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Background: Perianal fistulas may affect 15% to 50% of patients with Crohn's disease. Treatment is complex, requiring a multidisciplinary approach. Darvadstrocel (allogenic mesenchymal cells obtained from lipoaspirates) was approved in 2018 by the European and Spanish Agencies of Medicines and Medical Products as a treatment for fistulas in Crohn's disease. Recent guidelines from the European Crohn's and Colitis Organisation and Spanish Working Group on Crohn's Disease and Ulcerative Colitis state that darvadstrocel is effective with a favorable safety profile and a strong level of evidence (n = 2)., Objective: Presenting real-world effectiveness data for darvadstrocel in a Spanish population., Design: Observational retrospective cohort study with prospective data gathering., Settings: The study was conducted at 14 institutions in Spain., Patients: From November 2019 to April 2022, all patients (n = 73) treated with darvadstrocel in these institutions were included, fulfilling the following criteria: 1) complex fistula/s in a patient with Crohn's disease; 2) failure of conventional and antitumor necrosis factor treatment; and 3) the absence of collections of >2 cm confirmed by pelvic MRI at the time of surgery., Interventions: Darvadstrocel treatment., Main Outcome Measures: Clinical response (closure of 50% or more of external openings), complete clinical closure (100% of external openings), and radiological closure (no fluid collection >2 cm, edema, or inflammation) evaluated 6 months after treatment., Results: Clinical response was observed in 63 patients (86.3%), complete clinical closure in 50 patients (68.5%), and radiological closure in 45 patients (69.2%). Combined clinical and radiological response was observed in 41 patients (63.1%). Not all clinically healed patients had radiological closure, and vice versa. No serious adverse events were reported., Limitations: Retrospective nature of the study., Conclusions: Study results were consistent with those reported in previous clinical trials, real-world efficacy findings from the INSPIRE study (assessing darvadstrocel effectiveness in Europe, Israel, Switzerland, United Kingdom, and Japan), and previously published literature. Darvadstrocel was effective and demonstrated a favorable safety profile when used in normal clinical practice for the treatment of fistulas in Crohn's disease. See Video Abstract ., Uso De Darvadstrocel Terapia Con Clulas Madre Alognicas Para Fstula En Enfermedad De Crohn En La Prctica Clnica Real El Proyecto Nacional Para Implementar De Clulas Madre Mesenquimales Para El Tratamiento De La Fstula De Crohn Perianal El Estudio Prime: ANTECEDENTES:Las fístulas perianales pueden afectar entre el 15 y el 50% de los pacientes con enfermedad de Crohn. El tratamiento es complejo y requiere un enfoque multidisciplinario. El darvadstrocel (células mesenquimales alogénicas obtenidas a partir de lipoaspirados) fue aprobado en 2018 por las Agencias Europea y Española de Medicamentos y Productos Sanitarios como tratamiento de las fístulas en la EC. Las recientes directrices de la Organización Europea de Crohn y Colitis y del Grupo de Trabajo Español sobre la Enfermedad de Crohn y Colitis Ulcerosa afirman que darvadstrocel es eficaz con un perfil de seguridad favorable y un sólido nivel de evidencia (2).OBJETIVO:Presentar datos de eficacia real de darvadstrocel en población española.DISEÑO:Estudio de cohorte retrospectivo observacional con recopilación prospectiva de datos.ESCENARIO:14 instituciones.PACIENTES:Desde noviembre de 2019 hasta abril de 2022, se incluyeron todos los pacientes (73) tratados con darvadstrocel en estas instituciones, que cumplieron los siguientes criterios: 1) fístula/s compleja/s en un paciente con enfermedad de Crohn; 2) fracaso del tratamiento convencional y anti factor de necrosis tumoral; 3) ausencia de colecciones > 2 cm confirmada por resonancia magnética pélvica en el momento de la cirugía.INTERVENCIONES:Tratamiento con Darvadstrocel.PRINCIPALES MEDIDAS DE RESULTADO:Respuesta clínica (cierre de ≥50% de las aberturas externas), cierre clínico completo (100% de las aberturas externas) y cierre radiológico (sin acumulación de líquido >2 cm, sin edema ni inflamación) evaluados 6 meses después del tratamiento.RESULTADOS:Se observó respuesta clínica en 63 pacientes (86.3%), cierre clínico completo en 50 pacientes (68.5%) y cierre radiológico en 45 pacientes (69.2%). Se observó respuesta clínica y radiológica combinada en 41 pacientes (63.1%). No todos los pacientes clínicamente curados tuvieron cierre radiológico y viceversa. No hubo eventos adversos graves reportados.LIMITACIONES:Estudio retrospectivoCONCLUSIONES:Los resultados del estudio fueron consistentes con los informados en ensayos clínicos anteriores, los hallazgos de eficacia en el mundo real del estudio INSPIRE (que evalúa la efectividad de darvadstrocel en Europa, Israel, Suiza, el Reino Unido y Japón) y la literatura publicada anteriormente. Darvadstrocel fue eficaz y demostró un perfil de seguridad favorable cuando se utiliza en la práctica clínica habitual para el tratamiento de fístulas en la enfermedad de Crohn. (Traducción-Dr. Jorge Silva Velazco )., (Copyright © The ASCRS 2024.)

Toxin-antidote systems are selfish genetic elements composed of a linked toxin and antidote. The peel-1 zeel-1 toxin-antidote system in C. elegans consists of a transmembrane toxin protein PEEL-1 which acts cell autonomously to kill cells. Here we investigate the molecular mechanism of PEEL-1 toxicity. We find that PEEL-1 requires a small membrane protein, PMPL-1, for toxicity. Together, PEEL-1 and PMPL-1 are sufficient for toxicity in a heterologous system, HEK293T cells, and cause cell swelling and increased cell permeability to monovalent cations. Using purified proteins, we show that PEEL-1 and PMPL-1 allow ion flux through lipid bilayers and generate currents which resemble ion channel gating. Our work suggests that PEEL-1 kills cells by co-opting PMPL-1 and creating a cation channel., Competing Interests: Competing interests: Authors declare no competing interests.

Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, chronic inflammation, oxidative stress, and impaired neuronal function. These factors can contribute to serious comorbidities, including metabolic disorders and cardiovascular diseases. To investigate the molecular impact of CIH, we examined male C57BL/6J mice exposed to CIH for 21 days, comparing with normoxic controls. We used single-nucleus RNA sequencing to comprehensively examine the transcriptomic impact of CIH on key cell classes within the brainstem, specifically excitatory neurons, inhibitory neurons, and oligodendrocytes. These cell classes regulate essential physiological functions, including autonomic tone, cardiovascular control, and respiration. Through analysis of 10,995 nuclei isolated from pontine-medullary tissue, we identified seven major cell classes, further subdivided into 24 clusters. Our findings among these cell classes, revealed significant differential gene expression, underscoring their distinct responses to CIH. Notably, neurons exhibited transcriptional dysregulation of genes associated with synaptic transmission, and structural remodeling. In addition, we found dysregulated genes encoding ion channels and inflammatory response. Concurrently, oligodendrocytes exhibited dysregulated genes associated with oxidative phosphorylation and oxidative stress. Utilizing CellChat network analysis, we uncovered CIH-dependent altered patterns of diffusible intercellular signaling. These insights offer a comprehensive transcriptomic cellular atlas of the pons-medulla and provide a fundamental resource for the analysis of molecular adaptations triggered by CIH. NEW & NOTEWORTHY This study on chronic intermittent hypoxia (CIH) from pons-medulla provides initial insights into the molecular effects on excitatory neurons, inhibitory neurons, and oligodendrocytes, highlighting our unbiased approach, in comparison with earlier studies focusing on single target genes. Our findings reveal that CIH affects cell classes distinctly, and the dysregulated genes in distinct cell classes are associated with synaptic transmission, ion channels, inflammation, oxidative stress, and intercellular signaling, advancing our understanding of CIH-induced molecular responses.

The sympathetic nervous system modulates arterial blood pressure. Individuals with obstructive sleep apnea (OSA) experience numerous nightly hypoxic episodes and exhibit elevated sympathetic activity to the cardiovascular system leading to hypertension. This suggests that OSA disrupts normal respiratory-sympathetic coupling. This study investigates the role of the postinspiratory complex (PiCo) and preBötzinger complex (preBötC) in respiratory-sympathetic coupling under control conditions and following exposure to chronic intermittent hypoxia (CIH) for 21 days (5% O 2 -80 bouts/day). The surface of the ventral brainstem was exposed in urethane (1.5 g/kg) anesthetized, spontaneously breathing adult mice. Cholinergic (ChAT), glutamatergic (Vglut2), and neurons that co-express ChAT and Vglut2 at PiCo, as well as Dbx1 and Vglut2 neurons at preBötC, were optogenetically stimulated while recording activity from the diaphragm (DIA), vagus nerve (cVN), and cervical sympathetic nerve (cSN). Following CIH exposure, baseline cSN activity increased, breathing frequency increased, and expiratory time decreased. In control mice, stimulating PiCo specific cholinergic-glutamatergic neurons caused a sympathetic burst during all phases of the respiratory cycle, whereas optogenetic activation of cholinergic-glutamatergic PiCo neurons in CIH mice increased sympathetic activity only during postinspiration and late expiration. Stimulation of glutamatergic PiCo neurons increased cSN activity during the postinspiratory phase in control and CIH mice. Optogenetic stimulation of ChAT containing neurons in the PiCo area did not affect sympathetic activity under control or CIH conditions. Stimulating Dbx1 or Vglut2 neurons in preBötC evoked an inspiration and a concomitant cSN burst under control and CIH conditions. Taken together, these results suggest that PiCo and preBötC contribute to respiratory-sympathetic coupling, which is altered by CIH, and may contribute to the hypertension observed in patients with OSA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Karlen-Amarante, Glovak, Huff, Oliveira and Ramirez.)

Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that results in multiple bouts of intermittent hypoxia. OSA has many neurological and systemic comorbidities, including dysphagia, or disordered swallow, and discoordination with breathing. However, the mechanism in which chronic intermittent hypoxia (CIH) causes dysphagia is unknown. Recently, we showed the postinspiratory complex (PiCo) acts as an interface between the swallow pattern generator (SPG) and the inspiratory rhythm generator, the preBötzinger complex, to regulate proper swallow-breathing coordination (Huff et al., 2023). PiCo is characterized by interneurons co-expressing transporters for glutamate (Vglut2) and acetylcholine (ChAT). Here we show that optogenetic stimulation of ChATcre:Ai32, Vglut2cre:Ai32, and ChATcre:Vglut2FlpO:ChR2 mice exposed to CIH does not alter swallow-breathing coordination, but unexpectedly disrupts swallow behavior via triggering variable swallow motor patterns. This suggests that glutamatergic-cholinergic neurons in PiCo are not only critical for the regulation of swallow-breathing coordination, but also play an important role in the modulation of swallow motor patterning. Our study also suggests that swallow disruption, as seen in OSA, involves central nervous mechanisms interfering with swallow motor patterning and laryngeal activation. These findings are crucial for understanding the mechanisms underlying dysphagia, both in OSA and other breathing and neurological disorders., Competing Interests: AH, MK, LO, JR No competing interests declared, (© 2023, Huff et al.)

Neuronal networks possess the ability to regulate their activity states in response to disruptions. How and when neuronal networks turn from physiological into pathological states, leading to the manifestation of neuropsychiatric disorders, remains largely unknown. Here, we propose that neuronal networks intrinsically maintain network stability even at the cost of neuronal loss. Despite the new stable state being potentially maladaptive, neural networks may not reverse back to states associated with better long-term outcomes. These maladaptive states are often associated with hyperactive neurons, marking the starting point for activity-dependent neurodegeneration. Transitions between network states may occur rapidly, and in discrete steps rather than continuously, particularly in neurodegenerative disorders. The self-stabilizing, metastable, and noncontinuous characteristics of these network states can be mathematically described as attractors. Maladaptive attractors may represent a distinct pathophysiological entity that could serve as a target for new therapies and for fostering resilience., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Volatile anesthetics induce hyperpolarizing potassium currents in spinal cord neurons that may contribute to their mechanism of action. They are induced at lower concentrations of isoflurane in noncholinergic neurons from mice carrying a loss-of-function mutation of the Ndufs4 gene, required for mitochondrial complex I function. The yeast NADH dehydrogenase enzyme, NDi1, can restore mitochondrial function in the absence of normal complex I activity, and gain-of-function Ndi1 transgenic mice are resistant to volatile anesthetics. The authors tested whether NDi1 would reduce the hyperpolarization caused by isoflurane in neurons from Ndufs4 and wild-type mice. Since volatile anesthetic behavioral hypersensitivity in Ndufs4 is transduced uniquely by glutamatergic neurons, it was also tested whether these currents were also unique to glutamatergic neurons in the Ndufs4 spinal cord., Methods: Spinal cord neurons from wild-type, NDi1, and Ndufs4 mice were patch clamped to characterize isoflurane sensitive currents. Neuron types were marked using fluorescent markers for cholinergic, glutamatergic, and γ-aminobutyric acid-mediated (GABAergic) neurons. Norfluoxetine was used to identify potassium channel type. Neuron type-specific Ndufs4 knockout animals were generated using type-specific Cre-recombinase with floxed Ndufs4., Results: Resting membrane potentials (RMPs) of neurons from NDi1;Ndufs4, unlike those from Ndufs4, were not hyperpolarized by 0.6% isoflurane (Ndufs4, ΔRMP -8.2 mV [-10 to -6.6]; P = 1.3e-07; Ndi1;Ndufs4, ΔRMP -2.1 mV [-7.6 to +1.4]; P = 1). Neurons from NDi1 animals in a wild-type background were not hyperpolarized by 1.8% isoflurane (wild-type, ΔRMP, -5.2 mV [-7.3 to -3.2]; P = 0.00057; Ndi1, ΔRMP, 0.6 mV [-1.7 to 3.2]; P = 0.68). In spinal cord slices from global Ndufs4 animals, holding currents (HC) were induced by 0.6% isoflurane in both GABAergic (ΔHC, 81.3 pA [61.7 to 101.4]; P = 2.6e-05) and glutamatergic (ΔHC, 101.2 pA [63.0 to 146.2]; P = 0.0076) neurons. In neuron type-specific Ndufs4 knockouts, HCs were increased in cholinergic (ΔHC, 119.5 pA [82.3 to 156.7]; P = 0.00019) and trended toward increase in glutamatergic (ΔHC, 85.5 pA [49 to 126.9]; P = 0.064) neurons but not in GABAergic neurons., Conclusions: Bypassing complex I by overexpression of NDi1 eliminates increases in potassium currents induced by isoflurane in the spinal cord. The isoflurane-induced potassium currents in glutamatergic neurons represent a potential downstream mechanism of complex I inhibition in determining minimum alveolar concentration., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: The COVID-19 pandemic necessitated rapid changes in healthcare delivery in Guatemala's public primary care settings. A new hypertension program, implemented as part of a type 2 hybrid trial since 2019, exemplifies an implementation effort amidst a changing context in an under-resourced setting. We assessed the implementation of an evidence-based intervention (EBI; protocol-based hypertension treatment) and one of its main implementation strategies (team-based collaborative care), raising implications for health equity and sustainability. We present innovative application of systems thinking visuals., Methods: Conducting a convergent mixed methods analysis, we assessed implementation in response to contextual changes across five Ministry of Health (MoH) districts at the pandemic's onset. Utilizing quantitative programmatic data and qualitative interviews with stakeholders (n=18; health providers, administrators, study staff), we evaluated dimensions of "Reach, Effectiveness, Adoption, Implementation and Maintenance," RE-AIM (Reach, Implementation delivery + adaptations), and "Practical Robust Implementation and Sustainability Model," PRISM (Organizational perspective on the EBI, Fit, Implementation and sustainability infrastructure) frameworks. We assessed representativeness by comparing participants to census data. To assess implementation delivery, we built behavior-over-time (BOT) graphs with quantitative programmatic data (July 2019-July 2021). To assess adaptations and contextual changes, we performed matrix-based thematic qualitative analysis. We converged quantitative implementation delivery data + qualitative adaptations data in joint displays. Finally, we analyzed qualitative and quantitative results across RE-AIM/PRISM and health districts to identify equity and sustainability considerations., Results: Contextual factors that facilitated program delivery included the perception that the EBI was beneficial, program champions, and staff communication. Key barriers to implementation delivery included competition with other primary care activities and limited implementation infrastructure (e.g., equipment, medications). Contextual changes related to COVID-19 hindered implementation delivery, threatened sustainability, and may have exacerbated inequities. However, adaptations that were planned enhanced implementation delivery and may have supported improved equity and sustainability., Conclusions: Recognition of an EBI's benefits and program champions are important for supporting initial uptake. The ability to plan adaptations amid rapid contextual changes has potential advantages for sustainability and equitable delivery. Systems thinking tools and mixed methods approaches may shed light on the relations between context, adaptations, and equitable and sustainable implementation., Trial Registration: NCT03504124., (© 2024. The Author(s).)

Breathing is vital and must be concurrently robust and flexible. This rhythmic behavior is generated and maintained within a rostrocaudally aligned set of medullary nuclei called the ventral respiratory column (VRC). The rhythmic properties of individual VRC nuclei are well known, yet technical challenges have limited the interrogation of the entire VRC population simultaneously. Here we characterize over 15,000 medullary units using high-density electrophysiology, opto-tagging and histological reconstruction. Population dynamics analysis reveals consistent rotational trajectories through a low-dimensional neural manifold. These rotations are robust and maintained even during opioid-induced respiratory depression. During severe hypoxia-induced gasping, the low-dimensional dynamics of the VRC reconfigure from rotational to all-or-none, ballistic efforts. Thus, latent dynamics provide a unifying lens onto the activities of large, heterogeneous populations of neurons involved in the simple, yet vital, behavior of breathing, and well describe how these populations respond to a variety of perturbations., (© 2024. The Author(s).)

This paper introduces an approach to quantifying ecological resilience in biological systems, particularly focusing on noisy systems responding to episodic disturbances with sudden adaptations. Incorporating concepts from nonequilibrium statistical mechanics, we propose a measure termed "ecological resilience through adaptation," specifically tailored to noisy, forced systems that undergo physiological adaptation in the face of stressful environmental changes. Randomness plays a key role, accounting for model uncertainty and the inherent variability in the dynamical response among components of biological systems. Our measure of resilience is rooted in the probabilistic description of states within these systems and is defined in terms of the dynamics of the ensemble average of a model-specific observable quantifying success or well-being. Our approach utilizes stochastic linear response theory to compute how the expected success of a system, originally in statistical equilibrium, dynamically changes in response to a environmental perturbation and a subsequent adaptation. The resulting mathematical derivations allow for the estimation of resilience in terms of ensemble averages of simulated or experimental data. Finally, through a simple but clear conceptual example, we illustrate how our resilience measure can be interpreted and compared to other existing frameworks in the literature. The methodology is general but inspired by applications in plant systems, with the potential for broader application to complex biological processes.

Proteins are important molecules involved in an immensely large number of biological processes. Being capable of manipulating proteins is critical for developing reliable and affordable techniques to analyze and/or detect them. Such techniques would enable the production of therapeutic agents for the treatment of diseases or other biotechnological applications (e.g., bioreactors or biocatalysis). Microfluidic technology represents a potential solution to protein manipulation challenges because of the diverse phenomena that can be exploited to achieve micro- and nanoparticle manipulation. In this review, we discuss recent contributions made in the field of protein manipulation in microfluidic systems using different physicochemical principles and techniques, some of which are miniaturized versions of already established macro-scale techniques., (© 2023 Wiley-VCH GmbH.)

Tuberous sclerosis complex is a neurocutaneous syndrome caused by an autosomal dominant genetic disorder. This condition can lead to the expression of many vascular anomalies especially, in the pediatric population. Likewise, it has been linked with aortic aneurysm development. We report a case of a 12-year-old boy who presented a 97 × 70 mm Crawford type IV thoracoabdominal aortic aneurysm. Satisfactory open surgical repair was performed with an 18-mm multibranched dacron tube graft. Clinical and imaging findings revealed a de novo tuberous sclerosis diagnosis. The patient was discharged uneventfully during a 1-month follow-up., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: HSV-1 causes lifelong, incurable infections and diseases ranging from mucocutaneous lesions to fatal encephalitis. Fusion of viral and host membranes is a critical step in HSV-1 infection of target cells that requires multiple factors on both the viral and host sides. Due to this complexity, many fundamental questions remain unanswered, such as the identity of the viral and host factors that are necessary and sufficient for HSV-1-mediated membrane fusion and the nature of the fusion trigger. Here, we developed a simplified in vitro fusion assay to examine the fusion requirements and identified low pH as a co-trigger for virus-mediated fusion in vitro . We hypothesize that low pH has a critical role in cell entry and, potentially, pathogenesis., Competing Interests: The authors declare no conflict of interest.

The integration of 3D printed sensors into hosting structures has become a growing area of research due to simplified assembly procedures, reduced system complexity, and lower fabrication cost. Embedding 3D printed sensors into structures or bonding the sensors on surfaces are the two techniques for the integration of sensors. This review extensively discusses the fabrication of sensors through different additive manufacturing techniques. Various additive manufacturing techniques dedicated to manufacture sensors as well as their integration techniques during the manufacturing process will be discussed. This review will also discuss the basic sensing mechanisms of integrated sensors and their applications. It has been proven that integrating 3D printed sensors into infrastructures can open new possibilities for research and development in additive manufacturing and sensor materials for smart goods and the Internet of Things.

Competing Interests: All authors declare no conflict of interest.

Learning Objectives: After studying this article, the participant should be able to: 1. Understand how bacteria negatively impact aesthetic and reconstructive breast implants. 2. Understand how bacteria infect breast implants. 3. Understand the evidence associated with common implant infection-prevention strategies, and their limitations. 4. Understand why implementation of bacteria-mitigation strategies such as antibiotic administration or "no-touch" techniques may not indefinitely prevent breast implant infection., Summary: Bacterial infection of aesthetic and reconstructive breast implants is a common and expensive problem. Subacute infections or chronic capsular contractures leading to device explantation are the most commonly documented sequelae. Although bench and translational research underscores the complexities of implant-associated infection, high-quality studies with adequate power, control groups, and duration of follow-up are lacking. Common strategies to minimize infections use antibiotics-administered systemically, in the breast implant pocket, or by directly bathing the implant before insertion-to limit bacterial contamination. Limiting contact between the implant and skin or breast parenchyma represents an additional common strategy. The clinical prevention of breast implant infection is challenged by the clean-contaminated nature of breast parenchyma, and the variable behavior of not only specific bacterial species but also their strains. These factors impact bacterial virulence and antibiotic resistance., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Mutations in the NADH dehydrogenase (ubiquinone reductase) iron‑sulfur protein 4 (NDUFS4) gene, which encodes for a key structural subunit of the OXFOS complex I (CI), lead to the most common form of mitochondrial disease in children known as Leigh syndrome (LS). As in other mitochondrial diseases, epileptic seizures constitute one of the most significant clinical features of LS. These seizures are often very difficult to treat and are a sign of poor disease prognosis. Mice with whole-body Ndufs4 KO are a well-validated model of LS; they exhibit epilepsy and several other clinical features of LS. We have previously shown that mice with Ndufs4 KO in only GABAergic interneurons (Gad2-Ndufs4-KO) reproduce the severe epilepsy phenotype observed in the global KO mice. This observation indicated that these mice represent an excellent model of LS epilepsy isolated from other clinical manifestations of the disease. To further characterize this epilepsy phenotype, we investigated seizure susceptibility to selected exogenous seizure triggers in Gad2-Ndufs4-KO mice. Then, using electrophysiology, imaging, and immunohistochemistry, we studied the cellular, physiological, and neuroanatomical consequences of Ndufs4 KO in GABAergic interneurons. Homozygous KO of Ndufs4 in GABAergic interneurons leads to a prominent susceptibility to exogenous seizure triggers, impaired interneuron excitability and interneuron loss. Finally, we found that the hippocampus and cortex participate in the generation of seizure activity in Gad2-Ndufs4-KO mice. These findings further define the LS epilepsy phenotype and provide important insights into the cellular mechanisms underlying epilepsy in LS and other mitochondrial diseases., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Orofacial clefts (OFC) remain among the most prevalent congenital abnormalities worldwide. In the United States in 2010 to 2014, 16.2 of 10,000 live births are born with OFC compared with 23.6 of 10,000 in Alta Verapaz, Guatemala in 2012. Demographics and cleft severity scores were retrospectively gathered from 514 patients with isolated OFC at the Children's Hospital of Philadelphia scheduled for surgery from 2012 to 2019 and from 115 patients seen during surgical mission trips to Guatemala City from 2017 to 2020. Risk factors were also gathered prospectively from Guatemalan families. The Guatemalan cohort had a significantly lower prevalence of cleft palate only compared with the US cohort, which may be a result of greater cleft severity in the population or poor screening and subsequent increased mortality of untreated cleft palate. Of those with lip involvement, Guatemalan patients were significantly more likely to have complete cleft lip, associated cleft palate, and right-sided and bilateral clefts, demonstrating an increased severity of Guatemalan cleft phenotype. Primary palate and lip repair for the Guatemalan cohort occurred at a significantly older age than that of the US cohort, placing Guatemalan patients at increased risk for long-term complications such as communication difficulties. Potential OFC risk factors identified in the Guatemalan cohort included maternal cooking-fire and agricultural chemical exposure, poor prenatal vitamin intake, poverty, and risk factors related to primarily corn-based diets. OFC patients who primarily rely on surgical missions for cleft care would likely benefit from more comprehensive screening and investigation into risk factors for more severe OFC phenotypes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

This study provides an in-depth analysis of the distinct consequences of the opioid drugs morphine and fentanyl during opioid-induced respiratory depression (OIRD). We explored the physiological implications of both drugs on ventilation and airway patency in anaesthetized mice. Our results revealed a similar reduction in respiratory frequency with equivalent scaled dosages of fentanyl and morphine, though the onset of suppression was more rapid with fentanyl. Additionally, fentanyl resulted in transient airflow obstructions during the inspiratory cycle, which were absent following morphine administration. Notably, these fentanyl-specific obstructions were eliminated with tracheostomy, implicating the upper airways as a major factor contributing to fentanyl-induced respiratory depression. We further demonstrate that bronchodilators salbutamol and adrenaline effectively reversed these obstructions, highlighting the bronchi's contribution to fentanyl-induced airflow obstruction. Our study also uncovered a significant reduction in sighs during OIRD, which were eliminated by fentanyl and markedly reduced by morphine. Finally, we found that fentanyl-exposed mice had reduced survival under hypoxic conditions compared to mice given morphine, demonstrating that fentanyl becomes more lethal in the context of hypoxaemia. Our findings shed light on the distinct and profound impacts of these opioids on respiration and airway stability and lay the foundation for improved opioid use guidelines and more effective OIRD prevention strategies. KEY POINTS: Both morphine and fentanyl significantly suppressed respiratory frequency, but the onset of suppression was faster with fentanyl. Also, while both drugs increased tidal volume, this effect was more pronounced with fentanyl. Fentanyl administration resulted in transient obstructions during the inspiratory phase, suggesting its unique impact on airway stability. This obstruction was not observed with morphine. The fentanyl-induced obstructions were reversed by administering bronchodilators such as salbutamol and adrenaline. This suggests a possible therapeutic strategy for mitigating the adverse airway effects of fentanyl. Both drugs reduced the frequency of physiological sighs, a key mechanism to prevent alveolar collapse. However, fentanyl administration led to a complete cessation of sighs, while morphine only reduced their occurrence. Fentanyl-treated mice showed a significantly reduced ability to survive under hypoxic conditions compared to those administered morphine. This indicates that the impacts of hypoxaemia during opioid-induced respiratory depression can vary based on the opioid used., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

There is increasing interest in the African spiny mouse (Acomys cahirinus) as a model organism because of its ability for regeneration of tissue after injury in skin, muscle, and internal organs such as the kidneys. A high-quality reference genome is needed to better understand these regenerative properties at the molecular level. Here, we present an improved reference genome for A. cahirinus generated from long Nanopore sequencing reads. We confirm the quality of our annotations using RNA sequencing data from 4 different tissues. Our genome is of higher contiguity and quality than previously reported genomes from this species and will facilitate ongoing efforts to better understand the regenerative properties of this organism., Competing Interests: Conflicts of interest DEM is engaged in a research agreement with Oxford Nanopore, and they have paid for him to travel to speak on their behalf. DEM is on a scientific advisory board at Oxford Nanopore. The other authors have no conflicts to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Bacterial infection is the most common complication following staged post-mastectomy breast reconstruction initiated with a tissue expander (TE). To limit bacterial infection, antibiotic irrigation of the surgical site is commonly performed despite little high-quality data to support this practice. We performed a prospective randomized control trial to compare the impact of saline irrigation alone to a triple antibiotic irrigation regimen (1 g cefazolin, 80 mg gentamicin, and 50,000 units of bacitracin in 500 mL of saline) for breast implant surgery. The microbiome in breasts with cancer ( n = 16) was compared to those without ( n = 16), as all patients ( n = 16) had unilateral cancers but bilateral mastectomies ( n = 32). Biologic and prosthetic specimens procured both at the time of mastectomy and during TE removal months later were analyzed for longitudinal comparison. Outcomes included clinical infection, bacterial abundance, and relative microbiome composition. No patient in either group suffered a reconstructive failure or developed an infection. Triple antibiotic irrigation administered at the time of immediate TE reconstruction did not reduce bacterial abundance or impact microbial diversity relative to saline irrigation at the time of planned exchange. Implanted prosthetic material adopted the microbial composition of the surrounding host tissue. In cancer-naïve breasts, relative to saline, antibiotic irrigation increased bacterial abundance on periprosthetic capsules ( P = 0.03) and acellular dermal matrices ( P = 0.04) and altered the microbiota on both. These data show that, relative to saline only, the use of triple antibiotic irrigation in TE breast reconstruction does impact the bacterial abundance and diversity of certain biomaterials from cancer-naïve breasts. IMPORTANCE The lifetime risk of breast cancer is ~13% in women and is treated with a mastectomy in ~50% of cases. The majority are reconstructed, usually starting with a tissue expander to help restore the volume for a subsequent permanent breast implant or the women's own tissues. The biopsychosocial benefits of breast reconstruction, though, can be tempered by a high complication rate of at least 7% but over 30% in some women. Bacterial infection is the most common complication, and can lead to treatment delays, patient physical and emotional distress and escalating health care cost. To limit this risk, plastic surgeons have tried a variety of strategies to limit bacterial infection including irrigating the pocket created after removing the breast implant with antibiotic solutions, but good-quality data are scarce. Herein, we study the value of antibiotics in pocket irrigation using a robust randomized clinical trial design and molecular microbiology approaches.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). In a mouse model of PD induced by the injection of 6-hydroxydopamine (6-OHDA) into the caudate putamen (CPu) dyspnea events are very common. Neuroanatomical and functional studies show that the number of glutamatergic neurons in the pre-Bötzinger Complex (preBötC) are reduced. We hypothesize that the neuronal loss, and consequently loss of glutamatergic connections in the respiratory network previously investigated, are responsible for the breathing impairment in PD. Here, we tested whether ampakines (CX614), a subgroup of AMPA receptor positive allosteric modulators, could stimulate the respiratory activity in PD-induced animals. CX614 (50 µM) injected intraperitoneally or directly into the preBötC region reduced the irregularity pattern and increased the respiratory rate by 37% or 82%, respectively, in PD-induced animals. CX614 also increased the respiratory frequency in healthy animals. These data suggest that ampakine CX614 could become a tool to restore breathing in PD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Sighs prevent the collapse of alveoli in the lungs, initiate arousal under hypoxic conditions, and are an expression of sadness and relief. Sighs are periodically superimposed on normal breaths, known as eupnea. Implicated in the generation of these rhythmic behaviors is the preBötzinger complex (preBötC). Our experimental evidence suggests that purinergic signaling is necessary to generate spontaneous and hypoxia-induced sighs in a mouse model. Our results demonstrate that driving calcium increases in astrocytes through pharmacological methods robustly increases sigh, but not eupnea, frequency. Calcium imaging of preBötC slices corroborates this finding with an increase in astrocytic calcium upon application of sigh modulators, increasing intracellular calcium through g-protein signaling. Moreover, photo-activation of preBötC astrocytes is sufficient to elicit sigh activity, and this response is blocked with purinergic antagonists. We conclude that sighs are modulated through neuron-glia coupling in the preBötC network, where the distinct modulatory responses of neurons and glia allow for both rhythms to be independently regulated., (© 2023. Springer Nature Limited.)

Background: In the United States (US) late stillbirth (at 28 weeks or more of gestation) occurs in 3/1000 births., Aim: We examined risk factors for late stillbirth with the specific goal of identifying modifiable factors that contribute substantially to stillbirth burden., Setting: All singleton births in the US for 2014-2015., Methods: We used a retrospective population-based design to assess the effects of multiple factors on the risk of late stillbirth in the US. Data were drawn from the US Centers for Disease Control and Prevention live birth and fetal death data files., Results: There were 6,732,157 live and 18,334 stillbirths available for analysis (late stillbirth rate = 2.72/1000 births). The importance of sociodemographic determinants was shown by higher risks for Black and Native Hawaiian and Other Pacific Islander mothers compared with White mothers, mothers with low educational attainment, and older mothers. Among modifiable risk factors, delayed/absent prenatal care, diabetes, hypertension, and maternal smoking were associated with increased risk, though they accounted for only 3-6% of stillbirths each. Two factors accounted for the largest proportion of late stillbirths: high maternal body mass index (BMI; 15%) and infants who were small for gestational age (38%). Participation in the supplemental nutrition for women, infants and children program was associated with a 28% reduction in overall stillbirth burden., Conclusions: This study provides population-based evidence for stillbirth risk in the US. A high proportion of late stillbirths was associated with high maternal BMI and small for gestational age, whereas participation in supplemental nutrition programs was associated with a large reduction in stillbirth burden. Addressing obesity and fetal growth restriction, as well as broadening participation in nutritional supplementation programs could reduce late stillbirths., Competing Interests: DT, SM, and JLF received salary from Microsoft Corporation while conducting this study. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Tanner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To determine the impact of illustrated postoperative instructions on patient-caregiver knowledge and retention., Design: Prospective study with all participants receiving an educational intervention., Setting: Pediatric plastic surgical missions in Guatemala City, Guatemala, between 2019 and 2020., Participants: A total of 63 majority-indigenous Guatemalan caregivers of patients receiving cleft lip and/or palate surgery., Intervention: Illustrated culturally appropriate postoperative care instructions were iteratively developed and given to caregivers who were surveyed on illustration-based and text-based information at preoperative, postoperative, and four-week follow-up time points., Main Outcome Measure: Postoperative care knowledge of illustration-based versus text-based information as determined by the ability to answer 11 illustration- and 8 text-based all-or-nothing questions, as well as retention of knowledge as determined by the same survey given at four weeks follow-up., Results: Scores for illustration-based and text-based information both significantly increased after caregivers received the postoperative instructions (+13.30 ± 3.78 % SE, + 11.26 ± 4.81 % SE; P  < .05). At follow-up, scores were unchanged for illustration-based (-3.42 ± 4.49 % SE, P  > .05), but significantly lower for text-based information (-28.46 ± 6.09 % SE, P  < .01). Retention of text-based information at follow-up correlated positively with education level and Spanish literacy, but not for illustration-based., Conclusions: In the setting of language and cultural barriers on a surgical mission, understanding of illustration-based and text-based information both increased after verbal explanation of illustrated postoperative instructions. Illustration-based information was more likely to be retained by patient caregivers after four weeks than text-based information, the latter of which correlated with increased education and literacy.

Background: A variety of molecular targets for volatile anesthetics have been suggested, including the anesthetic-sensitive potassium leak channel, TREK-1. Knockout of TREK-1 is reported to render mice resistant to volatile anesthetics, making TREK-1 channels compelling targets for anesthetic action. Spinal cord slices from mice, either wild type or an anesthetic- hypersensitive mutant, Ndufs4, display an isoflurane-induced outward potassium leak that correlates with their minimum alveolar concentrations and is blocked by norfluoxetine. The hypothesis was that TREK-1 channels conveyed this current and contribute to the anesthetic hypersensitivity of Ndufs4. The results led to evaluation of a second TREK channel, TREK-2, in control of anesthetic sensitivity., Methods: The anesthetic sensitivities of mice carrying knockout alleles of Trek-1 and Trek-2, the double knockout Trek-1;Trek-2, and Ndufs4;Trek-1 were measured. Neurons from spinal cord slices from each mutant were patch clamped to characterize isoflurane-sensitive currents. Norfluoxetine was used to identify TREK-dependent currents., Results: The mean values for minimum alveolar concentrations (± SD) between wild type and two Trek-1 knockout alleles in mice (P values, Trek-1 compared to wild type) were compared. For wild type, minimum alveolar concentration of halothane was 1.30% (0.10), and minimum alveolar concentration of isoflurane was 1.40% (0.11); for Trek-1tm1Lex, minimum alveolar concentration of halothane was 1.27% (0.11; P = 0.387), and minimum alveolar concentration of isoflurane was 1.38% (0.09; P = 0.268); and for Trek-1tm1Lzd, minimum alveolar concentration of halothane was 1.27% (0.11; P = 0.482), and minimum alveolar concentration of isoflurane was 1.41% (0.12; P = 0.188). Neither allele was resistant for loss of righting reflex. The EC50 values of Ndufs4;Trek-1tm1Lex did not differ from Ndufs4 (for Ndufs4, EC50 of halothane, 0.65% [0.05]; EC50 of isoflurane, 0.63% [0.05]; and for Ndufs4;Trek-1tm1Lex, EC50 of halothane, 0.58% [0.07; P = 0.004]; and EC50 of isoflurane, 0.61% [0.06; P = 0.442]). Loss of TREK-2 did not alter anesthetic sensitivity in a wild-type or Trek-1 genetic background. Loss of TREK-1, TREK-2, or both did not alter the isoflurane-induced currents in wild-type cells but did cause them to be norfluoxetine insensitive., Conclusions: Loss of TREK channels did not alter anesthetic sensitivity in mice, nor did it eliminate isoflurane-induced transmembrane currents. However, the isoflurane-induced currents are norfluoxetine-resistant in Trek mutants, indicating that other channels may function in this role when TREK channels are deleted., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Mechanical bowel obstruction is a common symptom for admission to emergency services, diagnosed annually in more than 300,000 patients in the States, from whom 51% will undergo emergency laparotomy. This condition is associated with serious morbidity and mortality, but it also causes a high financial burden due to long hospital stay. The EUPEMEN project aims to incorporate the expertise and clinical experience of national clinical specialists into development of perioperative rehabilitation protocols. Providing special recommendations for all aspects of patient perioperative care and the participation of diverse specialists, the EUPEMEN protocol for bowel obstruction, as presented in the current paper, aims to provide faster postoperative recovery and reduce length of hospital stay, postoperative morbidity and mortality rate.

Breathing needs to be tightly coordinated with upper airway behaviors, such as swallowing. Discoordination leads to aspiration pneumonia, the leading cause of death in neurodegenerative disease. Here, we study the role of the postinspiratory complex (PiCo) in coordinating breathing and swallowing. Using optogenetic approaches in freely breathing anesthetized ChATcre:Ai32, Vglut2cre:Ai32 and intersectional recombination of ChATcre:Vglut2FlpO:ChR2 mice reveals PiCo mediates airway protective behaviors. Activation of PiCo during inspiration or the beginning of postinspiration triggers swallow behavior in an all-or-nothing manner, while there is a higher probability for stimulating only laryngeal activation when activated further into expiration. Laryngeal activation is dependent on stimulation duration. Sufficient bilateral PiCo activation is necessary for preserving the physiological swallow motor sequence since activation of only a few PiCo neurons or unilateral activation leads to blurred upper airway behavioral responses. We believe PiCo acts as an interface between the swallow pattern generator and the preBötzinger complex to coordinate swallow and breathing. Investigating PiCo's role in swallow and laryngeal coordination will aid in understanding discoordination with breathing in neurological diseases., Competing Interests: AH, MK, LO, JR No competing interests declared, (© 2023, Huff et al.)

Background: The prognostic value of ambulatory blood pressure (BP) monitoring (ABPM) is poorly understood in Latin American populations., Methods: A prospective observational study was conducted on 1339 patients with hypertension who underwent 24-h BP monitoring between 2015 and 2019. The incidence of serious adverse cardiovascular events (MACE) was analysed using a Cox proportional hazards model adjusted for potential confounders. Three previously reported morning surge definitions were evaluated for SBP and DBP using different ABPM components: sleep-through morning surge, pre-awakening, and morning night-time difference., Results: The mean age was 62 years, 52% were female, 32.8% had dyslipidaemia, 27.2% were smokers, and 7.8% had diabetes. During a median follow-up period of 32 months, 197 MACE occurred. In men, the adjusted hazard ratio (HR) was 1.84 [95% confidence interval (CI), 1.35-2.49; P  < 0.001). The HR increased to 2.03 (95% CI, 1.89-2.17; P  < 0.001) with a cut-off value of 35 mmHg for a 10 mmHg increase in sleep-through morning surge. The increased adjusted HR associated with the morning rise persisted for each secondary endpoint, including 21 cardiovascular deaths [HR: 2.70 (95% CI, 2.03-3.60; P  < 0.001)], 78 myocardial infarctions [HR: 1.92 (95% CI, 1.72-2.15; P  < 0.001)], 24 hospitalisations for heart failure [HR: 1.77 (95% CI, 1.48-2.12; P  < 0.001)], 22 strokes [HR: 2.32 (95% CI, 1.85-2.91; P  < 0.001)], and 52 atrial fibrillations [HR: 1.94 (95% CI, 1.71-2.20; P  < 0.001)]., Conclusion: The morning BP rise was the most important circadian prognostic factor for MACE in patients with hypertension, which deserves more attention., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Disorders of autonomic functions are typically characterized by disturbances in multiple organ systems. These disturbances are often comorbidities of common and rare diseases, such as epilepsy, sleep apnea, Rett syndrome, congenital heart disease or mitochondrial diseases. Characteristic of many autonomic disorders is the association with intermittent hypoxia and oxidative stress, which can cause or exaggerate a variety of other autonomic dysfunctions, making the treatment and management of these syndromes very complex. In this review we discuss the cellular mechanisms by which intermittent hypoxia can trigger a cascade of molecular, cellular and network events that result in the dysregulation of multiple organ systems. We also describe the importance of computational approaches, artificial intelligence and the analysis of big data to better characterize and recognize the interconnectedness of the various autonomic and non-autonomic symptoms. These techniques can lead to a better understanding of the progression of autonomic disorders, ultimately resulting in better care and management., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Infection is thought to play a part in some infant deaths. Maternal infection in pregnancy has focused on chlamydia with some reports suggesting an association with sudden unexpected infant death (SUID)., Objectives: We hypothesized that maternal infections in pregnancy are associated with subsequent SUID in their offspring., Setting: All births in the United States, 2011-2015., Data Source: Centers for Disease Control and Prevention (CDC) Birth Cohort Linked Birth-Infant Death Data Files., Study Design: Cohort study, although the data were analysed as a case control study. Cases were infants that died from SUID. Controls were randomly sampled infants that survived their first year of life; approximately 10 controls per SUID case., Exposures: Chlamydia, gonorrhea and hepatitis C., Results: There were 19,849,690 live births in the U.S. for the period 2011-2015. There were 37,143 infant deaths of which 17,398 were classified as SUID cases (a rate of 0.86/1000 live births). The proportion of the control mothers with chlamydia was 1.7%, gonorrhea 0.2% and hepatitis C was 0.3%. Chlamydia was present in 3.8% of mothers whose infants subsequently died of SUID compared with 1.7% of controls (unadjusted OR = 2.35, 95% CI = 2.15, 2.56; adjusted OR = 1.08, 95% CI = 0.98, 1.19). Gonorrhea was present in 0.7% of mothers of SUID cases compared with 0.2% of mothers of controls (OR = 3.09, (2.50, 3.79); aOR = 1.20(0.95, 1.49)) and hepatitis C was present in 1.3% of mothers of SUID cases compared with 0.3% of mothers of controls (OR = 4.69 (3.97, 5.52): aOR = 1.80 (1.50, 2.15))., Conclusions: The marked attenuation of SUID risk after adjustment for a wide variety of socioeconomic and demographic factors suggests the small increase in the risk of SUID of the offspring of mothers with infection with hepatitis C in pregnancy is due to residual confounding., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Weatherly et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This proceedings article presents the scope of pediatric coma and disorders of consciousness based on presentations and discussions at the First Pediatric Disorders of Consciousness Care and Research symposium held on September 14th, 2021. Herein we review the current state of pediatric coma care and research opportunities as well as shared experiences from seasoned researchers and clinicians. Salient current challenges and opportunities in pediatric and neonatal coma care and research were identified through the contributions of the presenters, who were Jose I. Suarez, MD, Nina F. Schor, MD, PhD, Beth S. Slomine, PhD Erika Molteni, PhD, and Jan-Marino Ramirez, PhD, and moderated by Varina L. Boerwinkle, MD, with overview by Mark Wainwright, MD, and subsequent audience discussion. The program, executively planned by Varina L. Boerwinkle, MD, Mark Wainwright, MD, and Michelle Elena Schober, MD, drove the identification and development of priorities for the pediatric neurocritical care community., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Breast implant-associated infections (BIAIs) are the primary complication following placement of breast prostheses in breast cancer reconstruction. Given the prevalence of breast cancer, reconstructive failure due to infection results in significant patient distress and health care expenditures. Thus, effective BIAI prevention strategies are urgently needed. This study tests the efficacy of one infection prevention strategy: the use of a triple antibiotic pocket irrigant (TAPI) against Staphylococcus aureus, the most common cause of BIAIs. TAPI, which consists of 50,000 U bacitracin, 1 g cefazolin, and 80 mg gentamicin diluted in 500 mL of saline, is used to irrigate the breast implant pocket during surgery. We used in vitro and in vivo assays to test the efficacy of each antibiotic in TAPI, as well as TAPI at the concentration used during surgery. We found that planktonically grown S. aureus BIAI isolates displayed susceptibility to gentamicin, cefazolin, and TAPI. However, TAPI treatment enhanced biofilm formation of BIAI strains. Furthermore, we compared TAPI treatment of a S. aureus reference strain (JE2) to a BIAI isolate (117) in a mouse BIAI model. TAPI significantly reduced infection of JE2 at 1 and 7 days postinfection (dpi). In contrast, BIAI strain 117 displayed high bacterial burdens in tissues and implants, which persisted to 14 dpi despite TAPI treatment. Lastly, we demonstrated that TAPI was effective against Pseudomonas aeruginosa reference (PAO1) and BIAI strains in vitro and in vivo. Together, these data suggest that S. aureus BIAI strains employ unique mechanisms to resist antibiotic prophylaxis treatment and promote chronic infection. IMPORTANCE The incidence of breast implant associated infections (BIAIs) following reconstructive surgery postmastectomy remains high, despite the use of prophylactic antibiotic strategies. Thus, surgeons have begun using additional antibiotic-based prevention strategies, including triple antibiotic pocket irrigants (TAPIs). However, these strategies fail to reduce BIAI rates for these patients. To understand why these therapies fail, we assessed the antimicrobial resistance patterns of Staphylococcus aureus strains, the most common cause of BIAI, to the antibiotics in TAPI (bacitracin, cefazolin, and gentamicin). We found that while clinically relevant BIAI isolates were more susceptible to the individual antibiotics compared to a reference strain, TAPI was effective at killing all the strains in vitro . However, in a mouse model, the BIAI isolates displayed recalcitrance to TAPI, which contrasted with the reference strain, which was susceptible. These data suggest that strains causing BIAI may encode specific recalcitrance mechanisms not present within reference strains.

Purpose: After a full-thickness total wall excision of a rectal tumor, suturing the defect is generally recommended. Recently, due to various contradictory studies, there is a trend to leave the defects open. Therefore, this study aimed to determine whether leaving the defect open is an adequate management strategy compared with suturing it closed based on postoperative outcomes and recurrences., Methods: A retrospective review of our prospectively maintained database was conducted. Adult patients who underwent transanal surgery for rectal neoplasm in our institution from 1997 to 2019 were analyzed. Patients were divided into two groups: sutured (group A) or unsutured (group B) rectal defect. The primary outcomes were morbidity (early and late) and recurrence., Results: In total, 404 (239 men) patients were analyzed, 143 (35.4%) from group A and 261 (64.6%) from group B. No differences were observed in tumor size, distance from the anal verge or operation time. The overall incidence of complications was significantly higher in patients from group B, which nearly double the rate of group A. With a mean follow-up of 58 (range, 12-96) months, seven patients presented with a rectal stricture, all of them from group B., Conclusions: We acknowledge the occasional impossibility of closing the defect in patients who undergo local excision; however, when it is possible, the present data suggest that there may be advantages to suturing the defect closed., (© 2023. The Author(s).)

Objective: To investigate the impact of discontinuation of mechanical bowel preparation in advanced ovarian cancer surgery within the context of the ERAS program., Methods: We retrospectively reviewed the medical records of patients with advanced ovarian cancer who underwent cytoreductive surgery with simultaneous colon and/or rectal resection from January 2012 to November 2020. Patients were divided into two groups based on whether preoperative mechanical bowel preparation (MBP) was given (pre-ERAS) or not (post-ERAS). Patient characteristics, including duration of antibiotic treatment, surgical complexity, and incidence of surgical and nonsurgical complications, were compared., Results: During the study period, 114 patients who underwent colon and/or rectal resection were examined, of whom 39 received MBP and 75 did not receive MBP (NMBP). On comparison between the two groups, no significant differences were noted in the assessed patient characteristics, including mean age, FIGO stage, ASA class, BMI, or residual tumor. One patient (2.6%) in the MBP group, and 4 patients (5.3%) in the NMBP group experienced an anastomotic leakage (p = 0.11). No significant differences were found with respect to surgical site infection. (p = 0.5)., Conclusion: MBP was not associated with any specific benefit for advanced ovarian cancer surgery. Gynecologic oncologists who use MBP should consider discontinuing this practice., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

After multiple waves of the COVID-19 pandemic, it has become clear that the impact of SARS-CoV-2 will carry on for years to come. Acutely infected patients show a broad range of disease severity, depending on virus variant, vaccination status, age and the presence of underlying medical and physical conditions, including obesity. Additionally, a large number of patients who have been infected with the virus present with post-COVID syndrome. In September 2020, the International Society for the Advancement of Respiratory Psychophysiology organized a virtual interest meeting on 'Respiratory research in the age of COVID-19', which aimed to discuss how research in respiratory psychophysiology could contribute to a better understanding of psychophysiological interactions in COVID-19. In the resulting current paper, we propose an interdisciplinary research agenda discussing selected research questions on acute and long-term neurobiological, physiological and psychological outcomes and mechanisms related to respiration and the airways in COVID-19, as well as research questions on comorbidity and potential treatment options, such as physical rehabilitation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Background: Leigh syndrome (LS) is a progressive neurodegenerative mitochondrial disease characterized by necrotizing lesions affecting different parts of the central nervous system, especially in the brainstem and basal ganglia. Lesions in this area may involve respiratory and sleep centers, resulting in the clinically significant disturbances seen-but poorly characterized-in LS. The purpose of the present study is to characterize and compare the physiologic responses to respiratory disturbances quantified by polysomnography metrics of children with LS with age-sex- and apnea-hypopnea index (AHI)-matched patients with obstructive sleep apnea (OSA), a common clinical population with similar burden of sleep-disordered breathing., Methods: Retrospective comparative study of polysomnographic data from six patients with LS were reviewed and compared with 18 age-sex-AHI-matched patients with OSA, with particular attention to cardiorespiratory and sleep architecture metrics., Results: Sleep architecture and stage duration were conserved in LS and OSA groups, but increased wake after sleep onset was seen among the first group. The LS group exhibited both obstructive and central sleep apnea. The group also had significantly greater values of heart rate, ≥3% oxygen desaturation index, and lower values of sleep efficiency, respiratory arousal index, and total sleep time when compared with the OSA group., Conclusions: Patients with LS exhibited significantly more sleep-related cardiorespiratory disturbances and sleep fragmentation when compared with neurotypical children with OSA. Given that these findings are plausibly detrimental to health and development, sleep evaluation in patients with similar conditions should be encouraged for early management., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We demonstrate a heterogeneously integrated III-V-on-SOI distributed feedback laser with a low grating strength (κ < 40 cm -1 ) and a narrow linewidth of Δν = 118 kHz. The laser operates single mode with a side-mode suppression ratio over 45 dB, provides a single-sided waveguide-coupled output power of 22 mW (13.4 dBm) and has a wall-plug efficiency of 17%. The dynamic characteristics were also evaluated, obtaining an intrinsic 3 dB modulation bandwidth of 14 GHz and a photon lifetime of 8 ps. Large-signal intensity modulation using a 2 31 -1 PRBS pattern length revealed open eye diagrams up to 25 Gb/s and a penalty on the dynamic extinction ratio lower than 1 dB after transmission over a 2 km standard single mode optical fiber.

A sigh is a distinct respiratory behavior with specific psychophysiological roles. In two accompanying reviews we will discuss the physiological and psychological functions of the sigh. The present review will focus on the psychological functions of the sigh. We discuss the regulatory effects of a sigh, and argue how these effects may become maladaptive when sighs occur excessively. The adaptive role of a sigh is discussed in the context of regulation of psychophysiological states. We propose that sighs facilitate transitions from one psychophysiological state to the next, and this way contribute to psychophysiological flexibility, via a hypothesized resetting mechanism. We discuss how a sigh resets respiration, by controlling mechanical and metabolic properties of respiration associated with respiratory symptoms. Next, we elaborate on a sigh resetting emotional states by facilitating emotional transitions. We attempt to explain the adaptive and maladaptive functions of a sigh in the framework of stochastic resonance, in which we propose occasional, spontaneous sighs to be noise contributing to psychophysiological regulation, while excessive sighs result in psychophysiological dysregulation. In this context, we discuss how sighs can contribute to therapeutic interventions, either by increasing sighs to improve regulation in case of a lack of sighing, or by decreasing sighs to restore regulation in case of excessive sighing. Finally, a research agenda on the psychology of sighs is presented., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The mechanisms of volatile anesthetic action remain among the most perplexing mysteries of medicine. Across phylogeny, volatile anesthetics selectively inhibit mitochondrial complex I, and they also depress presynaptic excitatory signaling. To explore how these effects are linked, we studied isoflurane effects on presynaptic vesicle cycling and ATP levels in hippocampal cultured neurons from wild-type and complex I mutant (Ndufs4(KO)) mice. To bypass complex I, we measured isoflurane effects on anesthetic sensitivity in mice expressing NADH dehydrogenase (NDi1). Endocytosis in physiologic concentrations of glucose was delayed by effective behavioral concentrations of isoflurane in both wild-type (τ [unexposed] 44.8 ± 24.2 s; τ [exposed] 116.1 ± 28.1 s; p < 0.01) and Ndufs4(KO) cultures (τ [unexposed] 67.6 ± 16.0 s; τ [exposed] 128.4 ± 42.9 s; p = 0.028). Increasing glucose, to enhance glycolysis and increase ATP production, led to maintenance of both ATP levels and endocytosis (τ [unexposed] 28.0 ± 14.4; τ [exposed] 38.2 ± 5.7; reducing glucose worsened ATP levels and depressed endocytosis (τ [unexposed] 85.4 ± 69.3; τ [exposed] > 1,000; p < 0.001). The block in recycling occurred at the level of reuptake of synaptic vesicles into the presynaptic cell. Expression of NDi1 in wild-type mice caused behavioral resistance to isoflurane for tail clamp response (EC 50 Ndi1(-) 1.27% ± 0.14%; Ndi1(+) 1.55% ± 0.13%) and halothane (EC 50 Ndi1(-) 1.20% ± 0.11%; Ndi1(+) 1.46% ± 0.10%); expression of NDi1 in neurons improved hippocampal function, alleviated inhibition of presynaptic recycling, and increased ATP levels during isoflurane exposure. The clear alignment of cell culture data to in vivo phenotypes of both isoflurane-sensitive and -resistant mice indicates that inhibition of mitochondrial complex I is a primary mechanism of action of volatile anesthetics., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)