Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Peripheral direct current reduces naturally evoked nociceptive activity at the spinal cord in rodent models of pain.

Objective.Electrical neuromodulation is an established non-pharmacological treatment for chronic pain. However, existing devices using pulsatile stimulation typically inhibit pain pathways indirectly and are not suitable for all types of chronic pain. Direct current (DC) stimulation is a recently developed technology which affects small-diameter fibres more strongly than pulsatile stimulation. Since nociceptors are predominantly small-diameter Aδand C fibres, we investigated if this property could be applied to preferentially reduce nociceptive signalling.Approach.We applied a DC waveform to the sciatic nerve in rats of both sexes and recorded multi-unit spinal activity evoked at the hindpaw using various natural stimuli corresponding to different sensory modalities rather than broad-spectrum electrical stimulus. To determine if DC neuromodulation is effective across different types of chronic pain, tests were performed in models of neuropathic and inflammatory pain.Main results.We found that in both pain models tested, DC application reduced responses evoked by noxious stimuli, as well as tactile-evoked responses which we suggest may be involved in allodynia. Different spinal activity of different modalities were reduced in naïve animals compared to the pain models, indicating that physiological changes such as those mediated by disease states could play a larger role than previously thought in determining neuromodulation outcomes.Significance.Our findings support the continued development of DC neuromodulation as a method for reduction of nociceptive signalling, and suggests that it may be effective at treating a broader range of aberrant pain conditions than existing devices.

Associations of urban versus rural patient residence on outcomes after burn: A national inpatient sample database study.

INTRODUCTION: Burn patients in rural areas may encounter poorer outcomes associated with barriers to care; however, residence has not been studied in a large sample. The association between rural-versus-urban residence and outcomes after burn was examined using the National Inpatient Sample (NIS) database. METHODS: Using the 2019 NIS database, patients over 18 years with a primary diagnosis of burn or corrosive injury were included. Level of urbanization was categorized into six groups. Outcomes after burn such as in-hospital mortality, multifactorial shock, prolonged mechanical ventilation, length of stay, and total costs were analyzed after adjusting for demographic factors and hospital characteristics. RESULTS: We included 4671 records, which represented a weighted population of 23,085 patients. Rural residence was associated with higher percentage of prior transfer but not in-hospital mortality. Compared to the most urbanized counties, encounters from the most rural counties were associated with higher odds of shock (aOR:2.62, 99% CI: 1.04-6.56, p = 0.007). CONCLUSION: Burn encounters from less urbanized counties did not experience differences in mortality, rates of skin grafting, prolonged mechanical ventilation, length of stay, or overall costs. However, odds of shock were higher among the least urbanized counties. Despite improved triage and transportation systems across the US, disparities and challenges exist for burn patients from rural residence.

Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors.

The presynaptic serotonin transporter (SERT) clears extracellular serotonin following vesicular release to ensure temporal and spatial regulation of serotonergic signalling and neurotransmitter homeostasis. Prescription drugs used to treat neurobehavioral disorders, including depression, anxiety, and obsessive-compulsive disorder, trap SERT by blocking the transport cycle. In contrast, illicit drugs of abuse like amphetamines reverse SERT directionality, causing serotonin efflux. Both processes result in increased extracellular serotonin levels. By combining molecular dynamics simulations with biochemical experiments and using a homologous series of serotonin analogues, we uncovered the coupling mechanism between the substrate and the transporter, which triggers the uptake of serotonin. Free energy analysis showed that only scaffold-bound substrates could initiate SERT occlusion through attractive long-range electrostatic interactions acting on the bundle domain. The associated spatial requirements define substrate and inhibitor properties, enabling additional possibilities for rational drug design approaches.

The Pseudomonas aeruginosa lectin LecB modulates intracellular reactive oxygen species production in human neutrophils.

Pseudomonas aeruginosa is a Gram-negative bacterium and an opportunistic pathogen ubiquitously present throughout nature. LecB, a fucose-, and mannose-binding lectin, is a prominent virulence factor of P. aeruginosa, which can be expressed on the bacterial surface but also be secreted. However, the LecB interaction with human immune cells remains to be characterized. Neutrophils comprise the first line of defense against infections and their production of reactive oxygen species (ROS) and release of extracellular traps (NETs) are critical antimicrobial mechanisms. When profiling the neutrophil glycome we found several glycoconjugates on granule and plasma membranes that could potentially act as LecB receptors. In line with this, we here show that soluble LecB can activate primed neutrophils to produce high levels of intracellular ROS (icROS), an effect that was inhibited by methyl fucoside. On the other hand, soluble LecB inhibits P. aeruginosa-induced icROS production. In support of that, during phagocytosis of wild-type and LecB-deficient P. aeruginosa, bacteria with LecB induced less icROS production as compared with bacteria lacking the lectin. Hence, LecB can either induce or inhibit icROS production in neutrophils depending on the circumstances, demonstrating a novel and potential role for LecB as an immunomodulator of neutrophil functional responses.

High levels of short-chain fatty acids secreted by Candida albicans hyphae induce neutrophil chemotaxis via free fatty acid receptor 2.

Candida albicans belongs to our commensal mucosal flora and in immune-competent individuals in the absence of epithelial damage, this fungus is well tolerated and controlled by our immune defense. However, C. albicans is an opportunistic microorganism that can cause different forms of infections, ranging from superficial to life-threatening systemic infections. C. albicans is polymorphic and switches between different phenotypes (e.g. from yeast form to hyphal form). C. albicans hyphae are invasive and can grow into tissues to eventually reach circulation. During fungal infections, neutrophils in particular play a critical role for the defense, but how neutrophils are directed toward the invasive forms of fungi is less well understood. We set out to investigate possible neutrophil chemoattractants released by C. albicans into culture supernatants. We found that cell-free culture supernatants from the hyphal form of C. albicans induced both neutrophil chemotaxis and concomitant intracellular calcium transients. Size separation and hydrophobic sorting of supernatants indicated small hydrophilic factors as responsible for the activity. Further analysis showed that the culture supernatants contained high levels of short-chain fatty acids with higher levels from hyphae as compared to yeast. Short-chain fatty acids are known neutrophil chemoattractants acting via the neutrophil free fatty acid receptor 2. In line with this, the calcium signaling in neutrophils induced by hyphae culture supernatants was blocked by a free fatty acid receptor 2 antagonist and potently increased in the presence of a positive allosteric modulator. Our data imply that short-chain fatty acids may act as a recruitment signal whereby neutrophils can detect C. albicans hyphae.

Leaky lessons learned: Efflux prone dopamine transporter variant reveals sex and circuit specific contributions of D2 receptor signalling to neuropsychiatric disease.

Aberrant dopamine (DA) signalling has been implicated in various neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder (BPD) and addiction. The availability of extracellular DA is sculpted by the exocytotic release of vesicular DA and subsequent transporter-mediated clearance, rendering the presynaptic DA transporter (DAT) a crucial regulator of DA neurotransmission. D2-type DA autoreceptors (D2ARs) regulate multiple aspects of DA homeostasis, including (i) DA synthesis, (ii) vesicular release, (iii) DA neuron firing and (iv) the surface expression of DAT and DAT-mediated DA clearance. The DAT Val559 variant, identified in boys with ADHD or ASD, as well as in a girl with BPD, supports anomalous DA efflux (ADE), which we have shown drives tonic activation of D2ARs. Through ex vivo and in vivo studies of the DAT Val559 variant using transgenic knock-in mice, we have uncovered a circuit and sex-specific capacity of D2ARs to regulate DAT, which consequently disrupts DA signalling and behaviour differently in males and females. Our studies reveal the ability of the construct-valid DAT Val559 model to elucidate endogenous mechanisms that support DA signalling, findings that may be of translational and/or therapeutic importance.

SARS-CoV-2 vaccination uptake in six ethnic groups living in Amsterdam, the Netherlands: A registry-based study within the HELIUS cohort.

OBJECTIVE: Ethnic minority groups have experienced a disproportionate burden of COVID-19, and should therefore be especially encouraged to receive SARS-CoV-2 vaccination. This study compared first-dose uptake of the primary SARS-CoV-2 vaccination series across six ethnic groups in Amsterdam, the Netherlands in 2021. METHODS: We analyzed data from participants of the population-based HELIUS cohort. We linked their data to the SARS-CoV-2 vaccination registry data of the Public Health Service of Amsterdam. We included registry data from January 6, 2021 (the start of the Dutch vaccination campaign) until September 6, 2021 (a date by which all adults in the Netherlands could have received one or two vaccine doses). SARS-CoV-2 vaccination uptake was defined as having received at least one vaccine dose of the primary vaccination series. We examined the association between ethnicity and vaccination uptake using multivariable logistic regression, while accounting for the age and sex distribution of ethnic groups in Amsterdam. RESULTS: We included 19,006 participants (median age 53 years [interquartile range 41-62], 57% female). SARS-CoV-2 vaccination uptake was highest in the South-Asian Surinamese group (60.3%, 95%CI = 58.2-62.3%), followed by the Dutch (59.6%, 95%CI = 58.0-61.1%), Ghanaian (54.1%, 95%CI = 51.7-56.5%), Turkish (47.7%, 95%CI = 45.9-49.6%), African Surinamese (43.0%, 95%CI = 41.2-44.7%), and Moroccan (35.8%, 95%CI = 34.1-37.5%) groups. After adjusting for age, sex, perceived social support, and presence of relevant comorbidities, participants of African Surinamese, Ghanaian, Turkish and Moroccan origin were significantly less likely to be vaccinated than those of Dutch origin. CONCLUSIONS: Prevention strategies should continue tailoring to specific ethnic groups to encourage vaccination uptake and reduce barriers to vaccination.

Analysis of gender representation, authorship inflation, and institutional affiliation in abstract acceptance: a 5-year study.

Purpose: Our goals were to characterize associations of author number, author gender, and institutional affiliation on ratings and acceptances of abstracts submitted to one surgical education conference over 5 years. Methods: We retrospectively reviewed all abstracts submitted between 2017 and 2021 to the annual meeting of the Association for Surgical Education (ASE). Abstract data included average rater scores, acceptance status, author lists, and institutional affiliations. We cross-referenced last author affiliation with top-40 National Institutes of Health (NIH)-funded institutions and used a gender determination software to code first and last author genders. Results: We analyzed 1,162 abstracts. Higher reviewer scores demonstrated positive, weak associations with more authors [r(1160) = 0.191, p < 0.001] and institutions [r(1160) = 0.182, p < 0.001]. Significantly higher scores were noted for abstracts with last authors affiliated with top-40 NIH-funded institutions [4.18 (SD 0.96) vs. 3.72 (SD 1.12), p < 0.001]. Women were first authors (51.8%) (n = 602) and last authors (35.4%) (n = 411) of the time. Abstracts were rated significantly higher with women rather than men as first authors [3.98 (SD 0.99) vs. 3.82 (SD 1.12), p = 0.011] or last [4.01 (SD 1.04) vs. 3.82 (SD 1.10), p = 0.005]. Across all years, abstracts were accepted more often as podium or plenary presentations when submitted by women first [n = 279, 59.7% (p = 0.002)] or last [n = 183, 38.4% (p = 0.095)] authors. Conclusion: Abstracts whose last authors were affiliated with top-40 NIH-funded institutions received significantly higher scores, possibly indicating increased tangible or intangible resources contributing to research efforts. Abstracts with women first and last authors scored higher and were more frequently invited for plenary and podium presentations.

Severe chronic non-bacterial osteomyelitis in combination with total MPO deficiency and responsiveness to TNFα inhibition.

We describe a female patient suffering from severe chronic non-bacterial osteomyelitis (CNO) with systemic inflammation and advanced malnutrition and complete deficiency of myeloperoxidase (MPO). CNO is a rare autoinflammatory bone disorder associated with dysregulation of the innate immune system. MPO deficiency is a genetic disorder with partial or complete absence of the phagocyte peroxidase MPO. MPO deficiency has no established clinical phenotype but reports indicate increased susceptibility to infection and chronic inflammation. The patient's symptoms began at 10 years of age with pain in the thighs, systemic inflammation and malnutrition. She was diagnosed with CNO at 14 years of age. Treatment with nonsteroidal anti-inflammatory drugs, corticosteroids, bisphosphonates or IL1-receptor antagonists (anakinra) did not relieve the symptoms. However, the patient responded instantly and recovered from her clinical symptoms when treated with TNFα blockade (adalimumab). Three years after treatment initiation adalimumab was withdrawn, resulting in rapid symptom recurrence. When reintroducing adalimumab, the patient promptly responded and went into remission. In addition to clinical and laboratory profiles, neutrophil functions (reactive oxygen species, ROS; neutrophil extracellular traps, NETs; degranulation; apoptosis; elastase activity) were investigated both in a highly inflammatory state (without treatment) and in remission (on treatment). At diagnosis, neither IL1ß, IL6, nor TNFα was significantly elevated in serum, but since TNFα blockade terminated the inflammatory symptoms, the disease was likely TNFα-driven. All neutrophil parameters were normal both during treatment and treatment withdrawal, except for MPO-dependent intracellular ROS- and NET formation. The role of total MPO deficiency for disease etiology and severity is discussed.

Are We Speaking the Same Language? A Systematic Review on the Use of Consistent Language in Reporting Fat Necrosis in Autologous Fat Grafting of the Breast.

BACKGROUND: Autologous fat grafting is a widely adopted approach to optimize outcomes in breast reconstruction and augmentation. Although fat necrosis is a well-known consequence of autologous fat grafting, it remains inconsistently defined in the literature. In late 2014, the Food and Drug Administration released a draft guidance to restrict future autologous fat grafting-a statement that was permissively modified in late 2017. In the context of evolving guidelines and autologous fat grafting outcome data, the language and descriptions of fat necrosis are inconsistent in the literature. METHODS: Five databases were queried for studies reporting fat necrosis following autologous fat grafting for breast reconstruction or augmentation from inception to August 11, 2022. Studies were temporally stratified according to released FDA guidelines: pre-2015, 2015-2017, and 2018-2022. RESULTS: Sixty-one articles met inclusion criteria. Prior to 2015, 6 of 21 studies (28.6%) offered clear definitions of fat necrosis. In contrast, the 2015-2017 period demonstrated an absence of clear fat necrosis definitions (0/13 studies, p = 0.03). Though the 2018-2022 period exhibited a rise in annual publications compared with the pre-2015 period (5.4 vs. 1.9, respectively, p = 0.04), this was not matched by a rise in clear fat necrosis reporting (14.8% studies, p = 0.45). Across all periods, only 16.4% of articles offered clear definitions, which exhibited wide heterogeneity. CONCLUSION: Despite the increasing popularity of autologous fat grafting, fat necrosis remains inconsistently defined and described, especially in the context of changing FDA guidelines. This limits the reliable interpretation and application of the current literature reporting fat necrosis outcomes. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Mephedrone induces partial release at human dopamine transporters but full release at human serotonin transporters.

Mephedrone (4-methylmethcathinone) is a cathinone derivative that is recreationally consumed for its energizing and empathogenic effects. The stimulating properties are believed to arise from the ability of mephedrone to interact with the high-affinity transporters for dopamine (DA) (DAT) and norepinephrine (NET), whereas the entactogenic effect presumably relies on its activity at the serotonin (5-HT) transporter (SERT). Early studies found that mephedrone acts as a releaser at NET, DAT and SERT, and thus promotes efflux of the respective monoamines. Evidence linked drug-induced reverse transport of 5-HT via SERT to prosocial effects, whereas activity at DAT is strongly correlated with abuse liability. Consequently, we sought to evaluate the pharmacology of mephedrone at human (h) DAT and SERT, heterologously expressed in human embryonic kidney 293 cells, in further detail. In line with previous studies, we report that mephedrone evokes carrier-mediated release via hDAT and hSERT. We found this effect to be sensitive to the protein kinase C inhibitor GF109203X. Electrophysiological recordings revealed that mephedrone is actively transported by hDAT and hSERT. However, mephedrone acts as a full substrate of hSERT but as a partial substrate of hDAT. Furthermore, when compared to fully efficacious releasing agents at hDAT and hSERT (i.e. S(+)-amphetamine and para-chloroamphetamine, respectively) mephedrone displays greater efficacy as a releaser at hSERT than at hDAT. In summary, this study provides additional insights into the molecular mechanism of action of mephedrone at hDAT and hSERT.

Relative contributions of pre-pandemic factors and intra-pandemic activities to differential COVID-19 risk among migrant and non-migrant populations in the Netherlands: lessons for future pandemic preparedness.

BACKGROUND: Although risk factors for differences in SARS-CoV-2 infections between migrant and non-migrant populations in high income countries have been identified, their relative contributions to these SARS-CoV-2 infections, which could aid in the preparation for future viral pandemics, remain unknown. We investigated the relative contributions of pre-pandemic factors and intra-pandemic activities to differential SARS-CoV-2 infections in the Netherlands by migration background (Dutch, African Surinamese, South-Asian Surinamese, Ghanaians, Turkish, and Moroccan origin). METHODS: We utilized pre-pandemic (2011-2015) and intra-pandemic (2020-2021) data from the HELIUS cohort, linked to SARS-CoV-2 PCR test results from Public Health Service of Amsterdam (GGD Amsterdam). Pre-pandemic factors included socio-demographic, medical, and lifestyle factors. Intra-pandemic activities included COVID-19 risk aggravating and mitigating activities such as physical distancing, use of face masks, and other similar activities. We calculated prevalence ratios (PRs) in the HELIUS population that was merged with GGD Amsterdam PCR test data using robust Poisson regression (SARS-CoV-2 PCR test result as outcome, migration background as predictor). We then obtained the distribution of migrant and non-migrant populations in Amsterdam as of January 2021 from Statistics Netherlands. The migrant populations included people who have migrated themselves as well as their offspring. We used PRs and the population distributions to calculate population attributable fractions (PAFs) using the standard formula. We used age and sex adjusted models to introduce pre-pandemic factors and intra-pandemic activities, noting the relative changes in PAFs. RESULTS: From 20,359 eligible HELIUS participants, 8,595 were linked to GGD Amsterdam PCR test data and included in the study. Pre-pandemic socio-demographic factors (especially education, occupation, and household size) resulted in the largest changes in PAFs when introduced in age and sex adjusted models (up to 45%), followed by pre-pandemic lifestyle factors (up to 23%, especially alcohol consumption). Intra-pandemic activities resulted in the least changes in PAFs when introduced in age and sex adjusted models (up to 16%). CONCLUSION: Interventions that target pre-pandemic socio-economic status and other drivers of health inequalities between migrant and non-migrant populations are urgently needed at present to better prevent infection disparities in future viral pandemics.

The kinesin Kif21b binds myosin Va and mediates changes in actin dynamics underlying homeostatic synaptic downscaling.

Homeostatic synaptic plasticity adjusts the strength of synapses to restrain neuronal activity within a physiological range. Postsynaptic guanylate kinase-associated protein (GKAP) controls the bidirectional synaptic scaling of AMPA receptors (AMPARs); however, mechanisms by which chronic activity triggers cytoskeletal remodeling to downscale synaptic transmission are barely understood. Here, we report that the microtubule-dependent kinesin motor Kif21b binds GKAP and likewise is located in dendritic spines in a myosin Va- and neuronal-activity-dependent manner. Kif21b depletion unexpectedly alters actin dynamics in spines, and adaptation of actin turnover following chronic activity is lost in Kif21b-knockout neurons. Consistent with a role of the kinesin in regulating actin dynamics, Kif21b overexpression promotes actin polymerization. Moreover, Kif21b controls GKAP removal from spines and the decrease of GluA2-containing AMPARs from the neuronal surface, thereby inducing homeostatic synaptic downscaling. Our data highlight a critical role of Kif21b at the synaptic actin cytoskeleton underlying homeostatic scaling of neuronal firing.

Dental students' perceptions and educational impact of preclinical interactive videos compared and in combination with live demonstrations.

OBJECTIVE: To study the utility of simulation videos with embedded quiz items compared and in combination with live hands-on demonstrations of dental procedures. METHODS: Thirty-three videos with embedded items were developed to help students understand the procedures they had to practice in the simulation laboratory. Videos were uploaded to the university LMS platform for students to watch and complete the embedded items as many times as they liked. All 76 students from 2021 and 73 from 2022 Integrated Dentistry III courses were invited to participate in the study. Practical (OSCE) and theoretical (MCQ) exam grades of the 2021 academic year, when interactive videos replaced live demonstrations, were collected and compared to those of the previous years (2017-2020) when only live demonstrations were performed, as were those from the 2022 academic year, when videos were complemented with hands-on live demonstrations. At the end of each year, a perception questionnaire was voluntarily completed by the students. RESULTS: Assessment grades were significantly higher in the 2021 academic year when interactive videos were incorporated versus the 2017-2020 period when only live demonstrations were performed. However, the combination of interactive videos with live demonstrations performed during 2022 showed the highest exam grades. Seventy-nine percent of students answered the questionnaire, highly valued the utility of the interactive videos and liked the embedded items. Overall, they stated that they learned from the videos. CONCLUSIONS: Interactive videos of preclinical procedures with embedded items combined with live demonstrations can significantly enhance students' learning and are valued by students.

Prior COVID-19 Infection Predisposes to Worse Outcomes After Autologous Breast Reconstruction: A Propensity Score-Matched Analysis.

BACKGROUND: Major shifts in health care systems worldwide have occurred because of coronavirus disease 2019 (COVID-19). With nearly half of all Americans now having a history of COVID-19 infection, there is a pressing need to better understand the importance of prior COVID-19 infection as a potential surgical risk factor. The aim of this study was to investigate the impact of a history of prior COVID-19 infection on patient outcomes after autologous breast reconstruction. METHODS: We performed a retrospective study using the TriNetX research database, which contains deidentified patient records from 58 participating international health care organizations. All patients who underwent autologous breast reconstruction between March 1, 2020, and April 9, 2022, were included and were grouped based on history of a prior COVID-19 infection. Demographic, preoperative risk factors, and 90-day postoperative complication data were compared. Data were analyzed by propensity score-matched analysis on TriNetX. Statistical analyses were performed by Fisher exact, χ2, and Mann-Whitney U tests as appropriate. Significance was set at P values of <0.05. RESULTS: Patients with a history of autologous breast reconstruction within our temporal study window (N = 3215) were divided into groups with (n = 281) and without (n = 3603) a prior COVID-19 diagnosis. Nonmatched patients with prior COVID-19 had increased rates of select 90-day postoperative complications, including wound dehiscence, contour deformities, thrombotic events, any surgical site complications, and any complications overall. Use of anticoagulant, antimicrobial, and opioid medications was also found to be higher in those with prior COVID-19.After performing propensity-score matching, each cohort consisted of 281 patients without statistically significant differences between any baseline characteristics. When comparing outcomes between matched cohorts, patients with a history of COVID-19 had increased rates of wound dehiscence (odds ratio [OR], 1.90; P = 0.030), thrombotic events (OR, 2.83; P = 0.0031), and any complications (OR, 1.52; P = 0.037). CONCLUSIONS: Our results suggest that prior COVID-19 infection is a significant risk factor for adverse outcomes after autologous breast reconstruction. Patients with a history of COVID-19 have 183% higher odds of postoperative thromboembolic events, warranting careful patient selection and postoperative management.

Food Security as a Predictor of Global Pediatric Postburn Mortality.

Food security (FS) is defined as access to sufficient and nutritious food. Children, especially those in low- and middle- income countries (LMICs), are disproportionately affected by low FS. We hypothesized high FS would be predictive of decreased pediatric postburn mortality in LMICs. Publicly-available, deidentified datasets were obtained from the World Health Organization's Global Burn Registry (GBR) and Economist Intelligence Unit's Global FS Index (GFSI). The GFSI calculates FS scores annually from intergovernmental organization data reviewed by a panel of experts. FS scores are reported on a 0 to 100 scale with 100 indicating the highest FS. Patients aged 0 to 19 yr were included; after linking GBR and GFSI datasets, countries with <100 burn patients were excluded. Data were analyzed with descriptive statistics and bivariate analyses. Multiple logistic regression controlling for confounders was used to quantify associations between mortality and FS score. Significance was set at P < 0.05. From 2016 to 2020, there were 2,246 cases including 259 deaths (11.5%) over nine countries. Those who died had a higher median age (7 [IQR 2, 15] vs 3 [2, 6] years, P < 0.001), higher proportion of females (48.6% vs 42.0%, P =0.048), and lower median FS score (55.7 [IQR 45.3, 58.2] vs 59.8 [IQR 46.7, 65.7], P < 0.001). Increasing FS score was associated with decreased odds of postburn mortality [multivariable odds ratio 0.78 (95% confidence interval 0.73 to 0.83), P < 0.001]. With the association between FS and mortality, international efforts to increase FS in LMICs may help improve pediatric burn patient survival.

Kappa Opioid Receptor Antagonism Rescues Genetic Perturbation of Dopamine Homeostasis: Molecular, Physiological and Behavioral Consequences.

Aberrant dopamine (DA) signaling is implicated in schizophrenia, bipolar disorder (BPD), autism spectrum disorder (ASD), substance use disorder, and attention-deficit/hyperactivity disorder (ADHD). Treatment of these disorders remains inadequate. We established that the human DA transporter (DAT) coding variant (DAT Val559), identified in individuals with ADHD, ASD, or BPD, exhibits anomalous DA efflux (ADE) that is blocked by therapeutic amphetamines and methylphenidate. As the latter agents have high abuse liability, we exploited DAT Val559 knock-in mice to identify non-addictive agents that can normalize DAT Val559 functional and behavioral effects ex vivo and in vivo. Kappa opioid receptors (KORs) are expressed by DA neurons and modulate DA release and clearance, suggesting that targeting KORs might offset the effects of DAT Val559. We establish that enhanced DAT Thr53 phosphorylation and increased DAT surface trafficking associated with DAT Val559 expression are mimicked by KOR agonism of wildtype preparations and rescued by KOR antagonism of DAT Val559 ex vivo preparations. Importantly, KOR antagonism also corrected in vivo DA release and sex-dependent behavioral abnormalities. Given their low abuse liability, our studies with a construct valid model of human DA associated disorders reinforce considerations of KOR antagonism as a pharmacological strategy to treat DA associated brain disorders.