A Recruitment Maneuver After Apnea Testing Improves Oxygenation and Reduces Atelectasis in Organ Donors After Brain Death.

BACKGROUND: Hypoxemia is the main modifiable factor preventing lungs from being transplanted from organ donors after brain death. One major contributor to impaired oxygenation in patients with brain injury is atelectasis. Apnea testing, an integral component of brain death declaration, promotes atelectasis and can worsen hypoxemia. In this study, we tested whether performing a recruitment maneuver (RM) after apnea testing could mitigate hypoxemia and atelectasis. METHODS: During the study period, an RM (positive end-expiratory pressure of 15 cm H2O for 15 s then 30 cm H2O for 30 s) was performed immediately after apnea testing. We measured partial pressure of oxygen, arterial (PaO2) before and after RM. The primary outcomes were oxygenation (PaO2 to fraction of inspired oxygen [FiO2] ratio) and the severity of radiographic atelectasis (proportion of lung without aeration on computed tomography scans after brain death, quantified using an image analysis algorithm) in those who became organ donors. Outcomes in RM patients were compared with control patients undergoing apnea testing without RM in the previous 2 years. RESULTS: Recruitment maneuver was performed in 54 patients after apnea testing, with a median immediate increase in PaO2 of 63 mm Hg (interquartile range 0-109, p = 0.07). Eighteen RM cases resulted in hypotension, but none were life-threatening. Of this cohort, 37 patients became organ donors, compared with 37 donors who had apnea testing without RM. The PaO2:FiO2 ratio was higher in the RM group (355 ± 129 vs. 288 ± 127, p = 0.03), and fewer had hypoxemia (PaO2:FiO2 ratio < 300 mm Hg, 22% vs. 57%; p = 0.04) at the start of donor management. The RM group showed less radiographic atelectasis (median 6% vs. 13%, p = 0.045). Although there was no difference in lungs transplanted (35% vs. 24%, p = 0.44), both better oxygenation and less atelectasis were associated with a higher likelihood of lungs being transplanted. CONCLUSIONS: Recruitment maneuver after apnea testing reduces hypoxemia and atelectasis in organ donors after brain death. This effect may translate into more lungs being transplanted.

Decrypting the multifaceted peripheral neuropathy based on molecular pathology and therapeutics: a comprehensive review.

CONTEXT: Peripheral neuropathy (PN) is a multifaceted complication characterized by nerve damage due to oxidative stress, inflammatory mediators, and dysregulated metabolic processes. Early PN manifests as sensory changes that develop progressively in a "stocking and glove" pattern. METHODS AND MECHANISMS: A thorough review of literature has been done to find the molecular pathology, clinical trials that have been conducted to screen the effects of different drugs, current treatments and novel approaches used in PN therapy. Diabetic neuropathy occurs due to altered protein kinase C activity, elevated polyol pathway activity in neurons, and Schwann cells-induced hyperglycemia. Other causes involve chemotherapy exposure, autoimmune ailments, and chronic ethanol intake. CONCLUSION: Symptomatic treatments for neuropathic pain include use of tricyclic antidepressants, anticonvulsants, and acetyl-L-carnitine. Patients will have new hope if clinicians focus on novel therapies including gene therapy, neuromodulation techniques, and cannabidiol as an alternative to traditional medications, as management is still not ideal.

Brainstem depolarization-induced lethal apnea associated with gain-of-function SCN1AL263V is prevented by sodium channel blockade.

Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1AL263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1aL263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function SCN1A mutations.

Care and three-year outcomes of children with Benign Epilepsy with Centro-Temporal Spikes in England.

PURPOSE: Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a pediatric epilepsy with typically good seizure control. Although BECTS may increase patients' risk of developing neurological comorbidities, their clinical care and short-term outcomes are poorly quantified. METHODS: We retrospectively assessed adherence to National Institute for Health and Care Excellence (NICE) guidelines relating to specialist referral, electroencephalogram (EEG) conduct and annual review in the care of patients with BECTS, and measured their seizure, neurodevelopmental and learning outcomes at three years post-diagnosis. RESULTS: Across ten centers in England, we identified 124 patients (74 male) diagnosed with BECTS between 2015 and 2017. Patients had a mean age at diagnosis of 8.0 (95% CI = 7.6-8.4) years. 24/95 (25%) patients were seen by a specialist within two weeks of presentation; 59/100 (59%) received an EEG within two weeks of request; and 59/114 (52%) were reviewed annually. At three years post-diagnosis, 32/114 (28%) experienced ongoing seizures; 26/114 (23%) had reported poor school progress; 15/114 (13%) were diagnosed with a neurodevelopmental disorder (six autism spectrum disorder, six attention-deficit/hyperactivity disorder); and 10/114 (8.8%) were diagnosed with a learning difficulty (three processing deficit, three dyslexia). Center-level random effects models estimated neurodevelopmental diagnoses in 9% (95% CI: 2-16%) of patients and learning difficulty diagnoses in 7% (95% CI: 2-12%). CONCLUSIONS: In this multicenter work, we found variable adherence to NICE guidelines in the care of patients with BECTS and identified a notable level of neurological comorbidity. Patients with BECTS may benefit from enhanced cognitive and behavioral assessment and monitoring.

CVVHD results in longer filter life than pre-filter CVVH: Results of a quasi-randomized clinical trial.

BACKGROUND: Filter clotting is a major issue in continuous kidney replacement therapy (CKRT) that interrupts treatment, reduces delivered effluent dose, and increases cost of care. While a number of variables are involved in filter life, treatment modality is an understudied factor. We hypothesized that filters in pre-filter continuous venovenous hemofiltration (CVVH) would have shorter lifespans than in continuous venovenous hemodialysis (CVVHD). METHODS: This was a single center, pragmatic, unblinded, quasi-randomized cluster trial conducted in critically ill adult patients with severe acute kidney injury (AKI) at the University of Iowa Hospitals and Clinics (UIHC) between March 2020 and December 2020. Patients were quasi-randomized by time block to receive pre-filter CVVH (convection) or CVVHD (diffusion). The primary outcome was filter life, and secondary outcomes were number of filters used, number of filters reaching 72 hours, and in-hospital mortality. RESULTS: In the intention-to-treat analysis, filter life in pre-filter CVVH was 79% of that observed in CVVHD (mean ratio 0.79, 95% CI 0.65-0.97, p = 0.02). Median filter life (with interquartile range) in pre-filter CVVH was 21.8 (11.4-45.3) and was 26.6 (13.0-63.5) for CVVHD. In addition, 11.8% of filters in pre-filter CVVH were active for >72 hours, versus 21.2% in the CVVHD group. Finally, filter clotting accounted for the loss of 26.7% of filters in the CVVH group compared to 17.5% in the CVVHD group. There were no differences in overall numbers of filters used or mortality between groups. CONCLUSIONS: Among critically patients with severe AKI requiring CKRT, use of pre-filter CVVH resulted in significantly shorter filter life compared to CVVHD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04762524. Registered 02/21/21-Retroactively registered, https://clinicaltrials.gov/ct2/show/NCT04762524?cond=The+Impact+of+CRRT+Modality+on+Filter+Life&draw=2&rank=1.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First-in-Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose).

ZYIL1 is a nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3-induced apoptosis-associated speck-like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18-55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single-ascending-dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1-1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half-life was 6-7 hours. In the multiple-ascending-dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration-time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose-proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)-1ß inhibition in all dose groups for both studies. Inhibition in IL-1ß and IL-18 was observed throughout the 14 days of treatment in the multiple-dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL-1ß and IL-18 level support its development for the management of inflammatory disorders.

Development of a novel method for multiple phytohormone analysis by UHPLC-MS/MS from bio-enriched organic fertilizer prepared using banana pseudostem sap waste.

Banana harvesting generates a large amount of banana pseudostem waste, which is generally burnt or thrown away, despite containing many nutrients. Bio-enriched organic fertilizer (BOF) was prepared from banana pseudostem sap (BPS), and it has been patented (Patent No. WO 2013/001478 Al). Several reports revealed that its application increases plant growth promotion of various horticulture crops. Apart from macro- and micronutrients, it also contained phytohormones. Hence, the present study aims to detect and quantify phytohormone in it. A novel method was developed to extract four phytohormones, viz., indole-3-acetic acid (IAA), indole-3-butyric acid (IBA), gibberellic acid (GA3), and salicylic acid (SA) using single solvent from BPS and BOF. Extracted hormones were analyzed by ultrahigh-performance liquid chromatography coupled with heated electrospray ionization tandem mass spectrometry (UHPLC-HESI-MS/MS). BOF showed a higher concentration of IAA, IBA, GA3, and SA than BPS. Thus, this is the first time a method has been reported to extract and detect phytohormones from banana pseudostem sap.

Atypical Location of Diffuse Large B-cell Lymphoma in the Nasal Septum.

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin's lymphoma (NHL). This subtype can be present in various extranodal sites, including the brain, bones, intestines, kidneys, adrenal glands, and other soft tissues. As demonstrated in this case, one rare site of DLBCL is the nasal septum, which presents as a rapidly enlarging mass resistant to antibiotics and steroids. The definitive diagnosis for this case involved biopsy, but further workup, such as computed tomography (CT) and fluorescence in situ hybridization (FISH), helped support the diagnosis of DLBCL. While determining the stage of the lymphoma, treatment with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) was initiated immediately. This case demonstrates a rare presentation of DLBCL in the nasal septum and describes the significance of urgent examination as well as treatment.

A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor.

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Effect of Endometrial Thickness and duration of Estrogen Supplementation on In Vitro Fertilization-Intracytoplasmic Sperm Injection Outcomes in Fresh Ovum/Embryo Donation Cycles.

BACKGROUND: There is no consensus regarding optimal endometrial thickness and duration of estrogen supplementation in embryo transfer cycles, at present. AIMS: To observe the effect of endometrial thickness and/or duration of estrogen supplementation on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes in fresh ovum/embryo donation cycles. SETTINGS AND DESIGN: This was a retrospective observational study. The study was conducted from January 2015 to November 2017. SUBJECTS AND METHODS: Nine hundred and fifty seven fresh blastocyst transfer cycles in the recipients of oocyte/embryo donation regardless of reproductive history and diagnosis conducted at Nova IVF Fertility, Ahmedabad, Gujarat, India. Of these, 315 women had single embryo transfer (SET), while 642 had double embryo transfer (DET). Only fresh blastocysts derived from oocytes of young donors (≤30 years) and transferred in a uniform hormone replacement therapy (HRT) cycle were included. The effect of endometrial thickness and duration of estrogen on live birth rate (LBR) and other IVF/ICSI outcomes were analyzed. STATISTICAL ANALYSIS: Univariate logistic regression. RESULTS: A significant improvement in LBR was noted in the recipients with each millimeter increase in endometrial thickness starting from 6 mm after transfer of either single (odds ratio [OR] = 1.3, P = 0.003) or double (OR = 1.14, P = 0.0218) blastocysts. Lower LBR was observed in recipients having SET and who received estrogen supplementation of <10 days (OR = 0.72; P = 0.02). Implantation rate and clinical pregnancy rate also improved significantly with endometrial thickness, but there was no change in clinical abortion rate and ectopic pregnancy rate. CONCLUSIONS: After minimizing the possible oocyte factor by including only donor oocytes and that of COH using a uniform HRT protocol, LBR improved with each millimeter increase in endometrial thickness starting from 6 mm. Shorter duration of estrogen supplementation (<10 days) reduced the chances of live birth in recipients after transfer of a single blastocyst.

Direct Chill Casting and Extrusion of AA6111 Aluminum Alloy Formulated from Taint Tabor Scrap.

AA6111 aluminum automotive body-sheet alloy has been formulated from 100% Taint Tabor scrap aluminum. Direct chill casting with and without high shear melt conditioning (HSMC) was used to produce the AA6111 alloy billets. Both homogenized and non-homogenized billets were extruded into sheets. The optical micrographs of the melt conditioned direct chill (MC-DC) samples showed refined equiaxed grains in comparison to direct chill (DC) cast and direct chill grain refined (DC-GR) samples. Optical metallography showed extensive peripheral coarse grain (PCG) for the DC, DC-GR and MC-DC planks extruded from the homogenized standard AA6111 billets while planks extruded from modified AA6111 billets (with recrystallization inhibitors) showed thin PCG band. The co-addition of recrystallization inhibitors Mn, Zr, and Cr with elimination of the billet homogenization step had a favorable impact on the microstructure of the AA6111 alloy following the extrusion process where a fibrous grain structure was retained across the whole section of the planks. The mechanical properties of as-cast planks extruded from non-homogenized billets were similar to those extruded from homogenized billets. Eliminating the homogenization heat treatment step prior to extrusion has important ramifications in terms of processing cost reduction.

Neurotoxoplasmosis mimicking primary brain malignancy.

Toxoplasma gondii infection is an uncommon and potentially life-threatening condition in immunocompromised patients in the setting of solid organ transplantation. We present the case of cerebral toxoplasmosis which presented as a solitary intracranial space-occupying lesion in a patient who received a combined kidney and pancreas transplant more than twenty years ago. Initially, the lesion was considered as a primary brain malignancy based on brain imaging but surprisingly the brain biopsy led to the correct diagnosis.

Melt Conditioned Direct Chill (MC-DC) Casting and Extrusion of AA5754 Aluminium Alloy Formulated from Recycled Taint Tabor Scrap.

The melt conditioned direct chill (MC-DC) casting process has been used to produce billets and extruded planks of AA5754 alloy formulated from 100% recycled Taint Tabor scrap aluminum. The billets were homogenized and then extruded into flat planks. Optical metallography of the MC-DC cast billets showed equiaxed refined grains in comparison to conventional direct chill (DC) cast and direct chill grain refined (DC-GR) cast billets formulated from the same Taint Tabor scrap. Microstructural evaluation of the extruded planks showed extensive peripheral coarse grain (PCG) for the DC, DC-GR and MC-DC cast planks. The 2 mm and 1 mm MC-DC cast planks produced after cold rolling and heat treatment showed a fully recrystallized microstructure at 380 °C and 300 °C for 10 min respectively with an improvement in mechanical properties over DC-GR cast and similarly processed planks. The as-extruded MC-DC cast planks tensile tested in the transverse direction showed 34% elongation and 213 MPa ultimate tensile strength. These tensile results showed 5.8% higher elongation and 1.2% higher ultimate tensile strength compared with the DC-GR planks after applying high shear melt conditioning.

Trend of influenza vaccine Facebook posts in last 4 years: a content analysis.

BACKGROUND: Decreasing immunization rates may be partly due to antivaccine campaigns and other sources of misinformation available on social media, particularly on Facebook. Given the potential impact of this medium for communicating vaccine-related information, it is important to analyze the trend of information available on Facebook. METHODS: We searched Facebook on August 15, 2018 to obtain posts containing relevant health information on influenza vaccine in years 2015-2018. We collected information regarding nature of the post (eg, pro-, antivaccine, and informational), number of shares and likes received, and ease of reading for each post. We evaluated these characteristics by year and type of post in our exploratory analyses. RESULTS: The proportion of pro-vaccine posts has increased compared to antivaccine and informational posts since 2016. There was no correlation between ease of reading and popularity of posts. Although the language of antivaccine posts was complex, they were shared and liked more than pro-vaccine posts. The pro-vaccine personal post by a nurse was the most popular in our study (shared over 46,000 times) in 2018. CONCLUSIONS: Though the number of pro-vaccine posts increased, antivaccine posts remained more popular. The government agency may use an emotive personal family-oriented message to promote vaccination.

Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.

The orexin system, which consists of the two G protein-coupled receptors OX1 and OX2, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX1 and OX2 can be achieved are discussed.

Serum and follicular fluid Stem Cell Factor assay in IVF poor responder and normal responder patients: a predictive biomarker of oocyte retrieval.

OBJECTIVE: The aim of the study is to investigate serum stem cell factor (SCF) concentrations as potential biomarker for oocyte retrieval efficiency in IVF patients with poor prognosis. METHODS: A pilot case-control study was performed on 30 poor and 30 normal responders that were stimulated with antagonist protocol. SCF concentrations were evaluated in samples of serum and follicular fluid obtained by all patients on the day of oocyte retrieval. At the time of oocyte retrieval, follicular fluid from at least two follicles ≥ 14 mm and two follicles < 14 mm was collected for SCF determination. RESULTS: We did not find any statistical difference when comparing serum and follicular fluid levels of SCF in both poor- and normal-responder patients, the same results were achieved when poor-responder patients were stratified according to the number of MII oocytes retrieved. Moreover, levels of SCF (OR 1.000, 0.994-1.006) or in follicular fluid from ovarian follicles ≥ 14 mm (OR 0.995, CI 0.989-1.001) or from ovarian follicles < 14 mm (OR 1.003, CI 0.999-1.0069), were not significantly associated with the chances of ongoing pregnancies in poor-responder patients. CONCLUSION: SCF was unable to predict oocyte retrieval efficiency or the chances of reaching embryo transfer.