bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospects for gene therapy in polycystic kidney disease
Authors: Chakraborty Anubhav , Yu Alan S.L.
Published: October 2024

Purpose of review

We aim to provide an updated perspective on the recent advancements in gene therapy for polycystic kidney disease (PKD), a genetic disorder with significant morbidity. Given the rapid evolution of gene therapy technologies and their potential for treating inherited diseases, this review explores the therapeutic prospects and challenges in applying these technologies to PKD.

Recent findings

Significant progress has been made in understanding the genetic underpinnings of PKD, making it a prime candidate for gene therapy. Re-expression of the PKD genes, treatment with the C-terminal tail of polycystin 1 protein and antagomir therapy against miR-17 have shown promise in reducing cyst formation and preserving kidney function. The rapid development of gene-editing tools, antisense oligonucleotide-based strategies, programmable RNA, and advanced gene delivery systems has opened new possibilities for PKD treatment. However, challenges such as off-target effects, delivery efficiency, and long-term safety remain significant barriers to clinical application.

Current research highlights the transformative potential of gene therapy for PKD. Ongoing studies are crucial to overcoming existing challenges and translating these findings into clinical practice. We highlight the need for multidisciplinary efforts to optimize gene-editing technologies and ensure their safety and efficacy in treating PKD.
A contemporary snapshot of familial hypercholesterolemia registries
Authors: Tamehri Zadeh Seyed Saeed , Pang Jing , Chan Dick C. , Watts Gerald F.
Published: October 2024

Purpose of review

Familial hypercholesterolemia (FH) registries can capture unique data on FH concerning real-world practice, clinic epidemiology, natural history, cascade testing, cardiovascular consequences of late diagnosis, and use of healthcare resources. Such registries are also valuable for identifying and bridging the gaps between guidelines and clinical practice. We reviewed recent findings from the principal FH registries.

Recent findings

Most adult patients with heterozygous FH (HeFH) are diagnosed late, undertreated, and do not reach guideline-recommended low density lipoprotein-cholesterol (LDL-C) goals. In children and adolescents with HeFH, detection relies principally on genetic testing and measurement of LDL-C levels. Similarly, the majority of patients with homozygous FH (HoFH) receive sub-optimal cholesterol-lowering treatments and do not attain recommended LDL-C goals, gaps being wider in lower income than higher income countries. In HeFH patients, men have a higher risk of atherosclerotic cardiovascular disease than women.

The evolving data from FH registries provide real-world evidence for developing implementation strategies to address gaps across the continuum of care of FH worldwide.
Establishing an upper extremity transplantation program: lessons learnt over 12 years
Authors: Zuo Kevin J. , Zaccardelli Alessandra , Talbot Simon G.
Published: October 2024

Purpose of review

As one of the early hand transplant programs in the world, we are often asked to educate other programs on the lessons we have learned and on how to set up a successful hand transplantation program.

Recent findings

Two decades of global experience with vascularized composite allotransplantation (VCA) of the upper limb have demonstrated improved functional outcomes and quality of life for carefully screened patients. Despite initial reticence about VCA, over 30 patients in the USA have benefited from hand transplantation, with around 80% long-term successes. We have experience with four bilateral upper extremity patients who have undergone bilateral upper extremity allotransplants. This review article highlights our personal experience and lessons with respect to VCA team assembly, logistics, patient selection, perioperative planning, the operative procedure, and postoperative management.

Continual learning and critical evaluation are crucial to maintaining a successful upper extremity VCA program. This will ensure that patients who stand to benefit most from this life-enhancing procedure are identified and are others optimized to achieve the best possible outcomes.
Dual PD-L1/SOX10 Immunohistochemistry Combined With Digital Imaging Enhances Stratification Accuracy of Patients With Metastatic Melanoma
Authors: Pineda-Reyes Juan , Arudra Sri Krishna , Aung Phyu P. , Nagarajan Priyadharsini , Curry Jonathan L. , Tetzlaff Michael , Prieto Victor G. , Wang Wei-Lien , Hwu Wen-Jen , Torres-Cabala Carlos A.
Published: October 2024

Immune checkpoint inhibitor therapy has demonstrated an overall survival benefit in patients with advanced melanoma. Though the significance of programmed death-ligand 1 (PD-L1) expression on melanoma cells as a predictive biomarker of response remains inconclusive, some reports indicate that a PD-L1 expression of <1% of tumor cells may be associated with better outcomes with dual immunotherapy. Adequate patient selection for combination therapy is critical given the higher frequency of adverse effects compared with monotherapy. Immunohistochemical (IHC) PD-L1 interpretation in tumor cells is challenging when inflammatory cells are present and cutoffs are low. We studied 36 metastatic melanoma biopsies from Immune checkpoint inhibitor–naive patients, previously stained and scored for PD-L1 IHC using the tumor proportion score (TPS). Cases were classified into 3 groups: <1%, 1% to 5%, and >5%. After de-coverslipping, SRY-related HMG-box-10 (SOX10) IHC was performed on PD-L1 IHC slides with a red chromogen, and subsequently scanned and scored by ≥2 dermatopathologists. This assessment determined that 25% of cases (9/36) had a TPS ≥ 1%, in contrast to the single IHC assay (63.8%). The majority of the 1-5% group (11/13, 84.6%) underwent a change of category to <1% TPS. In the >5% group, 60% of cases (6/10) were downgraded to <1% and 1% to 5% (4 and 2 cases, respectively). Our study suggests that PD-L1 IHC evaluation could benefit from dual PD-L1/SOX10 IHC. Dual IHC is expected to decrease the interference caused by PD-L1 expression on inflammatory cells, and digital imaging proves useful for the preservation and analysis of stains. Refining PD-L1 evaluation in metastatic melanoma may improve clinical decisions between single and combination immunotherapy, with potentially profound consequences in response and quality of life.
Infant Motor Milestones: Analysis of Content and Variability Among Popular Sources for Parents
Authors: Orlando Julie M. , Cunha Andrea B. , Namit Samantha , Banoub Abram , Alharbi Bashayer M. , Lobo Michele A.
Published: October 2024

Purpose:

Evaluate the content and variability of infant motor milestone education provided to parents in popular sources.

Methods:

Sources were screened for inclusion, and their motor milestone content was coded. Descriptive and inferential analyses were performed.

Results:

Content from 241 websites, applications, and books was evaluated; 6984 motor milestones were extracted, representing 146 unique milestone codes across 14 categories. Books and applications had more milestone content than websites. There was variability in the milestones mentioned and their associated ages across the sources and relative to the American Academy of Pediatrics (AAP) and Centers for Disease Control and Prevention (CDC) content. Several frequently mentioned milestones were behaviors that facilitate early learning.

Conclusions:

There is variability among sources in the motor milestones they provide to parents of infants. The AAP and CDC content likely has some influence on the broader content available, but there is substantial deviation from the information they provide.
Superthin Anterolateral Thigh Flap for Head and Neck Reconstruction
Authors: Kamizono Kenichi , Kadota Hideki , Yoshida Sei
Published: October 2024

This study was performed to clarify whether the superthin anterolateral thigh (ALT) flap is an appropriate choice for head and neck reconstructions requiring thinner and more pliable flaps. Data of patients who underwent head and neck reconstruction from January 2020 to December 2022 were retrospectively collected. Nine patients (4.2%) underwent reconstruction with a superthin ALT flap. All the flaps survived with no cases of total or partial necrosis. Six patients treated with superthin ALT flaps and 15 patients treated with conventional ALT flaps who underwent oral cavity reconstruction were compared. The mean body mass index was significantly higher in the superthin flap group than in the conventional ALT flap group (25.2 vs 21.2 kg/m2, respectively; P = 0.04). The rate of postoperative complications requiring debridement was 0% and 13% (P = 0.37). The mean postoperative Hirose score was 9.7 and 8.7 (P = 0.17). The mean postoperative Functional Oral Intake Scale score was 6.7 and 5.9 (P = 0.12). Secondary flap refinement surgery after facial skin reconstruction was performed in 0 of 2 patients (0.0%) in the superthin flap group and 4 of 52 patients (7.7%) in the conventional ALT flap group (P = 0.04). Oral cavity reconstruction with superthin ALT flaps did not increase the incidence of postoperative flap necrosis and resulted in comparable postoperative function. In addition, superthin ALT flaps did not require additional flap refinement surgeries after facial skin reconstruction. The superthin ALT flap is a safe and reliable choice for obese patients with thick thigh subcutaneous tissue.
Simultaneous Coronoid Bone Grafting in Ballistic Facial Trauma Patients Undergoing Coronoidectomy
Authors: Sood Rachita , Froimson Jill R. , Reid Russell R.
Published: October 2024

Ballistic facial trauma can cause complex fractures and overlying soft tissue damage, with a zone of injury that extends beyond the bullet tract. Early skeletal fixation is indicated, and previous large case series describe the use of debrided bone fragments as ‘spare part’ grafts. This series presents the indications and techniques for simultaneous coronoid bone grafting in 2 patients who sustained a gunshot wound to the right midface and required coronoidectomy. The coronoid process was used as (1) an interposition graft in the lateral buttress of the right maxilla for stability, and (2) an onlay graft on the right inferior orbital rim for contour. Both patients did not have graft infection, extrusion, or malposition at the 1-month clinic follow-up. The coronoid process of the mandible is a viable, safe spare-part option, despite the possible location of the coronoid process within the zone of injury in the reconstruction of complex ballistic facial trauma.
Perioperative Management and Outcomes of Pediatric Craniosynostosis Patients Undergoing Cranioplasty: A Retrospective Analysis
Authors: Battistelli Elisa Zoe , Calabria Orlando , Giani Marco , Moretto Alessandra , Cattaneo Federico , Alberio Giovanni , Trezza Andrea , Ventura Maria Luisa , Mazzoleni Fabio , Biondi Andrea , Citerio Giuseppe , Giussani Carlo , Foti Giuseppe
Published: October 2024

Cranioplasty is a major surgical procedure typically performed in children under 1 year of age, often associated with significant complications. The scientific literature on perioperative management for children with craniosynostosis undergoing cranioplasty is limited. The authors' objective was to retrospectively evaluate the management, complication rates, and outcomes among children undergoing cranioplasty at our institution. The authors conducted a single-center retrospective analysis of craniosynostosis children who underwent cranioplasty at Fondazione IRCCS San Gerardo dei Tintori between 2009 and 2023. 102 children were studied. Median admission age was 307 days, 30.4% of patients had syndromic disease; 28.4% underwent multi-suture cranioplasty. Median blood loss was 225 ml, and 85% of patients required red blood cell transfusion. There was a significant difference neither in indexed blood loss between the single and the multi-suture groups nor in perioperative transfusion requirement. 93.2% of patients in the single-suture group were extubated upon completion of the procedure against 65.5% of multi-suture group. No deaths were recorded. All patients were admitted to the intensive care unit after surgery. 8.8% patients suffered at least one complication. Airway management was the most common (7.8% of patients), intraoperative blood loss >90% of estimated blood volume occurred in 4 (3.9%) patients, whereas 3 children (2.9%) developed intracranial hypertension. Syndromic patients exhibited a significantly higher incidence of perioperative complications. Managing children’s cranioplasty perioperative care is challenging, especially in multi-suture and syndromic cases. These findings stress the importance of multidisciplinary collaboration, precise intraoperative management, and comprehensive postoperative monitoring.
Psychiatric Sequelae in Adult Open Globe Injury Patients
Authors: Ünal Gonca Ayşe , Özer Ömer
Published: October 2024

Background:

The aim of this study was to investigate psychiatric sequelae in open globe injury patients and to identify the risk factors associated with these sequelae.

Methods:

After a complete ophthalmologic examination, Davidson Trauma Scale (DTS), State-Trait Anxiety Inventory (STAI), and Zung Depression Scale (ZDS) scores were administered to all patients. Patients were divided into 5 groups according to final best corrected visual acuity (BCVA): group 1 (no perception of light, NPL), group 2 [perception of light (PL) or hand movements (HM)], group 3 (1/200 to 19/200), group 4 (20/200 to 20/50), and group 5 (20/40 or above).

Results:

A total of 113 patients with open globe injuries were included. The mean ZDS scores were 78.5±35.9 in group 1, 66.2±24.5 in group 2, and 27.6±2.1 in group 5. In group 1, 8 patients (66.7%) had moderate depression. In group 2, 20 patients (60.6%) had mild depression. All patients in group 4 and group 5 had ZDS scores in the normal range. There is a statistically significant difference between the groups in terms of ZDS scores. In univariate analysis, depression (ZDS) and trauma (DTS) scores were associated with younger age (P=0.016 and P=0.003, respectively) and lower final visual acuity level (P<0.001, for both). In multivariate analysis adjusted for age and sex, a lower final visual acuity level (P<0.001, for both) was also associated.

Conclusions:

In conclusion, high anxiety and depression scores can be seen in open globe injury patients. Patients with young age and lower final visual acuity should be carefully screened, and the presence of a psychiatric pathology should be investigated. Amelioration of psychiatric pathologies may improve patient compliance with treatment and clinical success.
Speech Outcome Audit for Cleft Lip and Palate Patient Population Correlated With Veau Cleft Type, Surgical Repair Technique, and Patient Age
Authors: Raposo-Amaral Cassio E. , Gil André , Sabbag Anelise , Vincenzi-Lemes Marcela , Raposo-Amaral Cesar A.
Published: October 2024

Objective:

The objective of this study is to determine speech outcome differences for specific palate repair techniques and correlate these data with patient age at the time of operation.

Methods:

A retrospective study was conducted on a cohort of consecutive nonsyndromic patients who underwent cleft lip and/or palate repair at the authors' hospital between 2010 and 2020. Only those patients who participated in at least 4 years of follow-up accompanied by audio-video recording were included. The patient cohort was divided into 2 age groups, between 1 year and 2 years of age versus older than 2 years of age. Standardized perceptual speech evaluations and nasopharyngoscopy were performed by the authors' team to detect the presence of velopharyngeal insufficiency.

Results:

A total of 481 patients were initially evaluated, and 323 of these patients met all inclusion criteria and were subsequently selected for this study. One hundred seventy-two patients (n = 172) underwent palatal surgery using the Bardach 2-flap palatoplasty technique, 47 patients (n = 47) underwent repair through the von Langenbeck palatoplasty technique, 78 patients (n = 78) underwent repair through Veau-Wardill-Killner palatoplasty technique, and 26 patients (n = 26) underwent repair through double-opposing Z-plasty palatoplasty. The rate of residual velopharyngeal insufficiency was statistically similar among all palatoplasty techniques. A comparison between these two age groups revealed that patients younger than 2 years of age showed higher speech outcome success.

Conclusion:

High rates of speech success are achieved for patients younger than 2 years of age. Speech outcomes success is maximized by proper technique selection in relation to cleft type.
Reconstruction of Complex Oral and Maxillofacial Defects After Oral Cancer Resection With Individualized Anterolateral Thigh Multiple Paddle Flaps
Authors: Zhang Shuai , Zhang Shanshan , Zou Jingyuan , Jiang Tiancheng , Chen Lin , Gong Zhaojian
Published: October 2024

Purpose:

This study aimed to use reconstructive methods for complex oral and maxillofacial defects, explore their feasibility, and evaluate the efficacy of defect reconstruction using anterolateral thigh (ALT) multiple paddle flaps.

Patients and Methods:

The authors performed a retrospective case series of 33 patients who underwent oral and maxillofacial defect reconstruction using the ALT multiple paddle flaps. The design and harvest of the flaps, methods for defects reconstruction, and reconstructive efficacy are described.

Results:

All 33 patients were men, with a mean age of 49.5 years. Of the flaps, triple skin paddles plus muscle paddles were included in 3 cases, triple skin paddles were included in 1 case, 2 skin paddles plus muscle paddles were included in 29 cases. The skin paddles measured 3×5 cm to 10×16 cm. Postoperatively, all flaps survived completely. Parotid salivary fistula and orocutaneous fistula occurred in 1 patient of each, thigh wound infection and effusion occurred in 1 and 2 patients, respectively. All patients were followed up for ~2 to 93 months; most patients’ oral functions and appearance were acceptable, and thigh motor dysfunction was not observed.

Conclusions:

With separate skin paddles for defects of different positions, individualized muscle flap for dead spaces, combination of different skin paddles for larger defects, effective reduction or avoidance of wound complications, and acceptable donor site morbidity, the ALT multiple paddle flaps are an ideal candidate for complex oral and maxillofacial defects reconstruction.
Role of caregivers being trained in assisting in end of life care – Latin American perspective
Authors: de Vries Esther , Calvache José A. , Hernández Zambrano Sandra M.
Published: October 2024

Purpose of review

Palliative care in Latin America is evolving, but training for informal caregivers remains underexplored. This review summarizes recent interventions to educate or train caregivers in end-of-life care.

Recent findings

The literature search identified three interventions published by 2023, two with reception evaluations, all with small sample sizes and no control groups. Needs of caregivers have been more frequently described and include training on aspects of the disease, nursing skills, how to handle patients´ and own emotions; help in navigating the complex healthcare systems in Latin America; help in conversations about the end of life and dying, still taboos in the region; help in finding additional caregivers or other types of support to make the caregiving role sustainable over time for the caregiver. Interventions mainly focused on emotional support and identifying additional caregivers without guilt; two included nursing skills training.

There are very few formal interventions described and evaluated to assist caregivers in end-of-life care in Latin America described in the literature. This illustrates the rather invisible but very important role of these important stakeholders in the care for patients. Multidimensional interventions should be developed and evaluated to support caregivers.
A rigidly foldable and reconfigurable thick origami antenna
Authors: Yao Shun , Zekios Constantinos L. , Georgakopoulos Stavros V.
Published: October 2024

A rigidly foldable and reconfigurable origami antenna is developed here. This antenna uses thick folding panels thereby providing robust operation and folding/unfolding actuation, which are very important for many applications in extreme environments, such as space. Also, this antenna can be constructed using standard printed circuit boards, which simplifies its manufacturing. For the reconfigurable antenna developed here, the origami flasher pattern is chosen to achieve a spatial transformation of a dipole operating at 0.48 GHz to a conical spiral antenna (CSA) operating from 2.1 to 3.7 GHz. The design equations for the origami CSA are derived. A prototype is built using a 0.81-mm-thick FR4 substrate to validate the proposed methodology. The antenna parameters are investigated in a wide frequency range. Our simulated results agree very well with the measurements. The rigid structure of the proposed design and its reconfigurable nature make it a good candidate for satellite communications.

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
Reprogramming multi-stable snapping and energy dissipation in origami metamaterials through panel confinement
Authors: Almessabi Abdulrahman , Li Xuwen , Jamalimehr Amin , Pasini Damiano
Published: October 2024

With a focus on a class of origami-inspired metamaterials, this work explores the role of panel confinement in their mechanical response under cyclic loading. The goal is twofold: (i) quantify the magnitude change in snapping force and energy dissipation attained by varying the severity of confinement of selected panels; and (ii) leverage insights to modulate
in situ
their mechanical response as dictated by a given application, hence propose panel confinement modulation as a practical design route for response reprogrammability. Through computational modelling, proof-of-concept fabrication and cyclic testing, we first identify and characterize the governing factors enabling either the alteration or the preservation of the snapping force magnitude during repeated cycles of forward and backward loading. Then, we demonstrate how the
in situ
modulation of the constrained distance between selected panels enables reprogramming their snapping sequence and energy dissipation. The results contribute to expanding the versatility and application of this class of origami metamaterial across sectors, from aerospace to protective equipment, requiring precise control of mechanical damping and energy dissipation.

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
Programmable adhesion through triangular and hierarchical cuts in metamaterial adhesives
Authors: Hwang Dohgyu , Lee Chanhong , Bartlett Michael D.
Published: October 2024

Metamaterial design approaches, which integrate structural elements into material systems, enable the control of uncommon behaviours by decoupling local and global properties. Leveraging this conceptual framework, metamaterial adhesives incorporate nonlinear cut architectures into adhesive films to achieve unique combinations of adhesion capacity, release, and spatial tunability by controlling how cracks propagate forward and in reverse directions during separation. Here, metamaterial adhesive designs are explored with triangular cut features while integrating hierarchical and secondary cut patterns among primary nonlinear cuts. Both cut geometry and secondary cut features tune adhesive force capacity and energy of separation. Importantly, the size and spacing of cut features must be designed around a critical length scale. When secondary cut features are greater than a critical length, cracks can be steered in multiple directions, going both forward and backwards within a primary attachment element. This control over crack dynamics enhances the work of separation by a factor of 1.5, while maintaining the peel force relative to a primary cut. If hierarchical cut features are too small or too compliant, they interact and do not distinctly modify crack behaviour. This work highlights the importance of adhesive length scales and stiffness for crack control and attachment characteristics in adhesive films.

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
Improving mass lumping and stiffness parameters of bar and hinge model for accurate modal dynamics of origami structures
Authors: Lahiri Anandaroop , Pratapa Phanisri Pradeep
Published: October 2024

The bar and hinge framework uses truss elements and rotational springs to efficiently model the structural behaviour of origami. The framework is especially useful to investigate origami metamaterials as they have repeating geometry, which makes conventional finite element simulations very expensive due to a large number of degrees of freedom. This work proposes improvements to the parameters of bar and hinge model within the context of structural dynamics, specifically modal analysis under small deformations, which has not been carried out previously in the literature. A range of low-frequency modes involving origami folding and panel bending deformations that can be accurately captured by the bar and hinge framework are identified. Within this range, bar and hinge parameters like the lumped masses and the rotational spring stiffness values are derived using conservation laws and finite element tests. The best among the proposed schemes is found to predict natural frequencies of the considered origami structures to within 10% maximum error, improving the accuracy by more than three times from existing schemes. In most cases, the errors in natural frequencies are less than 5%.

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
Reconfigurable origami with variable stiffness joints for adaptive robotic locomotion and grasping
Authors: Lerner Elisha , Chen Zhe , Zhao Jianguo
Published: October 2024

With its compactness and foldability, origami has recently been applied to robotic systems to enable versatile robots and mechanisms while maintaining a low weight and compact form. This work investigates how to generate different motions and shapes for origami by tuning its creases’ stiffness on the fly. The stiffness tuning is realized by a composite material made by sandwiching a thermoplastic layer between two shape memory polymer layers. This enables the composite to act as a living hinge, whose stiffness can be actively controlled through Joule heating. To demonstrate our concept, we fabricate an origami module with four variable stiffness joints (VSJs), allowing it to have freely controlled crease stiffnesses across its surface. We characterize the origami module’s versatile motion when heating different VSJs with different temperatures. We further use two origami modules to build a two-legged robot that can locomote on the ground with different locomotion gaits. The same robot is also used as an adaptive gripper for grasping tasks. Our work can potentially enable more versatile robotic systems made from origami as well as other mechanical systems with programmable properties (e.g. mechanical metamaterials).

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
Toward mechanical proprioception in autonomously reconfigurable kirigami-inspired mechanical systems
Authors: Jiao Weijian , Shu Hang , He Qiguang , Raney Jordan R.
Published: October 2024

Mechanical metamaterials have recently been exploited as an interesting platform for information storing, retrieval and processing, analogous to electronic devices. In this work, we describe the design and fabrication a two-dimensional (2D) multistable metamaterial consisting of building blocks that can be switched between two distinct stable phases, and which are capable of storing binary information analogous to digital bits. By changing the spatial distribution of the phases, we can achieve a variety of different configurations and tunable mechanical properties (both static and dynamic). Moreover, we demonstrate the ability to determine the phase distribution via simple probing of the dynamic properties, to which we refer as mechanical proprioception. Finally, as a simple demonstration of feasibility, we illustrate a strategy for building autonomous kirigami systems that can receive inputs from their environment. This work could bring new insights for the design of mechanical metamaterials with information processing and computing functionalities.

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
Lagrangian approach to origami vertex analysis: kinematics
Authors: Grasinger Matthew , Gillman Andrew , Buskohl Philip R.
Published: October 2024

The use of origami in engineering has significantly expanded in recent years, spanning deployable structures across scales, folding robotics and mechanical metamaterials. However, finding foldable paths can be a formidable task as the kinematics are determined by a nonlinear system of equations, often with several degrees of freedom. In this article, we leverage a Lagrangian approach to derive reduced-order compatibility conditions for rigid-facet origami vertices with reflection and rotational symmetries. Then, using the reduced-order conditions, we derive exact, multi-degree of freedom solutions for degree 6 and degree 8 vertices with prescribed symmetries. The exact kinematic solutions allow us to efficiently investigate the topology of allowable kinematics, including the consideration of a self-contact constraint, and then visually interpret the role of geometric design parameters on these admissible fold paths by monitoring the change in the kinematic topology. We then introduce a procedure to construct lower-symmetry kinematic solutions by breaking symmetry of higher-order kinematic solutions in a systematic way that preserves compatibility. The multi-degree of freedom solutions discovered here should assist with building intuition of the kinematic feasibility of higher-degree origami vertices and also facilitate the development of new algorithmic procedures for origami-engineering design.

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
The Feline calicivirus capsid protein VP1 is a client of the molecular chaperone Hsp90
Authors: Pérez-Ibáñez Carolina , Peñaflor-Téllez Yoatzin , Miguel Rodríguez Carlos Emilio , Gutiérrez Escolano Ana Lorena
Published: October 2024

Feline calicivirus (FCV) icosahedral viral capsids are composed of dozens of structural subunits that rely on cellular chaperones to self-assemble in an orderly fashion. Here, we report that the heat shock protein 90 (Hsp90) inhibition significantly reduced FCV particle production, suggesting a role in the replicative cycle. We found that Hsp90 inhibition was not related to the synthesis or stability of the early proteins that translate from the gRNA nor to the minor capsid protein VP2 but with a reduction in the major capsid protein VP1 levels, both translated late in infection from the subgenomic RNAs. Reduction in VP1 levels was observed despite an augment of the leader of the capsid (LC)–VP1 precursor levels, from which the LC and VP1 proteins are produced after proteolytic processing by NS6/7. The direct interaction of VP1 with Hsp90 was observed in infected cells. These results suggest that upon release from the polyprotein precursor, VP1 becomes a client of Hsp90 and that this interaction is required for an efficient FCV replicative cycle.
Exploring the Educational Potential of Instagram in the New Generations: A Study on the Impact of "Adopt a Bacterium"
Authors: Rodrigues Cintra Armellini Bárbara , Nardi Baroni Lara , Carvalho Maia Brito Samantha , Ramos Moreno Ana Carolina , de Souza Robson Francisco , Lellis-Santos Camilo , Café Ferreira Rita de Cássia
Published: October 2024

In 2013, the “Adopt a Bacterium” project was created, which originally proposed the use of the social network Facebook® as an educational tool to engage students in learning microbiology through personalized posts. However, the generational alignment dynamic presents contemporary challenges for educators. Given the relevance and success of the project in recent years, the use of an alternative social network is sought for the application of the methodology. In the present study, we describe the use of the social network Instagram as a tool to understand the impacts of the “Adopt a Bacterium” project on microbiology learning among new generations of students. To verify the effectiveness of the methodology, the following steps were taken: i) voluntary and anonymous questionnaires with an open-ended question about knowledge of the adopted bacterium were applied before the start of the project (Q1), at the end of the project (Q2), and five months after the end (Q3), to Biomedical Sciences students in the years 2020, 2021, and 2022; and ii) a project evaluation questionnaire was administered to students. The data were analyzed using thematic categorization, calculation of the richness of student’s discourse through the Shannon Diversity Index, and the creation of word clouds to visualize student suggestions, as well as the use of Python language tool to demonstrate citations of specific themes, comparing Facebook and Instagram as Virtual Learning Enviroments. The results revealed an improvement in student learning, as demonstrated by the increase in the frequency of content categories related to bacteriology and the richness of discourse, indicated by higher Shannon Diversity Index values in Q2 and Q3 compared to Q1. In conclusion, the results demonstrate that the methodology of the “Adopt a Bacterium” can be applied in different virtual environments, such as the social network Instagram® resulting in increased learning and student interest in Microbiology.
Clinical characteristics and serotype association of dengue and dengue like illness in Pakistan
Authors: Iqbal Najeeha Talat , Ahmed Kumail , Khalid Aqsa , Imtiaz Kehkashan , Ali Qamreen Mumtaz , Munir Tania , Mahmood Syed Faisal , Khan Unab , Afzal Badar , Qamar Farah , Waggoner Jesse J. , Fenelon Hannah , McOwen Helene , Khan Erum , Rabinowitz Peter , Van Voorhis Wesley C.
Published: October 2024

Background

Pakistan has been an endemic country for dengue virus since 1994, with a significant increase in cases reported in 2022 largely due to heavy rainfall and flooding. All four serotypes of the dengue virus (DENV) are present in Pakistan, with DENV 1 and DENV 2 being the most prevalent. The current study aimed to explore the clinical presentations and features of dengue fever in a tertiary care hospital.

Methodology

We enrolled and studied 349 cases of suspected and confirmed dengue presenting for care at the Aga Khan University Hospital in Karachi between June 2021 and November 2023. Collected data on cases including clinical symptoms and laboratory results including qRT-PCR and serotype characterization.

Findings

The majority of subjects enrolled (75%) had mild disease without warning signs, while 11% exhibited warning signs, 1.4% had severe dengue, and 12.6 % had no dengue diagnosis. Patients with severe dengue (SD) had significantly higher levels of liver enzymes (AST and ALT) compared to those with non-severe dengue (NSD) (AST; p=0.024 and ALT; p=0.047). Additionally, a higher grade of thrombocytopenia was significantly associated with hospitalization (p=0.0008), and prolonged illness (p=0.03). Both Platelet (p<0.0001) and WBC counts (p=0.001) were significantly lower in dengue PCR-positive patients in comparison to Dengue PCR-negative. Among those tested for dengue serotypes, DENV 1 (34%) and DENV 2 (45%) emerged as the predominant serotypes, with mixed infections accounting for 17%. The sensitivity of clinical diagnosis was found to be 87.25% and specificity of 68.35%. qRT-PCR detected 43.5% of cases with viral fever initially screened negative.

Conclusion

Epidemiology of dengue fever during a widespread outbreak in 2022 showed a predominance of DENV 1 and DENV 2 serotypes with milder phenotype of viral illness. Screening with rapid tests requires further confirmation by molecular assay in cases with dengue and dengue-like illness.
Metrics based on habitat area and condition are poor proxies for invertebrate biodiversity
Authors: Duffus Natalie E. , Atkins Thomas B. , zu Ermgassen Sophus O.S.E. , Grenyer Richard. , Bull Joseph W. , Castell Dan A. , Stone Ben. , Tooher Niamh. , Milner-Gulland E.J. , Lewis Owen T.
Published: October 2024

There is increasing demand for standardised, easy-to-use metrics to assess progress towards achieving biodiversity targets and the effectiveness of ecological compensation schemes. Biodiversity metrics based on combining habitat area and habitat condition scores are proliferating rapidly, but there is limited evidence on how they relate to ecological outcomes. Here, we test the relationship between the statutory biodiversity metric used for Biodiversity Net Gain (BNG) in England — and as the basis for new biodiversity credit systems around the world — and invertebrate richness, abundance, and community composition. We find that the combined area-condition BNG metric does not capture the value of arable farmland and grassland sites for invertebrate biodiversity: invertebrate communities were highly variable across sites that had the same type and condition under the BNG metric. There was no significant relationship between invertebrate abundance or species richness and metric scores. Our results highlight the need to incorporate factors beyond habitat type and condition into site evaluations, and to complement metric use with species-based surveys.
GRIN2B disease-associated mutations disrupt the function of BK channels and NMDA receptor signalling nanodomains
Authors: Martínez-Lázaro Rebeca , Minguez-Viñas Teresa , Alvarez de la Rosa Diego , Bartolomé-Martín David , Giraldez Teresa
Published: October 2024

Large conductance calcium-activated potassium channels (BK channels) are unique in their ability to respond to two distinct physiological stimuli: intracellular Ca2+and membrane depolarization. In neurons, these channels are activated through a coordinated response to both signals; however, for BK channels to respond to physiological voltage changes, elevated concentrations of intracellular Ca2+(ranging from 1 to 10 μM) are necessary. As a result, it is believed that BK channels are typically localized within nanodomains near Ca2+sources (approximately 20-50 nm), such as N-methyl-D-aspartate receptors (NMDARs). Since the first evidence of NMDAR-BK channel coupling reported by Isaacson and Murphy in 2001 in the olfactory bulb, further studies have identified functional coupling between NMDARs and BK channels in other regions of the brain, emphasizing their importance in neuronal function. Mutations in the genes encoding NMDAR subunits have been directly linked to various neurodevelopmental disorders, including intellectual disability, epilepsy, and autism spectrum disorders. For instance, mutations such as V15M and V618G in the GRIN2B gene, which encodes the GluN2B subunit of NMDARs, are implicated in the pathogenesis of early infantile epileptic encephalopathy (EIEE27). Here, we explored the effects of these two GluN2B mutations on NMDAR-BK channel coupling, employing a combination of electrophysiological, biochemical, and imaging techniques. Taken together, our results demonstrate that mutation V618G specifically disrupts NMDAR-BK complex formation, impairing functional coupling, in spite of robust individual channel expression in the membrane. These results provide a potential mechanistic basis for EIEE27 pathophysiology and uncover new clues about NMDAR-BK complex formation.
Disruption of Normal Saline Supply Chain due to Natural Disaster: an analysis of the impact of normal saline shortage on anesthesia practice in a large hospital system and models towards resiliency
Authors: Hussain Rashid , Pickle Elizabeth , Lonjin Taylor , Then Janine , Rivosecchi Ryan , Cassavaugh Jessica , Fichman Mark , Kaynar Ata Murat
Published: October 2024

In the wake of the COVID-19 pandemic and upheaval in the global supply chain, the healthcare sector has grappled with acute shortages of essential resources. Such shortages, while intensified recently in scale and frequency, are not new, as natural disasters have posed recurrent challenges. An illustrative example is the impact of Hurricane Maria in September 2017, which severely disrupted the production of normal saline (% 0.9 NaCl fluid bags) in Puerto Rico. Hospitals relying on “just in time” delivery models found themselves in a precarious situation, prompting a need for innovative solutions to sustain care delivery amidst the crisis. The occurrence underscores the vulnerability of healthcare infrastructure to external disruptions and emphasizes the need for adaptive strategies to ensure the resilience of the system in the face of unforeseen challenges.

Consequently, our focus shifted to an examination of the impact of Hurricane Maria on saline supplies at the University of Pittsburgh Medical Center (UPMC) towards building a resilient model. This study aims to elucidate how the flagship hospitals of the system navigated the challenges posed by the shortage, both at the individual provider level and on a broader, system-wide scale.

This investigation spanned an 18-month study period, encompassing the analysis of intravenous (IV) fluid demand and usage patterns before, during, and after the hurricane. Employing a multi-faceted approach, we integrated quantitative data with qualitative insights derived from three months of “participant observation” and survey data. This mixed-methods approach enabled us to see how individuals and systems within UPMC adapted to the crisis. Systems level adaptation occurred at UPMC’s operating room (OR), pharmacy and distribution supply chain levels, including by decreasing OR demand, while at the individual level healthcare providers changed their behavior by turning to alternative medications and carrier fluids. These adaptive measures undertaken at UPMC offer insights for future crises at both the organizational and individual levels within the healthcare system.
Enhancing Breast Cancer Classification: A Few-Shot Meta-Learning Framework with DenseNet-121 for Improved Diagnosis
Authors: Upadhyay Nidhi , Bhargava Anuja , Singh Upasana , Alsharif Mohammed H. , Cho Ho-Shin
Published: October 2024

Breast cancer is a significant health concern globally, requiring early and accurate detection to improve patient outcomes. However, manual detection of breast cancer from medical images is time-consuming and inaccurate. Accurate assessment of cancer stages is critical for effective treatment and post-diagnosis handling. The goal of this research is to develop a specialized meta-learning method for classifying breast cancer images, particularly effective when working with limited data. Traditional cancer stage classification methods often struggle with insufficient labeled data, but meta-learning addresses this challenge by rapidly adapting to new tasks with few examples. The proposed method begins with image segmentation to identify regions of interest in the medical images, followed by thorough feature extraction to capture essential data representations. The critical meta-training phase involves refining a classifier within a metric space, utilizing cosine distance and an adaptable scale parameter. During the meta-testing stage, the adapted classifier predicts cancer stages using minimal support samples, achieving approximately 96% accuracy. This approach shows significant promise for the medical field, providing practical solutions to enhance diagnostic processes and improve predictions for breast cancer detection and treatment.
Genome-wide scan of Flortaucipir PET levels findsJARID2associated with cerebral tau deposition
Authors: Gunasekaran Tamil Iniyan , Meena Devendra , Lee Annie J , Wu Siwei , Dumitrescu Logan , Sperling Reisa , Hohman Timothy J ,   Alzheimer’s Disease Neuroimaging Initiative and the A4 Study, Huang Jingxian , Dehghan Abbas , Tzoulaki Ioanna , Mayeux Richard , Vardarajan Badri
Published: October 2024

BACKGROUND

Genetic research on Alzheimer’s disease (AD) has primarily focused on amyloid-β (Aβ) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD.

METHODS

We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from[18]F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from[18]F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses.

RESULTS

GWAS of tau-SUVR revealed two significant loci: rs78636169 (P=5.76×10-10) inJARID2and rs7292124 (P=2.20×10-8) nearISX. Gene-based analysis of tau deposition highlightedAPOE(P=2.55×10-6),CTNNA3(P=2.86×10-6) andJARID2(P=1.23×10-4), a component of thePRC2multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds withPRC2multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in youngerAPOE-ε4 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers.

CONCLUSION

We identified a novel potential therapeutic target,JARID2in thePRC2multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of Aβ and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.