PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury (though this effect depended on the anesthetic regimen used during recording), while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.

Environmental DNA-based biodiversity profiling along the Houdong River in north-eastern Taiwan.

Background: This paper describes two datasets: species occurrences, which were determined by environmental DNA (eDNA) metabarcoding and their associated DNA sequences, originating from a research project which was carried out along the Houdong River (), Jiaoxi Township, Yilan, Taiwan. The Houdong River begins at an elevation of 860 m and flows for approximately 9 km before it empties into the Pacific Ocean. Meandering through mountains, hills, plains and alluvial valleys, this short river system is representative of the fluvial systems in Taiwan. The primary objective of this study was to determine eukaryotic species occurrences in the riverine ecosystem through the use of the eDNA analysis. The second goal was, based on the current dataset, to establish a metabarcoding eDNA data template that will be useful and replicable for all users, particularly the Taiwan community. The species occurrence data are accessible at the Global Biodiversity Information Facility (GBIF) portal and its associated DNA sequences have been deposited in the European Nucleotide Archive (ENA) at EMBL-EBI, respectively. A total of 12 water samples from the study yielded an average of 1.5 million reads. The subsequent species identification from the collected samples resulted in the classification of 432 Operational Taxonomic Units (OTUs) out of a total of 2,734. Furthermore, a total of 1,356 occurrences with taxon matches in GBIF were documented (excluding 4,941 incertae sedis, accessed 05-12-2023). These data will be of substantial importance for future species and habitat monitoring within the short river, such as assessment of biodiversity patterns across different elevations, zonations and time periods and its correlation to water quality, land uses and anthropogenic activities. Further, these datasets will be of importance for regional ecological studies, in particular the freshwater ecosystem and its status in the current global change scenarios. New information: The datasets are the first species diversity description of the Houdong River system using either eDNA or traditional monitoring processes.

Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation.

Adult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like deficits and demonstrated an antidepressant-like effect, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescuing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.

Determining Ultrasound Parameters for Bursting Polymer Microbubbles for Future Use in Spinal Cord Injury.

OBJECTIVE: We believe our poly(lactic acid) (PLA) microbubbles are well suited for therapeutic delivery to spinal cord injury (SCI) using ultrasound-triggered bursting. We investigated the feasibility of clinical ultrasound bursting in situ, the optimal bursting parameters in vitro and the loading and release of a model bio-active DNA. METHODS: Microbubbles were tested using clinical ultrasound in a rat cadaver SCI model. Burst pressure thresholds were determined using the change in enhancement after ultrasound exposure. Resonance frequency, acoustic enhancement, sizing and morphology were evaluated by comparing two microbubble porogens, ammonium carbonate and ammonium carbamate. Oligonucleotides were loaded into the shell and released using the found optimized ultrasound bursting parameters. RESULTS: In situ imaging and bursting were successful. In vitro bursting thresholds using frequencies 1, 2.25 and 5 MHz were identified between peak negative pressures 0.2 and 0.5 MPa, believed to be safe for spinal cord. The pressure threshold decreased with decreasing frequencies. PLA bursting was optimized near the resonance frequency of 2.5 to 3.0 MHz using 2.25 MHz and not at lower frequencies. PLA microbubbles, initially with a mean size of approximately 2 µm, remained in one piece, collapsed to between 0.5 and 1 µm and did not fragment. Significantly more oligonucleotide was released after ultrasound bursting of loaded microbubbles. Microbubble-sized debris was detected when using ammonium carbamate, leading to inaccurate microbubble concentration measurements. CONCLUSION: PLA microbubbles made with ammonium carbonate and burst at appropriate parameters have the potential to safely improve intrathecal therapeutic delivery to SCI using targeted ultrasound.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a clinically-relevant rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury, while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion that is most relevant to the SCI clinical population, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function. HIGHLIGHTS: PTEN antagonist peptide promotes partial diaphragm function recovery in chronic cervical contusion SCI.PTPσ inhibitory peptide does not impact diaphragm function recovery in chronic cervical contusion SCI.PTEN antagonist peptide promotes growth of bulbospinal rVRG axons in chronic cervical contusion SCI.PTPσ peptide does not affect rVRG axon growth in chronic cervical contusion SCI.

EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.

Convalescent plasma as adjunctive therapy for hospitalized patients with COVID-19:The Co-CLARITY Trial

Background and Objective@#Convalescent plasma therapy (CPT) may reduce the risk of disease progression among patients with COVID-19. This study was undertaken to evaluate the efficacy and safety of CPT in preventing ICU admission among hospitalized COVID-19 patients.@*Methods@#In this open-label randomized controlled trial, we randomly assigned hospitalized adult patients with COVID-19 in a 1:1 ratio to receive convalescent plasma as an adjunct to standard of care or standard of care alone. The primary endpoint was ICU admission within first 28 days of enrolment. Primary safety endpoints include rapid deterioration of respiratory or clinical status within four hours of convalescent plasma transfusion and cumulative incidence of serious adverse events during the study period including transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), severe allergic reactions, and transfusion-related infections.@*Results@#A total of 22 patients were assigned to receive convalescent plasma as an adjunct to standard of care and 22 to receive standard of care alone. The median time from onset of COVID-19 symptoms to study enrolment was eight days (IQR, 4 to 10). Two patients (9.1%) in the CPT group and one patient (4.5%) in the control group were admitted to the ICU. The primary outcome measure, ICU admission, was not different between the two groups (q-value >0.9). No patient who received convalescent plasma had rapid deterioration of respiratory/clinical status within four hours of transfusion and none developed TRALI, TACO, anaphylaxis, severe allergic reactions, or transfusion-related infections. There was also no significant difference in the secondary outcomes of 28-day mortality (two patients in the CPT group and none in the control group, q-value >0.90), dialysis-free days, vasopressor-free days, and ICU-free days.@*Conclusions@#Among hospitalized COVID-19 patients, no significant differences were observed in the need for ICU admission between patients given CPT as adjunct to standard of care and those who received standard of care alone. Interpretation is limited by early termination of the trial which may have been underpowered to detect a clinically important difference.

Seroprevalence of human adenovirus type 5 neutralizing antibodies in the Philippines.

Human adenovirus (HAdV), particularly the HAdV type 5 (HAdV-5), has been extensively utilized in the development of vector vaccines due to its high immunogenicity, good safety profile, and ease of propagation. However, one of the main challenges in its use is the presence of pre-existing immunity among vaccine recipients. Pre-existing neutralizing antibodies (NAbs) can prevent the uptake of HAdV-5 vectors and reduce vaccine efficacy. Hence, this study investigated the seroprevalence of NAbs against HAdV-5 in urban and rural regions of the Philippines. Luciferase-based neutralization assay was performed on 391 plasma/serum samples. Out of these samples, 346 or 88.5% were positive for HAdV-5 NAbs, and the majority of them (56.8%) had high titers against the virus. Among the regions included in this study, Bicol (Region V) had the highest seroprevalence rate (94.1%). Our findings show that a significant number of adults in the Philippines have pre-existing immunity against HAdV-5. This supports the recommendation that vaccination programs in the country should consider implementing vaccination techniques, such as a prime-boost regimen or addition of booster doses, to address the potential negative effects of pre-existing HAdV-5 immunity in the efficacy of adenoviral vector-based vaccines.

Artificial light at night (ALAN) disrupts behavioural patterns of reef corals.

Increasing levels of Artificial Light At Night (ALAN) alter the natural diel cycles of organisms at global scale. ALAN constitutes a potential threat to the light-dependent functioning of symbiotic scleractinian corals, the habit-founders of warm, shallow water reefs. Here, we show that ALAN disrupts the natural diel tentacle expansion and contraction behaviour, a key mechanism for prey capture and nutrient acquisition in corals. We exposed four symbiotic scleractinian coral species to different ALAN treatments (0.4-2.5 µmol quanta m-2 s-1). Exposure to ALAN levels of 1.2 µmol quanta m-2 s-1 and above altered the normal tentacle expansion response in diurnal species (Stylophora pistillata and Duncanopsammia axifuga). The tentacle expansion pattern of nocturnal species (Montastraea cavernosa and Lobophyllia hemprichii) was less affected, which may indicate a greater capacity to tolerate ALAN exposure. The results of this work suggest that ALAN has the potential to affect nutrient acquisition mechanisms of symbiotic corals which may in turn result in changes in the coral community structure in shallow water reefs in ALAN-exposed areas.

High degree of consensus on diagnosis and management of rotator cuff tears: a Delphi approach.

PURPOSE: To develop a consensus on diagnosis and treatment of rotator cuff tears. The study focused on selected areas: imaging, prognostic factors, treatment options, surgical techniques. METHODS: Panel was composed of all members of the shoulder committee of the Italian Society of Arthroscopy, Knee, Upper arm, Sport, Cartilage and Orthopedic techniques (SIAGASCOT). Four rounds were performed. The first round consisted of gathering questions which were then divided into seven blocks referring to: imaging, patient-related prognostic factors, treatment options, surgical steps, reparative techniques, surgical predictive factors, advanced techniques. Subsequent rounds consisted of condensation by means of online questionnaire and debates. Consensus was defined as two-thirds agreement on one answer. Descriptive statistic was used to summarize the data. RESULTS: Forty-one shoulder experts were involved. Fifty-six statements were finally formulated. A consensus could be achieved on 51. Experts agreed that preoperative magnetic resonance imaging is strongly recommended because it allows a careful evaluation of tear characteristics, while the role of US remains debatable. Controversial patient-related factors such as age, comorbidities, smoking and stiffness do not contraindicate the repair. From a surgical standpoint, the experts highlighted that pseudo-paralysis is not a contraindication to rotator cuff repair. Consensus on specific surgical steps was also achieved: capsular release should be performed only in stiff shoulders; footprint preparation is mandatory, while debridement of tendon edges is not essential. If necessary, a rotator interval release could be performed without interrupting the continuity between subscapularis and supraspinatus tendon; posterior delamination should be always included in the repair. Advanced techniques such as tendon transfers should be selected based on the main clinical deficit, while the superior capsule reconstruction plays a role only in combination with a functional repair. CONCLUSION: A consensus was achieved almost on every topic of controversy explored. Particularly, MRI was deemed necessary to determine tear characteristics, while radiographs remain important for differential diagnosis; age should not be considered a contraindication to surgery; pseudo-paralysis does not represent a contraindication to arthroscopic rotator cuff repair, but superior capsule reconstruction plays a role only in combination with a functional repair. Latissimus dorsi transfer plays a role when the main functional deficit is in elevation, while the lower trapezius transfer plays a role when the main functional deficit is the external-rotation. LEVEL OF EVIDENCE: V.

Therapeutic Strategies Targeting Respiratory Recovery after Spinal Cord Injury: From Preclinical Development to Clinical Translation.

High spinal cord injuries (SCIs) lead to permanent functional deficits, including respiratory dysfunction. Patients living with such conditions often rely on ventilatory assistance to survive, and even those that can be weaned continue to suffer life-threatening impairments. There is currently no treatment for SCI that is capable of providing complete recovery of diaphragm activity and respiratory function. The diaphragm is the main inspiratory muscle, and its activity is controlled by phrenic motoneurons (phMNs) located in the cervical (C3-C5) spinal cord. Preserving and/or restoring phMN activity following a high SCI is essential for achieving voluntary control of breathing. In this review, we will highlight (1) the current knowledge of inflammatory and spontaneous pro-regenerative processes occurring after SCI, (2) key therapeutics developed to date, and (3) how these can be harnessed to drive respiratory recovery following SCIs. These therapeutic approaches are typically first developed and tested in relevant preclinical models, with some of them having been translated into clinical studies. A better understanding of inflammatory and pro-regenerative processes, as well as how they can be therapeutically manipulated, will be the key to achieving optimal functional recovery following SCIs.

JAK/STAT as a Potential Therapeutic Target for Osteolytic Diseases.

Several cytokines with major biological functions in inflammatory diseases exert their functions through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction pathway. JAKs phosphorylate the cytoplasmic domain of the receptor, inducing the activation of its substrates, mainly the proteins known as STATs. STATs bind to these phosphorylated tyrosine residues and translocate from the cytoplasm to the nucleus, further regulating the transcription of several genes that regulate the inflammatory response. The JAK/STAT signaling pathway plays a critical role in the pathogenesis of inflammatory diseases. There is also increasing evidence indicating that the persistent activation of the JAK/STAT signaling pathway is related to several inflammatory bone (osteolytic) diseases. However, the specific mechanism remains to be clarified. JAK/STAT signaling pathway inhibitors have gained major scientific interest to explore their potential in the prevention of the destruction of mineralized tissues in osteolytic diseases. Here, our review highlights the importance of the JAK/STAT signaling pathway in inflammation-induced bone resorption and presents the results of clinical studies and experimental models of JAK inhibitors in osteolytic diseases.

EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1-G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.

PARP1 allows proper telomere replication through TRF1 poly (ADP-ribosyl)ation and helicase recruitment.

Telomeres are nucleoprotein structures at eukaryotic chromosome termini. Their stability is preserved by a six-protein complex named shelterin. Among these, TRF1 binds telomere duplex and assists DNA replication with mechanisms only partly clarified. Here we found that poly (ADP-ribose) polymerase 1 (PARP1) interacts and covalently PARylates TRF1 in S-phase modifying its DNA affinity. Therefore, genetic and pharmacological inhibition of PARP1 impairs the dynamic association of TRF1 and the bromodeoxyuridine incorporation at replicating telomeres. Inhibition of PARP1 also affects the recruitment of WRN and BLM helicases in TRF1 containing complexes during S-phase, triggering replication-dependent DNA-damage and telomere fragility. This work unveils an unprecedented role for PARP1 as a "surveillant" of telomere replication, which orchestrates protein dynamics at proceeding replication fork.

Pharmacogenetics in critical care: association between CYP3A5 rs776746 A/G genotype and acetaminophen response in sepsis and septic shock.

BACKGROUND: Pharmacogenetics could represent a further resource to understand the interindividual heterogeneity of response of the host to sepsis and to provide a personalized approach to the critical care patient. METHODS: Secondary analysis of data from the prospective observational study NCT02750163, in 50 adult septic and septic shock patients treated with Acetaminophen (ACT) for pyrexia. We investigated the presence of two polymorphisms, located respectively in the genes UGT1A1 and CYP3A5, that encode for proteins related to the hepatic metabolism of ACT. The main dependent variables explored were plasmatic concentration of ACT, body temperature and hepatic parameters. RESULTS: 8% of the patients carried CYP3A5 rs776746 A/G genotypes and showed significantly higher plasma levels of ACT than GG wild type patients, and than patients with UGT1A1 rs8330 C/G genotypes. CONCLUSIONS: Identifying specific genotypes of response to ACT may be helpful to guide a more personalized titration of therapy in sepsis and septic shock. CYP3A5 might be a good biomarker for ACT metabolism; however further studies are needed to confirm this result. TRIAL REGISTRATION: NCT02750163.

A multicenter, real-world experience with recombinant FXIII for the treatment of patients with FXIII deficiency: from pharmacokinetics to clinical practice. The Italian FXIII Study.

BACKGROUND: Congenital factor XIII (FXIII) deficiency is a rare coagulation disorder characterized by muscular or mucocutaneous bleeding with life-threatening intracranial hemorrhages (ICHs), especially in cases with severe disease. The best treatment is the use of prophylactic plasma-derived or recombinant FXIII (rFXIII). Few data on the use of rFXIII in the real-world scenario are available. The main goal of this study was to assess the efficacy and safety of catridecacog (NovoThirteen®) in a population of patients with FXIII deficiency. Other objectives were to compare the different pharmacokinetic (PK) profiles of each patient and to use them to create a tailored prophylaxis regimen. MATERIALS AND METHODS: We collected and analyzed all pharmacokinetic and clinical data in our registry of the patients with congenital FXIII deficiency treated with rFXIII at eleven Italian hemophilia centers. Data were collected from January 2019 to December 2020. RESULTS: Overall, data on 20 patients with FXIII deficiency were collected, 16 of whom presented with severe disease. Pharmacokinetics was assessed in 18 cases before starting prophylaxis. Prophylaxis was subsequently started in these patients using a wide range of dosages (25.0-80.0 IU/kg; mean 33.8 IU/kg) and infusion intervals (3.0-8.0 weeks). During a mean follow up of 47 months, two minor bleeds and one ICH in a severe patient who had remained under on-demand treatment were reported. DISCUSSION: Efficacy and safety of rFXIII were proven in all patients. The dosage and infusion timing for the treated patients sometimes differed to those reported in the MENTOR pivotal studies, thus underlying the importance of tailored management in a real-world scenario.

Intestinal neuropod cell GUCY2C regulates visceral pain.

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient - but not GUCY2C-deficient - neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.

Medication Initiation, Patient-directed Discharges, and Hospital Readmissions Before and After Implementing Guidelines for Opioid Withdrawal Management.

OBJECTIVES: Rising rates of hospitalization for patients with opioid use disorder (OUD) result in high rates of patient-directed discharge (PDD, also called "discharge against medical advice") and 30-day readmissions. Interdisciplinary addiction consult services are an emerging criterion standard to improve care for these patients, but these services are resource- and expertise-intensive. A set of withdrawal guidelines was developed to guide generalists in caring for patients with opioid withdrawal at a hospital without an addiction consult service. METHODS: Retrospective chart review was performed to determine PDD, 30-day readmission, and psychiatry consult rates for hospitalized patients with OUD during periods before (July 1, 2017, to March 31, 2018) and after (January 1, 2019, to July 31, 2019) the withdrawal guidelines were implemented. Information on the provision of opioid agonist therapy (OAT) was also obtained. RESULTS: Use of OAT in patients with OUD increased significantly after guideline introduction, from 23.3% to 64.8% ( P < 0.001). Patient-directed discharge did not change, remaining at 14% before and after. Thirty-day readmissions increased 12.4% to 15.7% ( P = 0.05065). Receiving any OAT was associated with increased PDD and readmission, but only within the postintervention cohort. CONCLUSIONS: A guideline to facilitate generalist management of opioid withdrawal in hospitalized patients improved the process of care, increasing the use of OAT and decreasing workload on the psychiatry consult services. Although increased inpatient OAT has been previously shown to decrease PDD, in this study PDD and readmission rates did not improve. Guidelines may be insufficient to impact these outcomes.

Unwrapping broken tails: Biological and environmental correlates of predation pressure in limbless reptiles.

Studying species interactions in nature often requires elaborated logistics and intense fieldwork. The difficulties in such task might hinder our ability to answer questions on how biotic interactions change with the environment. Fortunately, a workaround to this problem lies within scientific collections. For some animals, the inspection of preserved specimens can reveal the scars of past antagonistic encounters, such as predation attempts. A common defensive behaviour that leaves scars on animals is autotomy, the loss of a body appendage to escape predation. By knowing the collection site of preserved specimens, it is possible to assess the influence of organismal biology and the surrounding environment in the occurrence of autotomy. We gathered data on tail loss for 8189 preserved specimens of 33 snake and 11 amphisbaenian species to investigate biological and environmental correlates of autotomy in reptiles. We applied generalized linear mixed effect models to evaluate whether body size, sex, life-stage, habitat use, activity pattern, biome, tropicality, temperature and precipitation affect the probability of tail loss in limbless reptiles. We observed autotomy in 23.6% of examined specimens, with 18.7% of amphisbaenian and 33.4% of snake specimens showing tail loss. The probability of tail loss did not differ between snakes and amphisbaenians, but it was higher among large-sized specimens, particularly in adults and females. Chance of tail loss was higher for diurnal and arboreal species, and among specimens collected in warmer regions, but it was unaffected by biome, precipitation, and tropicality. Autotomy in limbless reptiles was affected by size-dependent factors that interplay with ontogeny and sexual dimorphism, although size-independent effects of life-stage and sex also shaped behavioural responses to predators. The increase in probability of tail loss with verticality and diurnality suggests a risk-balance mechanism between species habitat use and activity pattern. Although autotomy is more likely in warmer regions, it seems unrelated to seasonal differences in snakes and amphisbaenians activity. Our findings reveal several processes related to predator-prey interactions involving limbless reptiles, demonstrating the importance of scientific collections to unveil ecological mechanisms at different spatio-temporal scales.

Experiences of COVID-19-Recovered Healthcare Workers in a Tertiary Hospital in the Philippines: A Mixed-Method Inquiry.

COVID-19 pandemic affected the mental health of the global population. Among the most vulnerable are the healthcare workers (HCWs) who got infected but returned to the frontline after recovery. Currently, there is a dearth of information and understanding on the psychological status and actual lived experience of the recovered HCWs in the Philippines. The present study investigated the psychological status and experiences of 93 COVID-19-recovered HCWs from a tertiary hospital in the Philippines using a mixed-method approach, particularly the explanatory-sequential design. Participants completed the Impact of Event Scale-Revised, and the Depression, Anxiety, and Stress Scale-21 in the quantitative phase. Selected participants took part in focus group discussions in the qualitative phase. Integrated results showed that our participants experienced significant COVID-19-related distress (mean IES-R score = 25.5; partial impact), anxiety (mean subscale score = 7.4; mild), and depression (mean subscale score = 8.1; mild). Certain sociodemographic and professional characteristics and the length of quarantine days appear to affect the psychometric scores. The quantitative results are supported by the participant's description of recovery experiences as living in uncertainty, distress, fatigue, dissociation, and valuation of life. In summary, adequate psychological support and intervention program should be prioritized and provided by hospital management for recovered HCWs to prevent the development of more serious mental health concerns that may significantly affect their tasks in caring for patients and in-hospital management.