derived phenotypes from visits for patients 18 years of age with at least one prior or current documentation of an opioid-related diagnosis. Natural language processing was used to extract clinical entities from notes, which were combined with structured data within the EHR to create a set of features. We performed Latent Dirichlet allocation to identify topics within these features. Groups of patient presentations with similar attributes were identified by cluster analysis.

Results

In total 82,577 ED visits met inclusion criteria. The 30 topics discovered ranged from those related to substance use disorder, chronic conditions, mental health, and medical management. Clustering on these topics identified nine unique cohorts with one-year survivals ranging from 84.2-96.8%, rates of one-year ED returns from 9-34%, rates of one-year opioid event 10-17%, rates of medications for opioid use disorder from 17-43%, and a median Carlson comorbidity index of 2-8. Two cohorts of phenotypes were identified related to chronic substance use disorder, or acute overdose.

Conclusions

Our results indicate distinct phenotypic clusters with varying patient-oriented outcomes which provide future targets better allocation of resources and therapeutics. This highlights the heterogeneity of the overall population, and the need to develop targeted interventions for each population.
Spatial neglect therapy with the augmented reality app 'Negami' for active exploration training; A randomized controlled trial
Authors: Stammler Britta , Flammer Kathrin , Schuster Thomas , Lambert Marian , Neumann Oliver , Lux Michael , Matuz Tamara , Karnath Hans-Otto
Published: March 2023

Background: A widely applied and effective rehabilitation method in stroke patients suffering from spatial neglect is the 'visual exploration training'. Patients improve their ipsilesional bias of attention and orientation by training of exploration movements and search strategies towards the contralesional side of space. Here we investigate the effectiveness of the augmented reality (AR)-based app 'Negami' for the treatment of spatial neglect in a randomized control trial. Negami combines a visual exploration training with active, contralesionally oriented rotation of eyes, head, and trunk. Methods: Twenty patients with spatial neglect were randomly assigned to the experimental Negami group or to a group receiving standard neglect therapy. Over a period of two weeks, both groups received five training sessions per week. Each session lasted about 25 minutes. Neglect behavior was assessed weekly over a five-week period, with the Negami therapy group receiving a second follow-up assessment at one-to-two-month intervals after completion of training. Results: Both groups improved significantly. While the Negami therapy group improved in four of five neglect tests used, the standard therapy group improved in only one of these tests. We observed significantly better improvement in the Negami group already after the first week of training. This difference was also significant after the end of the training as well as one week after the end of training and remained stable one to two months after the end of treatment. Conclusion: Negami can be used as an effective alternative or addition to current standard neglect therapy, and may even be superior to it.
The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young
Authors: Puckelwartz Megan J. , Pesce Lorenzo L. , Hernandez Edgar J. , Webster Gregory , Dellefave-Castillo Lisa M. , Russell Mark W. , Geisler Sarah S. , Kearns Samuel D. , Etheridge Felix K , Etheridge Susan P. , Monroe Tanner O. , Pottinger Tess D. , Kannankeril Prince J. , Shoemaker M. Benjamin , Fountain Darlene , Roden Dan M. , MacLeod Heather , Burns Kristin M. , Yandell Mark , Tristani-Firouzi Martin , George Alfred L. , McNally Elizabeth M.
Published: March 2023

Background

Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing.

Methods

The SDY Case Registry is a National Institutes of Health/Centers for Disease Control surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases <20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015-2019. The cohort included 211 children (mean age 1 year; range 0-20 years), determined to have died suddenly and unexpectedly and in whom DNA biospecimens and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex-and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, genetic variation predicted to be damaging was identified using a Bayesian-based artificial intelligence (AI) tool.

Results

The SDY cohort was 42% European, 30% African, 17% Hispanic, and 11% with mixed ancestries, and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, damaging variants in epilepsy, cardiomyopathy and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death.

Conclusions

While damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort, and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.
Kidney Failure Prediction: Multicenter External Validation of KFRE Model in Patients with CKD Stages 3-4 in Peru
Authors: Bravo-Zúñiga J , Chávez-Gómez R , Soto-Becerra P
Published: March 2023

Background

To externally validate the 4-variable Kidney Failure Risk Equation (KFRE) in the Peruvian population for predicting kidney failure at 2 and 5 years.

Methods

We included patients from 17 primary care centers from the Health’s Social Security of Peru. Patients older than 18 years, diagnosed with chronic kidney disease (CKD) stage 3a-3b-4 and 3b-4, between January 2013 and December 2017. Patients were followed until they developed kidney failure, died, were lost, or ended the study (December 31, 2019), whichever came first. Performance of the KFRE model was assessed based on discrimination and calibration measures considering the competing risk of death.

Results

We included 7519 patients in stages 3a-4 and 2,798 patients in stages 3b-4. KFRE discrimination at 2 and 5 years was high, with Time-Dependent Area Under the Curve (AUC-td) and C-index > 0.8 for all populations. Regarding calibration in-the-large, the Observed-to-Expected (O/E) ratio and the calibration intercept indicated that KFRE underestimates the overall risk at two years and overestimates it at 5-years in all populations.

Conclusions

The 4-variable KFRE models have good discrimination but poor calibration in the Peruvian population. The model underestimates the risk of kidney failure in the short term and overestimates it in the long term.

SIGNIFICANCE STATEMENT

The Kidney Failure Risk Equation (KFRE) is a widely used prediction model for kidney failure risk assessment in patients with chronic kidney disease (CKD). However, its performance in Latin American populations remains unclear, particularly in primary care settings. This study externally validated the KFRE in Peruvian CKD patients, demonstrating high discrimination but revealing miscalibration that could lead to adverse patient outcomes resulting from over- or under-estimation of risk. These results underscore the need for model updating and further research to optimize the KFRE’s use in clinical practice in Latin America, provide valuable insights for applying the KFRE in Latin American settings, and highlight the importance of continuous evaluation and refinement of prediction models in diverse populations.
Safety and Feasibility of a “Fast-Track” Monitoring Protocol for Patients Treated with Intravenous Thrombolytic Therapy
Authors: Fukuda Keiko A , Shah Kavit , Kenmuir Cynthia , Barnagian Derrick , Nawash Baraa , Nelson Mackenzie , Desai Shashvat , Rocha Marcelo , Starr Matthew , Roach Eileen , Henry Stephanie , Molyneaux Bradley J , Jadhav Ashutosh P
Published: March 2023

Introduction

Our health care systems continue to face significant strain due to chronically taxed intensive care resources. A subgroup of post-thrombolytic stroke patients may not require prolonged intensive monitoring, alleviating some burden. Here we describe the safety, feasibility, and utility of a Fast-Track Protocol (FTP) for early de-escalation of high-acuity monitoring.

Methods

We compared a prospective cohort of FTP patients at our stroke centers from April 2020 – February 2022 to a similar retrospective cohort. Those on presentation with NIHSS < 10 and without large vessel occlusion or flow-limiting stenosis, intravenous anti-hypertensive use, and any hemodynamic or respiratory concerns were eligible. Primary outcomes included early neurologic deterioration, defined as worsening of NIHSS ≥ 4-points at 24 hours, parenchymal hemorrhage, and symptomatic intracranial hemorrhage.

Results

Of 574 thrombolysis patients, 119 (21%) were eligible for FTP. One hundred (88%) were included for analysis. The median ± IQR hospitalization was 2.0 ± 1.6 days. None of the four patients with early neurologic deterioration were due to hemorrhage. No symptomatic intracranial hemorrhages occurred, and no FTP patients were transferred back to the ICU. Median ± IQR 90-day modified Rankin scale was 1 ± 1.

Discussion

FTP is a safe and feasible strategy to triage ICU patients and decrease unnecessary ICU monitoring. This is important in a post-pandemic era as ICU resources continue to fluctuate. Future studies are needed to establish the optimal level of monitoring in post thrombolytic patients.
Axial segmentation by iterative mechanical signaling
Authors: Wopat Susan , Adhyapok Priyom , Daga Bijoy , Crawford Janice M. , Peskin Brianna , Norman James , Bagwell Jennifer , Fogerson Stephanie M. , Di Talia Stefano , Kiehart Daniel P. , Charbonneau Patrick , Bagnat Michel
Published: March 2023

In bony fishes, formation of the vertebral column, or spine, is guided by a metameric blueprint established in the epithelial sheath of the notochord. Generation of the notochord template begins days after somitogenesis and even occurs in the absence of somite segmentation. However, patterning defects in the somites lead to imprecise notochord segmentation, suggesting these processes are linked. Here, we reveal that spatial coordination between the notochord and the axial musculature is necessary to ensure segmentation of the zebrafish spine both in time and space. We find that the connective tissues that anchor the axial skeletal musculature, known as the myosepta in zebrafish, transmit spatial patterning cues necessary to initiate notochord segment formation, a critical pre-patterning step in spine morphogenesis. When an irregular pattern of muscle segments and myosepta interact with the notochord sheath, segments form non-sequentially, initiate at atypical locations, and eventually display altered morphology later in development. We determine that locations of myoseptum-notochord connections are hubs for mechanical signal transmission, which are characterized by localized sites of deformation of the extracellular matrix (ECM) layer encasing the notochord. The notochord sheath responds to the external mechanical changes by locally augmenting focal adhesion machinery to define the initiation site for segmentation. Using a coarse-grained mathematical model that captures the spatial patterns of myoseptum-notochord interactions, we find that a fixed-length scale of external cues is critical for driving sequential segment patterning in the notochord. Together, this work identifies a robust segmentation mechanism that hinges upon mechanical coupling of adjacent tissues to control patterning dynamics.
De novoassembly of the black flounder genome. Why do pleuronectiformes have such a small genome size?
Authors: Villarreal Fernando , Burguener Germán F. , Sosa Ezequiel J. , Stocchi Nicolas , Somoza Gustavo M. , Turjanski Adrián , Blanco Andrés , Viñas Jordi , Mechaly Alejandro S.
Published: March 2023

Black flounder (Paralichthys orbignyanus) is an economically important ma-rine fish with aquaculture potential in Argentina due to its market value. In this study, we sequenced the whole genome using an Illumina sequencing technology. We started with two independent libraries (from one female and one pool of females; each with 150 bp paired-end reads, a mean insert length of 350 bp, and >35 X-fold coverage). Each library was assembled separately using SOAPdenovo2 and the resulting contigs were scaffolded with SSPACE3 before gaps were filled with GapCloser. In vertebrates, including teleosts, the number of transposable elements (TEs) is related to genome size, but it remains unclear whether the size of introns and exons also plays a role. Therefore, the main objective of the present study was to test whether the small genome size of Pleuronectiformes is related to the size of their introns and exons. The assemblies re-sulted in a genome size of ∼538 Mbp (41.35% GC content, 0.11% undetermined bases). Analysis of the assemblies at the core genes level (subset of the 458 universally ex-pressed KOG families) revealed that more than 98% of core genes are present, with more than 78% of them having more than 50% coverage. This indicates a fairly complete and accurate genome at the coding sequence level. Prediction of genes based on statistical predictors (geneid) and sequence-based predictors (Exonerate, using a closely related species,Paralichthys olivaceus, as a reference) was performed. This revealed 25,231 protein-coding genes, 445 tRNAs, 3 rRNAs, and more than 1,500 non-coding RNAs of other types (including a complete set of spliceosomes and several types of snoRNA and miRNA). As a result, this study concluded that the reduced genome size of flounders is related to a reduction in transcript size, mainly through a reduction in exon number, but also through a reduction in large introns. Thus, both components seem to be involved in the strategy of genome reduction in Pleuronectiformes.
Massively Parallel Profiling of RNA-targeting CRISPR-Cas13d
Authors: Kuo Hung-Che , Prupes Joshua , Chou Chia-Wei , Finkelstein Ilya J.
Published: March 2023

Type VI CRISPR enzymes cleave target RNAs and are widely used for gene regulation, RNA tracking, and diagnostics. However, a systematic understanding of their RNA binding specificity and cleavage activation is lacking. Here, we describeRNAchip-hybridizedassociation-mappingplatform (RNA-CHAMP), a massively parallel platform that repurposes next-generation DNA sequencing chips to measure the binding affinity for over 10,000 RNA targets containing structural perturbations, mismatches, insertions, and deletions relative to the CRISPR RNA (crRNA). Deep profiling of Cas13d, a compact and widely used RNA nuclease, reveals that it does not require a protospacer flanking sequence (PFS) but is exquisitely sensitive to secondary structure within the target RNA. Cas13d binding is strongly penalized by mismatches, insertions, and deletions in the distal crRNA-target RNA regions, while alterations in the proximal region inhibit nuclease activity without affecting binding. A biophysical model built from these data reveals that target recognition begins at the distal end of unstructured target RNAs and proceeds to the proximal end. Using this model, we designed a series of partially mismatched guide RNAs that modulate nuclease activity to detect single nucleotide polymorphisms (SNPs) in circulating SARS-CoV-2 variants. This work describes the key determinants of RNA targeting by a type VI CRISPR enzyme to improve CRISPR diagnostics andin vivoRNA editing. More broadly, RNA-CHAMP provides a quantitative platform for systematically measuring protein-RNA interactions.
Principles and best practices of optimizing a micromirror-based multicolor TIRF microscopy system
Authors: McCluskey Kaley , Dekker Nynke H.
Published: March 2023

TIRF (Total Internal Reflection Fluorescence) microscopy is a powerful tool for measuring the intra- and intermolecular dynamics of fluorescently-labeled single molecules. As TIRF measurements move to more complex biological systems with more fluorescent probes, the multi-band-pass dichroic that separates excitation from emission becomes limiting for the microscope’s detection efficiency. To avoid this, multicolor colocalization-based experiments can employ “micromirror” (mm)TIRF, which replaces the dichroic with two 45°-angled rod mirrors that control the TIR excitation beam(s). Whereas a dichroic spectrally separates excitation and emission wavelengths, the micromirrors act to spatially separate the excitation beams from the collected emission photons within the objective lens itself. Comprehensive control of the TIR beam in mmTIRF can yield excellent signal to noise, and hence data quality, but at the price of increased optical complexity. Here, we introduce the theory behind these additional optical components and provide practical advice from our experience on the best way to set up, align, optimize, and maintain a mmTIRF instrument. We also demonstrate the practical effects of small misalignments to illustrate both the optimized signal quality and the degree of accuracy required to achieve it. We hope that this guide increases the accessibility of this type of instrumentation and helps researchers use it to produce data of the highest quality possible.
Selective S1PR1 activation improves brain infarction, neurological outcome, and cerebrovascular endothelial health following experimental ischemic injury
Authors: Shi Samuel X. , Li Yu-Jing , Wendt Trevor S. , Shi Kaibin , Jin Weina , Liu Qiang , Gonzales Rayna J.
Published: March 2023

Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in endothelial cells and receptor activation plays an important role in mediating endothelial function and health, thus showing promise as a pharmacologic target for acute ischemic stroke (AIS) treatment. Here, we examined the effect of a selective S1PR1 ligand, RP101075, on infarct volume and neurological outcome in adult male mice subjected to transient middle cerebral artery occlusion (tMCAO). Concomitantly, we examined S1PR1 expression profile in the ischemic mouse brain, as well as S1PR1 expression and impact of receptor activation on human brain microvascular endothelial cell (HBMEC) proliferation and survival following hypoxia plus glucose deprivation (HGD). We observed that RP101075 administration at onset of reperfusion reduced infarct volume and lessened neurological deficits in tMCAO mice and these responses were S1PR1 dependent. Additionally, we observed that tMCAO increased brain S1PR1 protein levels and flow cytometry revealed increases in S1PR1 levels are greatest in brain endothelial cells compared to other brain cell types (astrocyte, neuron, microglia). In cultured HBMECs, RP101075 increased cell proliferation and ozanimod, parent compound of RP1010175, increased live cell count during HGD; this response was S1PR1 dependent. In conclusion, S1PR1 activation improves neuroprotection/outcome post-stroke and preserves brain endothelial cell survival following ischemia-like injury.