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Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.
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Doença de Alzheimer , Encéfalo , Idoso , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Cognição , Disfunção Cognitiva/metabolismo , Neurônios/metabolismoRESUMO
While the physical signs of opioid withdrawal are most readily observable, withdrawal insidiously drives relapse and contributes to compulsive drug use, by disrupting emotional learning circuits. How these circuits become disrupted during withdrawal is poorly understood. Because amygdala neurons mediate relapse, and are highly opioid sensitive, we hypothesized that opioid withdrawal would induce adaptations in these neurons, opening a window of disrupted emotional learning circuit function. Under normal physiological conditions, synaptic transmission between the basolateral amygdala (BLA) and the neighboring main island (Im) of GABAergic intercalated cells (ITCs) is strongly inhibited by endogenous opioids. Using patch-clamp electrophysiology in brain slices prepared from male rats, we reveal that opioid withdrawal abruptly reduces the ability of these peptides to inhibit neurotransmission, a direct consequence of a protein kinase A (PKA)-driven increase in the synaptic activity of peptidases. Reduced peptide control of neurotransmission in the amygdala shifts the excitatory/inhibitory balance of inputs onto accumbens-projecting amygdala cells involved in relapse. These findings provide novel insights into how peptidases control synaptic activity within the amygdala and presents restoration of endogenous peptide activity during withdrawal as a viable option to mitigate withdrawal-induced disruptions in emotional learning circuits and rescue the relapse behaviors exhibited during opioid withdrawal and beyond into abstinence.SIGNIFICANCE STATEMENT We find that opioid withdrawal dials down inhibitory neuropeptide activity in the amygdala. This disrupts both GABAergic and glutamatergic transmission through amygdala circuits, including reward-related outputs to the nucleus accumbens. This likely disrupts peptide-dependent emotional learning processes in the amygdala during withdrawal and may direct behavior toward compulsive drug use.
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Analgésicos Opioides , Síndrome de Abstinência a Substâncias , Ratos , Masculino , Animais , Analgésicos Opioides/farmacologia , Tonsila do Cerebelo/fisiologia , Transmissão Sináptica/fisiologia , Peptídeos/farmacologia , Síndrome de Abstinência a Substâncias/metabolismo , Peptídeo Hidrolases/metabolismoRESUMO
Atrial Fibrillation (AFib) is a heart condition that occurs when electrophysiological malformations within heart tissues cause the atria to lose coordination with the ventricles, resulting in "irregularly irregular" heartbeats. Because symptoms are subtle and unpredictable, AFib diagnosis is often difficult or delayed. One possible solution is to build a system which predicts AFib based on the variability of R-R intervals (the distances between two R-peaks). This research aims to incorporate the transition matrix as a novel measure of R-R variability, while combining three segmentation schemes and two feature importance measures to systematically analyze the significance of individual features. The MIT-BIH dataset was first divided into three segmentation schemes, consisting of 5-s, 10-s, and 25-s subsets. In total, 21 various features, including the transition matrix features, were extracted from these subsets and used for the training of 11 machine learning classifiers. Next, permutation importance and tree-based feature importance calculations determined the most predictive features for each model. In summary, with Leave-One-Person-Out Cross Validation, classifiers under the 25-s segmentation scheme produced the best accuracies; specifically, Gradient Boosting (96.08%), Light Gradient Boosting (96.11%), and Extreme Gradient Boosting (96.30%). Among eleven classifiers, the three gradient boosting models and Random Forest exhibited the highest overall performance across all segmentation schemes. Moreover, the permutation and tree-based importance results demonstrated that the transition matrix features were most significant with longer subset lengths.
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Fibrilação Atrial , Humanos , Fibrilação Atrial/diagnóstico , Eletrocardiografia/métodos , Algoritmos , Aprendizado de Máquina , Átrios do CoraçãoRESUMO
We show a double-functional fluorescence sensing paradigm that can retrieve nanometric pH information on biological structures. We use this method to measure the extent of protonic condensation around microtubules, which are protein polymers that play many roles crucial to cell function. While microtubules are believed to have a profound impact on the local cytoplasmic pH, this has been hard to show experimentally due to the limitations of conventional sensing techniques. We show that subtle changes in the local electrochemical surroundings cause a double-functional sensor to transform its spectrum, thus allowing a direct measurement of the protonic concentration at the microtubule surface. Microtubules concentrate protons by as much as one unit on the pH scale, indicating a charge storage role within the cell via the localized ionic condensation. These results confirm the bioelectrical significance of microtubules and reveal a sensing concept that can deliver localized biochemical information on intracellular structures.
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Microtúbulos , Prótons , Biofísica , Citoplasma/fisiologia , Concentração de Íons de Hidrogênio , Microtúbulos/metabolismoRESUMO
Tubulin is an electrostatically negative protein that forms cylindrical polymers termed microtubules, which are crucial for a variety of intracellular roles. Exploiting the electrostatic behavior of tubulin and microtubules within functional microfluidic and optoelectronic devices is limited due to the lack of understanding of tubulin behavior as a function of solvent composition. This work displays the tunability of tubulin surface charge using dimethyl sulfoxide (DMSO) for the first time. Increasing the DMSO volume fractions leads to the lowering of tubulin's negative surface charge, eventually causing it to become positive in solutions >80% DMSO. As determined by electrophoretic mobility measurements, this change in surface charge is directionally reversible, i.e., permitting control between -1.5 and + 0.2 cm2 (V s)-1 . When usually negative microtubules are exposed to these conditions, the positively charged tubulin forms tubulin sheets and aggregates, as revealed by an electrophoretic transport assay. Fluorescence-based experiments also indicate that tubulin sheets and aggregates colocalize with negatively charged g-C3 N4 sheets while microtubules do not, further verifying the presence of a positive surface charge. This study illustrates that tubulin and its polymers, in addition to being mechanically robust, are also electrically tunable.
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Polímeros , Tubulina (Proteína) , Microtúbulos , Eletricidade EstáticaRESUMO
BACKGROUND: Implantable Dopplers (IDs) are widely used for postoperative free flap vascular monitoring. However, IDs may contribute to free flap complications or failure and better understanding of device malfunctions is needed. METHODS: The U.S. Food and Drug Administration's Manufacturer and User Facility Device Experience database was queried for all reports of ID adverse events from two leading manufacturers (Cook Vascular and Synovis Life Technologies) in free flap surgery from January 2010 to March 2020. Reports were reviewed and categorized. A comparison of reoperations within select categories was performed using Chi-square analysis. RESULTS: Of 209 included reports, the most common device malfunctions were venous anastomotic coupler misalignment (35.4%) and coupler ring detachment (24.4%). Synovis devices were used in 100% of reports of vessel compression and Cook Vascular devices were used in 77.7% of reports of probe detachment. Of 74 patient-related adverse events, the most common were reoperation (47.3%) and vessel occlusion (28.4%). Of five reported events of flap failure, two were associated with loss of ID signal. The proportion of Doppler signal loss events leading to reoperation was significantly greater than the proportion of any other Doppler-related event leading to reoperation. Intraoperative coupler replacement was the most commonly reported intervention (n = 86), and venous anastomosis with hand-suturing occurred in 30 device malfunctions. CONCLUSION: This study demonstrates a variety of ID-related malfunctions. One-third of device malfunctions were associated with patient complications, and false-positive Doppler signal loss contributed substantially to the requirement of surgical re-exploration. These are important considerations for surgical teams utilizing IDs in free tissue transfer procedures.
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Retalhos de Tecido Biológico , Anastomose Cirúrgica , Humanos , Microcirurgia , Próteses e Implantes , Ultrassonografia DopplerRESUMO
Manual assembly of atomically thin materials into heterostructures with desirable electronic properties is an approach that holds great promise. Despite the rapid expansion of the family of ultrathin materials, stackable and stable ferro/ferri magnets that are functional at room temperature are still out of reach. We report the growth of air-stable, transferable ultrathin iron oxide crystals that exhibit magnetic order at room temperature. These crystals require no passivation and can be prepared by scalable and cost-effective chemical vapor deposition. We demonstrate that the bonding between iron oxide and its growth substrate is van der Waals-like, enabling us to remove the crystals from their growth substrate and prepare iron oxide/graphene heterostructures.
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Neural circuits in the amygdala are important for associating the positive experience of drug taking with the coincident environmental cues. During abstinence, cue re-exposure activates the amygdala, increases dopamine release in the amygdala and stimulates relapse to drug use in an opioid dependent manner. Neural circuits in the amygdala and the learning that underlies these behaviours are inhibited by GABAergic synaptic inhibition. A specialised subtype of GABAergic neurons in the amygdala are the clusters of intercalated cells. We focussed on the main-island of intercalated cells because these neurons, located ventromedial to the basolateral amygdala, express very high levels of dopamine D1-receptor and µ-opioid receptor, release enkephalin and are densely innervated by the ventral tegmental area. However, where these neurons project to was not fully described and their regulation by opioids and dopamine was incomplete. To address this issue we electrically stimulated in the main-island of the intercalated cells in rat brain slices and made patch-clamp recordings of GABAergic synaptics from amygdala neurons. We found that main-island neurons had a strong GABAergic inhibitory output to pyramidal neurons of the basolateral nucleus and the medial central nucleus, the major output zones of the amygdala. Opioids inhibited both these synaptic outputs of the intercalated neurons and thus would disinhibit these target zones. Additionally, dopamine acting at D1-receptors inhibited main-island neuron synapses onto other main-island neurons. This data indicates that the inhibitory projections from the main-island neurons could influence multiple aspects of addiction and emotional processing in an opioid and dopamine dependent manner.
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Analgésicos Opioides/farmacologia , Dopamina/farmacologia , Sinapses/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Masculino , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/metabolismoRESUMO
We study the surface diffusion and alloying of Sb into GaAs nanowires (NWs) with controlled axial stacking of wurtzite (Wz) and zinc blende (Zb) crystal phases. Using atomically resolved scanning tunneling microscopy, we find that Sb preferentially incorporates into the surface layer of the {110}-terminated Zb segments rather than the {112Ì 0}-terminated Wz segments. Density functional theory calculations verify the higher surface incorporation rate into the Zb phase and find that it is related to differences in the energy barrier of the Sb-for-As exchange reaction on the two surfaces. These findings demonstrate a simple processing-free route to compositional engineering at the monolayer level along NWs.
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BACKGROUND AND AIMS: The lay public frequently access and rely on online information as a source of their medical knowledge. Many medical societies are unaware of national patient education material guidelines and subsequently fail to meet them. The goal of the present study was to evaluate the readability of patient education materials within the medical field of gastroenterology. METHODS: Two hundred fourteen articles pertaining to patient education materials were evaluated with ten well-established readability scales. The articles were available on the websites for the American College of Gastroenterology (ACG), the American Gastroenterological Association (AGA), the American Society of Gastrointestinal Endoscopy (ASGE), the British Society of Gastroenterology (BSG), and the NIH section National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). One-way analysis of variance (ANOVA) and Tukey's honest significant difference (HSD) post hoc analysis were conducted to determine any differences in level of readability between websites. RESULTS: The 214 articles were written at an 11.8 ± 2.1 grade level with a range of 8.0 to 16.0 grade level. A one-way ANOVA and Tukey's HSD post hoc analysis determined the ACG was written at a significantly (p < 0.05) more difficult level when compared to the AGA, the BSG, and the NIDDK websites. No differences were noted when comparing the ASGE website. CONCLUSIONS: None of the patient education materials were written at a level that met national guidelines. If the materials are redrafted, the general American public will likely have a greater understanding of the gastroenterology content.
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Gastroenterologia/educação , Recursos em Saúde , Internet , Educação de Pacientes como Assunto , Sociedades Médicas , HumanosRESUMO
Two novel compounds, pyridopyrimidines (1) and naphthyridines (2) were identified as potent inhibitors of bacterial NAD(+)-dependent DNA ligase (Lig) A in a fragment screening. SAR was guided by molecular modeling and X-ray crystallography. It was observed that the diaminonitrile pharmacophore made a key interaction with the ligase enzyme, specifically residues Glu114, Lys291, and Leu117. Synthetic challenges limited opportunities for diversification of the naphthyridine core, therefore most of the SAR was focused on a pyridopyrimidine scaffold. The initial diversification at R(1) improved both enzyme and cell potency. Further SAR developed at the R(2) position using the Negishi cross-coupling reaction provided several compounds, among these compounds 22g showed good enzyme potency and cellular potency.
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Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , DNA Ligases/antagonistas & inibidores , NAD/metabolismo , Naftiridinas/farmacologia , Pirimidinas/farmacologia , Antibacterianos/síntese química , Proteínas de Bactérias/química , DNA Ligases/química , Haemophilus influenzae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Naftiridinas/síntese química , Pirimidinas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Primary yolk sac tumor (YST) of the liver is an extremely rare extragonadal germ cell tumor. Here, we present a case of a young man who developed primary YST of the liver which metastasized to periductal lymph nodes causing bile duct obstruction. A 32-year-old male was referred from an outside hospital for evaluation of painless jaundice. Initial investigation showed common bile duct compression from periductal lymph nodes. Inital biopsy results were concerning for adenocarcinoma. The patient was ultimately diganosed with primary YST of the liver. He was then started on a curative-intent chemotherapy regimen of bleomycin, etoposide, and cisplatin. This case highlights the importance of keeping the primary YST of the liver on the differential diagnosis as initial staining patterns are similar to adenocarcinoma which has a very different management.
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BACKGROUND Intussusception occurs when a proximal region of the intestine telescopes into a distal region. It is more common in the pediatric population, with only 5% of cases occurring in adults. The most frequent causes of adult intussusception are malignancy, polyps, or diverticula. A very rare cause is neuroendocrine tumor (NET). NETs are a diverse group of neoplasms that arise from endocrine cells throughout the body. Here, we present a case of a patient who presented with ileo-ileal intussusception due to a T3N1 NET, grade 1. CASE REPORT A 60-year-old man with a medical history of peptic ulcer disease presented for evaluation of lower abdominal pain, dark "maroon" colored stools, and hematemesis for the past 2 days. Computed tomography (CT) of the abdomen and pelvis showed ileo-ileal intussusception. Exploratory laparotomy revealed a small bowel mass approximately 30 cm from the ileocecal valve. After removal of 15 cm of small bowel and 13 lymph nodes, pathology confirmed the diagnosis of a T3N1 NET, grade 1. He was subsequently referred to the Oncology Department, where he was cleared, with no need for additional surveillance. CONCLUSIONS In adult patients presenting with nonspecific abdominal pain and concern for small bowel obstruction, a CT scan can be helpful in diagnosing intussusception. When dealing with adult intussusception, the etiology needs to be carefully investigated to search for an underlying malignancy. In rare occasions, small bowel NETs can be the cause of intussusception and can therefore be identified early, before they metastasize and present with carcinoid syndrome.
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Intussuscepção , Tumores Neuroendócrinos , Humanos , Intussuscepção/etiologia , Masculino , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico , Pessoa de Meia-Idade , Doenças do Íleo/etiologia , Tomografia Computadorizada por Raios XRESUMO
In recent years, diagnostic radiology has become increasingly competitive leaving many applicants seeking to increase the strength of their applications. This paper aims to help inform future radiology applicants on how to prepare for a successful match into radiology. Using data from previous match cycles and from the radiology community, we provide recommendations on how to demonstrate commitment to radiology through creating interest groups, leading changes in their academic curriculums, becoming involved in local and national organizations, performing research, networking with fellow radiology colleagues, and seeking mentorship. In conclusion, this paper provides recommendations for medical students to enhance their competitiveness and increase the chances of matching into a competitive field.
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Internato e Residência , Radiologia , Estudantes de Medicina , Humanos , Radiologia/educação , Radiografia , MentoresRESUMO
Objective: To determine whether socio-demographic and preoperative clinical factors contribute to the percent total body weight loss (%TBWL) after bariatric surgery (BS). Background: BS is the most effective long-term treatment for medically complicated obesity. More information is needed about the factors that contribute to postoperative %TBWL in large and ethnically diverse cohorts. Methods: This retrospective study conducted in the Kaiser Permanente Northern California region included 7698 patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) between January 2009 and March 2015. Trajectory analyses were conducted from 5-year follow-up data to assign patients to "low," "average," or "high" postoperative %TBWL groups. We then evaluated whether age, sex, race/ethnicity, neighborhood deprivation index and preoperative body mass index (BMI)/weight loss, diabetes, hypertension, and sleep apnea contributed to postoperative %TBWL using logistic regression models. Results: Of 7698 patients (83.2% women), 48.6% underwent a RYGB and 51.4% underwent a SG. Postoperative %TBWL trajectories over 5 years were obtained in 6229 (81%) of 7698 eligible patients. About 27.8% and 29.3% of patients followed the "low" postoperative %TBWL trajectory, for RYGB and SG, respectively. Men, older patients, and Asian, Black, and Hispanic/Latino patients were more likely to be classified in the low postoperative %TBWL group. Patients showing lower postoperative %TBWL had a lower preoperative BMI (but lost less weight before surgery) and were more likely to have preoperative comorbidities. Conclusions: This study confirms and extends prior findings of the effects of several demographic and preoperative clinical factors on postoperative weight loss. Findings could improve the support of patients to achieve desired surgical outcomes.
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Introduction Resource overload describes the feeling medical students experience in choosing formal (faculty-prescribed) and informal study resources (not faculty-prescribed). This study aims to characterize students' use and perceptions of formal and informal study resources to inform their use in medical education. Methods This is a mixed-methods study utilizing a convenience sample of first-year medical students enrolled at the University of Central Florida College of Medicine during the academic year 2020-2021. A 40-question, five-point Likert scale, survey based on Keller's Attention, Relevance, Confidence, and Satisfaction (ARCS) Model of Motivational Design was distributed to medical students during the end of their first year of medical school. Multivariate analysis of variance determined differences between formal and informal resources for each construct. Interviews were also conducted by first-year medical students and analyzed using thematic analysis. Learning logs were completed during the beginning of the medical students' second year to assess daily study habits. Results Fifty-one students completed the survey with a response rate of 42.5%. Informal resources scored higher across all constructs: attention (formal: 3.4±1.2, informal: 4.0±1.1; p<.0125), relevance (formal: 3.8±1.1, informal: 4.3±1.0; p<.0125), confidence (formal: 3.2±1.2, informal: 4.1±1.1; p<.0125), satisfaction (formal: 2.8±1.2, informal: 3.6±1.2; p<.0125) (Likert scale 1-5, Mean±SD). Students found formal resources lacked depth and organization while informal resources allowed for concise understanding with retention cues. Learning log data reported similar use of formal and informal resources during week 1 (88.2% formal vs. 87.8% informal) and week 2 (84.6% formal vs. 82.6% informal). Conclusions Students preferred informal resources based on ARCS constructs. However, the actual usage of formal and informal resources was similar. Formal resources align more with curricular assessments, but informal resources aid student retention and understanding. Therefore, students find both formal and informal resources necessary for success. Faculty should consider integrating informal curriculum resources to optimize student learning.
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OBJECTIVE: Two-tiered preference signaling has been implemented in the radiology residency application system to reduce congestion in the setting of high-volume applications. Signals are an indicator of strong interest that an applicant can transmit to a limited number of programs. This study assessed the impact of program signaling on interview invitations, how applicants strategically used signals based on their application's competitiveness, and applicants' attitudes toward the current signaling system. METHODS: A survey was sent to radiology residency applicants registered with TheRadRoom during the 2024 application cycle. We queried the applicant's background, applications, signal distribution, and interview outcome depending on the type of signal sent. We also asked whether respondents received an interview invitation from a hypothetical "comparator non-signaled program" if they had one additional signal to use. Group differences were assessed using nonparametric Wilcoxon signed rank test. RESULTS: A total of 202 applicants completed the survey (28% response rate). Most applied to diagnostic radiology (81%). Nearly all respondents utilized all 6 gold (98%) and 6 silver (96.5%) signals. Interview invitation rates were significantly higher for signaled programs (59.8%±27.4%) than non-signaled (8.5%±8.5%); the invitation rate at the comparator non-signaled programs was 37%. Gold signaled programs had significantly higher interview rates (67.8%±29.3) than silver (51.8%±31.3%). Respondents used 49.2%(±21.7%) of their signals for "likely to match" programs, 33.1%(±20.9%) for "aspirational" programs, and 17.6%(±15.8%) for "safety" programs. Most respondents (146;76%) supported continuing the signaling system for future cycles. CONCLUSION: Signaling programs significantly enhanced interview invitation rates, with gold signals being more effective than silver. The applicants used about 6 total signals for "likely-to-match" programs, 2 for "aspirational" programs, and about 4 for "safety" programs.
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BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a complication of measles, occurring after a latency of 4-10 years. It continues to occur in developing countries although resurgence is being reported from developed countries. Characteristic features include progressive neuropsychiatric issues, myoclonus, seizures, movement disorders and visual impairment. Electroencephalography (EEG) typically shows periodic generalized discharges, and elevated CSF anti-measles antibodies are diagnostic. Movement disorders are being increasingly recognized as part of the clinical spectrum, and range from hyperkinetic (chorea, dystonia, tremor, tics) to hypokinetic (parkinsonism) disorders and ataxia. OBJECTIVES: This article aims to comprehensively review the spectrum of movement disorders associated with SSPE. METHODS: A literature search was conducted in PubMed and EMBASE databases in December 2023 and articles were identified for review. RESULTS: Movement disorders reported in SSPE included hyperkinetic (chorea, dystonia, tremor and tics), hypokinetic (parkinsonism), ataxia and extraocular movement disorders. Myoclonus, a core clinical feature, was the most frequent "abnormal movement." Movement disorders were observed in all clinical stages, and could also be a presenting feature, even sans myoclonus. Hyperkinetic movement disorders were more common than hypokinetic movement disorders. An evolution of movement disorders was observed, with ataxia, chorea and dystonia occurring earlier, and parkinsonism later in the disease. Neuroradiological correlates of movement disorders remained unclear. CONCLUSION: A wide spectrum of movement disorders was observed throughout the clinical stages of SSPE. Most data were derived from case reports and small case series. Multicentric longitudinal studies are required to better delineate the spectrum and evolution of movement disorders in SSPE.
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Transtornos dos Movimentos , Panencefalite Esclerosante Subaguda , Humanos , Coreia/etiologia , Coreia/fisiopatologia , Coreia/diagnóstico , Distonia/etiologia , Distonia/fisiopatologia , Eletroencefalografia , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/fisiopatologia , Transtornos dos Movimentos/diagnóstico , Mioclonia/etiologia , Mioclonia/fisiopatologia , Panencefalite Esclerosante Subaguda/complicações , Panencefalite Esclerosante Subaguda/diagnóstico , Panencefalite Esclerosante Subaguda/fisiopatologia , Tremor/etiologiaRESUMO
Acute limb ischaemia (ALI) is an emergent clinical condition that strains pre-hospital resources and impacts healthcare costs and patient quality of life. Hypothermia has long been used in clinical and research settings to mitigate ischaemic damage in tissues, but prompt reperfusion is needed to prevent loss of limb or function from ALI. To address the unmet need for pre-hospital intervention of threatened limbs awaiting definitive specialty care, we have focused on controlled application of hypothermia. Over years of animal experiments, phantom limb creation, and materials selection, we conceptualised and created a portable limb-cooling device that can be used alone or combined with a traditional tourniquet or resuscitative endovascular balloon occlusion of the aorta. Here, we describe our process of building and testing the device, from computer simulation through animal-limb metabolic studies, to prototype testing.