bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying individuals with intellectual disability who access mental health support and are at high risk for adverse clinical outcomes: cohort study
Authors: Baksh R. Asaad , Sheehan Rory , Hassiotis Angela , Smith James , Strydom Andre 
Published: October 2023

Background
People with intellectual disability often experience aggressive challenging behaviour and mental health issues. It can be difficult to identify those who are at higher risk of adverse clinical outcomes when in clinical care.

Aims
To characterise potential subgroups in adults with intellectual disability referred to mental health services in those presenting with aggressive behaviour or common mental disorders (CMDs).

Method
There were 836 adults (≥18 years) with intellectual disability and a record of aggressive challenging behaviour, and 205 patients with intellectual disability and CMDs, who were seen in specialist mental health services over a 5-year period. Cluster analysis was used to define patient characteristics associated with clinical outcome.

Results
Distinct patient groups with differentiated profiles were observed in people with intellectual disability displaying aggressive challenging behaviour, and in those presenting with CMDs. Characteristics of the aggressive behaviour group who experienced adverse outcomes included being <30 years old, being male, more mentions of aggression and agitation in their clinical record, a diagnosis of pervasive developmental disorder and prescription of psychotropic medication. Characteristics of the CMD cluster that experienced adverse clinical outcomes were being older, being a White male, having a mild intellectual disability and physical health concerns.

Conclusions
People with intellectual disability who experience adverse clinical outcomes can be identified with a cluster analysis approach of common features, but differ by clinical presentation. This could be used not only to stratify this clinically heterogeneous population in terms of response to interventions, but also improve precision in the development of tailored interventions.
A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer
Authors: Zeng Jianhao , Singh Shambhavi , Zhou Xian , Jiang Ying , Casarez Eli , Atkins Kristen A. , Janes Kevin A. , Zong Hui 
Published: October 2023

ABSTRACT
Basal-like breast cancer (BLBC) is highly aggressive, and often characterized by BRCA1 and p53 deficiency. Although conventional mouse models enabled the investigation of BLBC at malignant stages, its initiation and pre-malignant progression remain understudied. Here, we leveraged a mouse genetic system known as mosaic analysis with double markers (MADM) to study BLBC initiation by generating rare GFP+Brca1, p53-deficient mammary cells alongside RFP+ wild-type sibling cells. After confirming the close resemblance of mammary tumors arising in this model to human BLBC at both transcriptomic and genomic levels, we focused our studies on the pre-malignant progression of BLBC. Initiated GFP+ mutant cells showed a stepwise pre-malignant progression trajectory from focal expansion to hyper-alveolarization and then to micro-invasion. Furthermore, despite morphological similarities to alveoli, hyper-alveolarized structures actually originate from ductal cells based on twin-spot analysis of GFP-RFP sibling cells. Finally, luminal-to-basal transition occurred exclusively in cells that have progressed to micro-invasive lesions. Our MADM model provides excellent spatiotemporal resolution to illuminate the pre-malignant progression of BLBC, and should enable future studies on early detection and prevention for this cancer.
High latitude northern bats (Eptesicus nilssonii) reveal adaptations to both high and low ambient temperatures
Authors: Sørås Rune , Fjelldal Mari Aas , Bech Claus , van der Kooij Jeroen , Eldegard Katrine , Stawski Clare 
Published: October 2023

ABSTRACT
Insectivorous bats at northern latitudes need to cope with long periods of no food for large parts of the year. Hence, bats which are resident at northern latitudes throughout the year will need to undergo a long hibernation season and a short reproductive season where foraging time is limited by extended daylight periods. Eptesicus nilssonii is the northernmost occurring bat species worldwide and hibernates locally when ambient temperatures (Ta) limit prey availability. Therefore, we investigated the energy spent maintaining normothermy at different Ta, as well as how much bats limit energy expenditure while in torpor. We found that, despite being exposed to Ta as low as 1.1°C, bats did not increase torpid metabolic rate, thus indicating that E. nilssonii can survive and hibernate at low ambient temperatures. Furthermore, we found a lower critical temperature (Tlc) of 27.8°C, which is lower than in most other vespertilionid bats, and we found no indication of any metabolic response to Ta up to 37.1°C. Interestingly, carbon dioxide production increased with increasing Ta above the Tlc, presumably caused by a release of retained CO2 in bats that remained in torpor for longer and aroused at Ta above the Tlc. Our results indicate that E. nilssonii can thermoconform at near-freezing Ta, and hence maintain longer torpor bouts with limited energy expenditure, yet also cope with high Ta when sun exposed in roosts during long summer days. These physiological traits are likely to enable the species to cope with ongoing and predicted climate change.
LONG-TERM OUTCOMES OF A RANDOMIZED CONTROLLED TRIAL COMPARING FIBULAR NAIL FIXATION WITH OPEN REDUCTION INTERNAL FIXATION IN PATIENTS WITH UNSTABLE ANKLE FRACTURES
Authors: Heinz N.R. , Bugler K.E. , Clement N.D. , Low X. , Duckworth A.D. , White T.O. 
Published: October 2023

To compare the long-term outcomes of fibular nailing and plate fixation for unstable ankle fractures in a cohort of patients under the age of 65 years.Patients from a previously conducted randomized control trial comparing fibular nailing and plate fixation were contacted at a minimum of 10 years post intervention at a single study centre. Short term data were collected prospectively and long-term data were collected retrospectively using an electronic patient record software.Ninety-nine patients from one trauma centre were included (48 fibular nails and 51 plate fixations). Groups were matched for gender (p = 0.579), age (p = 0.811), body mass index (BMI)(p = 0.925), smoking status (p = 0.209), alcohol status (p = 0.679) and injury type (p = 0.674). Radiographically at an average of 2 years post-injury, there was no statistically significant difference between groups for development of osteoarthritis (p = 0.851). Both groups had 1 tibio-talar fusion (2% of both groups) secondary to osteoarthritis with no statistically significant difference in overall re-operation rate between groups identified (p = 0.518,). Forty-five percent (n=42) of patients had so far returned patient reported outcome measures at a minimum of 10 years (Fibular nail n=19, plate fixation n=23). No significant difference was found between groups at 10 years for the Olerud and Molander Ankle Score (p = 0.990), the Manchester-Oxford Foot Questionnaire (p = 0.288), Euroqol-5D Index (p = 0.828) and Euroqol-5D Visual Analogue Score (p = 0.769).The current study illustrates no difference between fibular nail fixation and plate fixation at a long-term follow up of 10 years in patients under 65 years old, although the study is currently under powered.
RELIABILITY AND VALIDITY OF COMPUTER VISION SOFTWARE TO MONITOR JOINT MOVEMENT FOR POSTOPERATIVE PHYSIOTHERAPY
Authors: Verma S. , Malaviya S. , Barker S. 
Published: October 2023

Technological advancements in orthopaedic surgery have mainly focused on increasing precision during the operation however, there have been few developments in post-operative physiotherapy. We have developed a computer vision program using machine learning that can virtually measure the range of movement of a joint to track progress after surgery. This data can be used by physiotherapists to change patients’ exercise regimes with more objectively and help patients visualise the progress that they have made. In this study, we tested our program's reliability and validity to find a benchmark for future use on patients.We compared 150 shoulder joint angles, measured using a goniometer, and those calculated by our program called ArmTracking in a group of 10 participants (5 males and 5 females). Reliability was tested using adjusted R squared and validity was tested using 95% limits of agreement. Our clinically acceptable limit of agreement was ± 10° for ArmTracking to be used interchangeably with goniometry.ArmTracking showed excellent overall reliability of 97.1% when all shoulder movements were combined but there were lower scores for some movements like shoulder extension at 75.8%. There was moderate validity shown when all shoulder movements were combined at 9.6° overestimation and 18.3° underestimation.Computer vision programs have a great potential to be used in telerehabilitation to collect useful information as patients carry out prescribed exercises at home. However, they need to be trained well for precise joint detections to reduce the range of errors in readings.
Increased local bone turnover in patients with chronic periprosthetic joint infection
Authors: Hinz Nico , Butscheidt Sebastian , Jandl Nico M. , Rohde Holger , Keller Johannes , Beil Frank T. , Hubert Jan , Rolvien Tim 
Published: October 2023

AimsThe management of periprosthetic joint infection (PJI) remains a major challenge in orthopaedic surgery. In this study, we aimed to characterize the local bone microstructure and metabolism in a clinical cohort of patients with chronic PJI.MethodsPeriprosthetic femoral trabecular bone specimens were obtained from patients suffering from chronic PJI of the hip and knee (n = 20). Microbiological analysis was performed on preoperative joint aspirates and tissue specimens obtained during revision surgery. Microstructural and cellular bone parameters were analyzed in bone specimens by histomorphometry on undecalcified sections complemented by tartrate-resistant acid phosphatase immunohistochemistry. Data were compared with control specimens obtained during primary arthroplasty (n = 20) and aseptic revision (n = 20).ResultsPJI specimens exhibited a higher bone volume, thickened trabeculae, and increased osteoid parameters compared to both control groups, suggesting an accelerated bone turnover with sclerotic microstructure. On the cellular level, osteoblast and osteoclast parameters were markedly increased in the PJI cohort. Furthermore, a positive association between serum (CRP) but not synovial (white blood cell (WBC) count) inflammatory markers and osteoclast indices could be detected. Comparison between different pathogens revealed increased osteoclastic bone resorption parameters without a concomitant increase in osteoblasts in bone specimens from patients with Staphylococcus aureus infection, compared to those with detection of Staphylococcus epidermidis and Cutibacterium spp.ConclusionThis study provides insights into the local bone metabolism in chronic PJI, demonstrating osteosclerosis with high bone turnover. The fact that Staphylococcus aureus was associated with distinctly increased osteoclast indices strongly suggests early surgical treatment to prevent periprosthetic bone alterations.Cite this article: Bone Joint Res 2023;12(10):644–653.
Delivery of RNP complexes for CRISPRi (dCas9) silencing in vitro and in vivo using crystalline ultrasmall particles (CUSP)
Authors: Unger Gretchen , Korman Viccie L , Kren Betsy T , Tobolt Diane L 
Published: October 2023

Delivery of ribonucleoprotein complexes (RNP) for CRISPR gene editing has emerged as a powerful strategy that minimizes off-targeting risks and simplifies dosing. However, RNP delivery approaches often rely upon bursting of endosomes for RNP release, a strategy that also triggers inflammatory responses, which can be exacerbated by the bacterial Cas9 endonuclease. Here, we describe initial results after encapsulating spCas9 or dead spCas9 (dCas9) RNPs in hepatocyte-targeting CUSP particles, comprising a shell with the glycoprotein ligand Asialoorosomucoid. CUSP particles are ~ 20 nm diameter and enter cells through size-limited lipid raft uptake to reach the nucleus without endosome capture. This design has been shown effective in plasmid delivery and treatment in vivo (1). Presently, we found CRISPR/Cas9 RNPs encapsulated in neutral-charge CUSP particles knocked down target F7 mRNA and protein in murine liver tissue and in 3D hepatocyte cell culture. Surprisingly, knockdown was via CRISPR interference (CRISPRi) and not CRISPR cleavage. A maximum effective dose of ~10e13 particles was observed in vivo
(40-85% knockdown of the three F7 protein fragments, 30% F7 mRNA knockdown by qPCR
) beyond which efficacy decreased. This finding corresponds with isotopic biodistribution studies and apparent dysregulation of intracellular trafficking, suggesting optimal dosing of CUSP-RNP particles could consist of repeat dosing at a non-saturating dose. We found no evidence of inflammation at the effective treatment dose. We further investigated CUSP delivery of dCas9 RNP and confirmed dCas9 mechanism, in knocking down F7 mRNA and protein in vitro. We observe that achieving DNA-cleaving activity with nanocapsule spCas9 RNPs may be particularly challenging, possibly due to large conformational changes required for activity (2). Conversely, dCas9 does not require large conformational changes, and CUSP’s repeatable-dosing and nuclear-homing platform can potentially exploit the efficient, inherently short-term activity of dCas9 RNP. We conclude CUSP RNP delivery is a promising strategy for overcoming CRISPR barriers to the clinic.
References

Kren et al, 2009, JCI 119(7); 2086-99, PMCID: PMC2861417

Jiang & Doudna, 2016, Annu Rev Biophys 46; 505–29, DOI:
doi.org/10.1146/annurev-biophys-062215-010822
Passive topical administration of nucleic acids to skin by cell-targeted sub-50 nanometer capsules
Authors: Unger Gretchen , Fuetes del Albin M , Kaspar R , Kren BT , Tobolt DT , Murtaugh M 
Published: October 2023

Passive topical administration of nucleic acid drugs and vaccines is a desirable goal for patient-friendly manipulation of target cells in the skin. However, two major delivery challenges that have impeded development are 1) penetrating the stratum corneum, and 2) avoiding endosomal entrapment and degradation.
GeneSegues has developed a novel drug delivery technology, sub-50 nanometer (s50) crystallized capsules, for intact delivery of nucleic acids to intracellular sites in target cells. s50 capsules are directed to specific tissue and cells by formulating appropriate targeting proteins, peptides or antibody ligands as the crystallized capsule shell. The novel size and structure of s50 capsules allows for efficient penetration of the stratum corneum and, by co-opting the non-endosomal pathway referred to as “lipid rafts”, intact delivery of nucleic acid cargo to the nucleus and cytoplasm of the target cell.
Here we show in pilot studies using pig dermis organ culture as an established and relevant model for human skin, transcutaneous passage of plasmid-bearing s50 capsules with cell-specific targeting. In these studies, we compared fibronectin, hyaluronan and tenascin as shell targeting components. We extended these studies of passive cutaneous delivery, using plasmid-bearing, fibronectin-coated s50 capsules, to in vivo timecourse studies in murine paws where stratum corneum layers in footpads are approximately 50 um thick, demonstrating uniform transfection of underlying basal keratinocytes.
In a further extension, using hyaluronan-coated s50 capsules together with a novel adjuvant, we demonstrate a functional response to model antigen in studies of passive topical DNA vaccine adminstration in weanling pigs. Skin is a powerful immune organ, not conveniently addressed by current methods of vaccine administration, e.g., injection, gene gun, or electroporation. We found improvement in mucosal and cell-mediated immune responses, relative to intradermal protein antigen injection that was biased towards distal and draining nodal lymphoctyes, demonstrating a functional response in a clinically relevant model to topical administration of nucleic acids using s50 capsules.
We expect that with further characterization, these studies may provide a solid framework for further development of s50-mediated cutaneous delivery of nucleic acid drugs and vaccines.

Grant acknowledgments: NIH R43 CA119556, R43 AI60268
COVID-19 Transition to Online
Authors: Moore-Beyioku Cheryl 
Published: October 2023

The need to quickly transition from face-to-face teaching using engaging, content-based activities to a new, online platform in just two weeks during the COVID-19 pandemic, made it necessary to try to migrate familiar activities that the students enjoyed into a virtual classroom. The activity that proved to be the most successful in maintaining a sense of community, engaging students, and reviewing content was playing Quizlet Live while in Breakout Rooms in Zoom.
Keywords: online teaching, gaming, pandemic, student participation, active learning, learner engagement, collaboration, educational technology, Distance Education.
High-performance wearable flexible strain sensors based on an AgNWs/rGO/TPU electrospun nanofiber film for monitoring human activities
Authors: Zhang Lu , Wu Minghua , Liu Qun , Wang Haidong 
Published: October 2023

Abstract
Wearable flexible strain sensors have attracted considerable attention in recent years, while it is still a significant challenge to fabricate wearable flexible strain sensors with high sensitivity and wide sensing range simultaneously. In this work, a high-performance wearable flexible strain sensor based on a thermoplastic polyurethane electrospun nanofibers (TPUNFs) film embedded with a silver nanowires/reduced graphene oxide (AgNWs/rGO) composite conductive material was fabricated via a simple drop-coating technique. The effect of the amount of AgNWs/rGO composite conductive material on the strain sensing range of the AgNWs/rGO/TPUNFs film flexible strain sensor was investigated, the strain sensing range of AgNWs/rGO/TPUNFs film flexible strain sensor was compared with that of the AgNWs/TPUNFs and GO/TPUNFs film flexible strain sensor, and the strain sensing properties of the AgNWs/rGO/TPUNFs film flexible strain sensor were measured. The results showed that the AgNWs/rGO/TPUNFs film flexible strain sensor with high sensitivity and wide sensing range simultaneously was achieved by compounding AgNWs and the reduced graphene oxide (rGO) conductive material. The strain sensing range of the AgNWs/rGO/TPUNFs film flexible strain sensor could be improved by increasing the amount of the AgNWs/rGO composite conductive material, and it was obviously better than that of AgNWs/TPUNFs and the rGO/TPUNFs film flexible strain sensor. The obtained AgNWs/rGO/TPUNFs film flexible strain sensor possessed high sensitivity (the gauge factor could reach a maximum of 2513.23.) as well as a wide sensing range (∼187%). Furthermore, the obtained AgNWs/rGO/TPUNFs film flexible strain sensor had a fast response/recovery time (200 ms/300 ms) and good cycling stability (∼3,000 cycles). Benefitting from the outstanding strain sensing performance, the AgNWs/rGO/TPUNFs film flexible strain sensor could detect large human motions such as finger, wrist, and knee bending as well as expression, which demonstrates great potential applications in wearable devices.
Neuronal Ensembles in the Infralimbic Cortex Dynamically Process Distinct Aspects of Hedonic Value
Authors: Hurley Seth W. , Douton Joaquin E. , Carelli Regina M. 
Published: October 2023

Hedonic processing is critical for guiding appropriate behavior, and the infralimbic cortex (IL) is a key neural substrate associated with this function in rodents and humans. We used deep brainin vivocalcium imaging and taste reactivity in freely behaving male and female Sprague Dawley rats to examine whether the infralimbic cortex is involved in encoding innate versus conditioned hedonic states. In experiment 1, we examined the IL neuronal ensemble responsiveness to intraoral innately rewarding (sucrose) versus aversive (quinine) tastants. Most IL neurons responded to either sucrose only or both sucrose and quinine, with fewer neurons selectively processing quinine. Among neurons that responded to both stimuli, some appear to encode hedonic processing. In experiment 2, we examined how IL neurons process devalued sucrose using conditioned taste aversion (CTA). We found that neurons that responded exclusively to sucrose were disengaged while additional quinine-exclusive neurons were recruited. Moreover, tastant-specific neurons that did not change their neuronal activity after CTA appeared to encode objective hedonic value. However, other neuronal ensembles responded to both tastants and appear to encode distinct aspects of hedonic processing. Specifically, some neurons responded differently to quinine and sucrose and shifted from appetitive-like to aversive-like activity after CTA, thus encoding the subjective hedonic value of the stimulus. Conversely, neurons that responded similarly to both tastants were heightened after CTA. Our findings show dynamic shifts in IL ensembles encoding devalued sucrose and support a role for parallel processing of objective and subjective hedonic value.SIGNIFICANCE STATEMENTDisrupted affective processing contributes to psychiatric disorders including depression, substance use disorder, and schizophrenia. We assessed how the infralimbic cortex, a key neural substrate involved in affect generation and affect regulation, processes innate and learned hedonic states using deep brainin vivocalcium imaging in freely behaving rats. We report that unique infralimbic cortex ensembles encode stimulus subjective and objective hedonic value. Further, our findings support similarities and differences in innate versus learned negative affective states. This study provides insight into the neural mechanisms underlying affect generation and helps to establish a foundation for the development of novel treatment strategies to reduce negative affective states that arise in many psychiatric disorders.