Intranasal Versus Intravenous Dexamethasone to Treat Hospitalized COVID-19 Patients: A Randomized Multicenter Clinical Trial.

BACKGROUND: SARS-CoV2 induces flu-like symptoms that can rapidly progress to severe acute lung injury and even death. The virus also invades the central nervous system (CNS), causing neuroinflammation and death from central failure. Intravenous (IV) or oral dexamethasone (DXM) reduced 28 d mortality in patients who required supplemental oxygen compared to those who received conventional care alone. Through these routes, DMX fails to reach therapeutic levels in the CNS. In contrast, the intranasal (IN) route produces therapeutic levels of DXM in the CNS, even at low doses, with similar systemic bioavailability. AIMS: To compare IN vs. IV DXM treatment in hospitalized patients with COVID-19. METHODS: A controlled, multicenter, open-label trial. Patients with COVID-19 (69) were randomly assigned to receive IN-DXM (0.12 mg/kg for three days, followed by 0.6 mg/kg for up to seven days) or IV-DXM (6 mg/d for 10 d). The primary outcome was clinical improvement, as defined by the National Early Warning Score (NEWS) ordinal scale. The secondary outcome was death at 28 d between IV and IN patients. Effects of both treatments on biochemical and immunoinflammatory profiles were also recorded. RESULTS: Initially, no significant differences in clinical severity, biometrics, and immunoinflammatory parameters were found between both groups. The NEWS-2 score was reduced, in 23 IN-DXM treated patients, with no significant variations in the 46 IV-DXM treated ones. Ten IV-DXM-treated patients and only one IN-DXM patient died. CONCLUSIONS: IN-DMX reduced NEWS-2 and mortality more efficiently than IV-DXM, suggesting that IN is a more efficient route of DXM administration.

A non-inferiority study comparing the ultrasound-guided parasacral with a novel greater ischiatic notch plane approach in canine cadavers.

OBJECTIVE: To describe the gross and ultrasound anatomy of the parasacral region and an ultrasound-guided greater ischiatic notch (GIN) plane approach aimed at staining the lumbosacral trunk (LST) in canine cadavers. To evaluate if the ultrasound-guided GIN plane approach is non-inferior to the previously described ultrasound-guided parasacral approach at staining the LST. STUDY DESIGN: Prospective, randomized, non-inferiority experimental anatomic study. ANIMALS: A total of 17 (23.9 ± 5.2 kg) mesocephalic canine cadavers. METHODS: Anatomic and echographic landmarks, and the feasibility of performing a GIN plane technique were evaluated using two canine cadavers. The remaining 15 cadavers had each hemipelvis randomly assigned to be administered either parasacral or GIN plane injection of 0.15 mL kg-1 dye solution. The parasacral region was dissected after injections to assess the staining of LST, cranial gluteal nerve, pararectal fossa and pelvic cavity. The stained LST were removed and processed for histological evaluation of intraneural injections. A one-sided z-test for non-inferiority (non-inferiority margin -14%) was used to statistically evaluate the success of the GIN plane versus the parasacral approach. Data were considered statistically significant when p < 0.05. RESULTS: The GIN plane and parasacral approach stained the LST in 100% and 93.3% of the injections, respectively. The success rate difference between treatments was 6.7% [95% confidence interval, -0.6 to 19.0%; p < 0.001 for non-inferiority]. The GIN plane and parasacral injections stained the LST for 32.7 ± 16.8 mm and 43.1 ± 24.3 mm, respectively (p = 0.18). No evidence of intraneural injection was found. CONCLUSIONS AND CLINICAL RELEVANCE: The ultrasound-guided GIN plane technique resulted in nerve staining that was non-inferior to the parasacral technique and may be considered an alternative to the parasacral approach to block the LST in dogs.

Low responsiveness of peripheral lymphocytes in extraparenchymal neurocysticercosis.

BACKGROUND: The morbidity and mortality of extraparenchymal neurocysticercosis (EP-NC) remain high and effectiveness of current medical treatment is suboptimal. Various factors have been implicated in the severity of EP-NC and in the poor response to treatment, but the possible role of host immune and endocrine systems has not yet been examined thoroughly. METHODOLOGY/PRINCIPAL FINDINGS: 42 participants with EP-NC before receiving standard treatment and 25 healthy controls were included in the study. Treatment response was assessed by comparing pre/post treatment parasite volumes from 3D MRI. Prior to treatment among participants with EP-NC, specific stimulation induced an increased specific proliferative response accompanied by a significant increase in IL-4, NK, NKT, Bregs and Tregs cells, whereas in healthy controls, specific stimulation induced a significant increase in IL-1ß, IL-5, CCL5, IL-6, TNF-α, NK and Bregs cells. Significant differences between participants with EP-NC and healthy controls in the specific inflammatory response were observed. Participants with EP-NC prior to treatment had significantly weaker responses of proinflammatory cytokines (IL-6, TNF-α) and NK cells, and stronger IL-4 response. Anthelmintic treatment did not promote significant peripheral immunological changes at any time, although inflammation was sustained in the cerebrospinal fluid. Serum estradiol concentration significantly decreased after anthelmintic treatment among males, and cortisol correlated negatively with IL-6 and positively with IFN-γ levels. No pre-treatment immunologic or endocrinologic parameters were significantly associated with response to treatment. CONCLUSION/SIGNIFICANCE: Prior to anthelmintic treatment, EP-NC was characterized by low lymphocyte reactivity accompanied by a regulatory response, which may be involved in the lack of peripheral immunological changes during and after treatment, although a central inflammatory response was present. This weak specific peripheral response could favor the chronicity of the infection and the poor response to treatment. Our findings highlight the need for new anti-inflammatory treatment focused on the central nervous system with less systemic immunosuppressive effects.

Sex hormone dose escalation for treating abnormal sleep in ovariectomized rats: in vitro GABA synthesis in sleep-related brain areas.

No data in the literature have evaluated sex hormone dose escalation for treating abnormal sleep of ovariectomized rats-nor studies on the role of sex hormones in GABA synthesis of rats' sleep-related areas. The main aim of this study was to determine the maximum tolerated dose (MTD) of estradiol (ET), progesterone (PT), and the mixture of both (EPT) to restore normal sleep in a model of menopause in rats. The second purpose was to describe the in vitro activity of glutamate decarboxylase (GAD) in sleep-related brain areas in the presence or absence of sex hormones. A weekly dose-escalation design of ET, PT, or EPT was implemented in ovariectomized rats (six per group). Dose escalation continued until the dose at which 100% of the rats exhibited a state of "complete somnolence." Doses that were not toxic or did not show side effects were considered. For in vitro experiments, sleep-related brain areas were separated and incubated with radiolabeled glutamate. Estradiol (17ß-E2), progesterone (P), and pyridoxal phosphate (PLP) were added to this assay, and GAD activity was determined. Under the same conditions, a second test was carried out, but the P antagonist RU486 was added to assess the role of P in GAD activity. Ovariectomy increased periodic awakenings compared to those determined for the SHAM group. The EPT for ovariectomized rats was very effective by the fifth week in decreasing arousal and achieving a similar sleep behavior to the SHAM-control group. Rats tolerated the ET, PT, and EPT well to the maximum planned dose (0.66 mg/kg and 4.4 mg/kg, respectively). No lethal events occurred; the MTD was reached. The in vitro studies indicated that the presence of 17ß-E2 plus P in the assay triggered the activity of isotype 65 GAD in all the studied brain areas. RU486 in the incubation medium blocked such activity; however, the action of isotype 67 GAD was not blocked by RU486. A dose-escalation model was determined; the MTD coincided with the maximum dose of ET and PT used. However, the EPT combination restored normal sleep in the menopause model compared to the SHAMs without toxic effects. The in vitro model demonstrated that 17ß-E2 plus P presence in the assay increased the activity of GAD65 in the studied brain tissues.

Effect of end-inspiratory pause on airway and physiological dead space in anesthetized horses.

OBJECTIVE: To evaluate the impact of a 30% end-inspiratory pause (EIP) on alveolar tidal volume (VTalv), airway (VDaw) and physiological (VDphys) dead spaces in mechanically ventilated horses using volumetric capnography, and to evaluate the effect of EIP on carbon dioxide (CO2) elimination per breath (Vco2br-1), PaCO2, and the ratio of PaO2-to-fractional inspired oxygen (PaO2:FiO2). STUDY DESIGN: Prospective research study. ANIMALS: A group of eight healthy research horses undergoing laparotomy. METHODS: Anesthetized horses were mechanically ventilated as follows: 6 breaths minute-1, tidal volume (VT) 13 mL kg-1, inspiratory-to-expiratory time ratio 1:2, positive end-expiratory pressure 5 cmH2O and EIP 0%. Vco2br-1 and expired tidal volume (VTE) of 10 consecutive breaths were recorded 30 minutes after induction, after adding 30% EIP and upon EIP removal to construct volumetric capnograms. A stabilization period of 15 minutes was allowed between phases. Data were analyzed using a mixed-effect linear model. Significance was set at p < 0.05. RESULTS: The EIP decreased VDaw from 6.6 (6.1-6.7) to 5.5 (5.3-6.1) mL kg-1 (p < 0.001) and increased VTalv from 7.7 ± 0.7 to 8.6 ± 0.6 mL kg-1 (p = 0.002) without changing the VTE. The VDphys to VTE ratio decreased from 51.0% to 45.5% (p < 0.001) with EIP. The EIP also increased PaO2:FiO2 from 393.3 ± 160.7 to 450.5 ± 182.5 mmHg (52.5 ± 21.4 to 60.0 ± 24.3 kPa; p < 0.001) and Vco2br-1 from 0.49 (0.45-0.50) to 0.59 (0.45-0.61) mL kg-1 (p = 0.008) without reducing PaCO2. CONCLUSIONS AND CLINICAL RELEVANCE: The EIP improved oxygenation and reduced VDaw and VDphys, without reductions in PaCO2. Future studies should evaluate the impact of different EIP in healthy and pathological equine populations under anesthesia.

A single-cohort retrospective analysis of factors associated with morbidity and mortality in 193 anesthetized domestic goats.

OBJECTIVE: To define the morbidity and mortality rates in goats undergoing general anesthesia at a large animal teaching hospital. STUDY DESIGN: Retrospective, single-cohort, observational study. ANIMALS: Records of 193 client-owned goats. METHODS: Data were collected from 218 medical records on 193 goats undergoing general anesthesia between January 2017 and December 2021. Demographic data, anesthetic management, recovery period and perianesthetic complications were recorded. Perianesthetic death was defined as anesthesia-related or anesthesia-contributory death occurring within 72 hours after recovery. Records of goats that were euthanized were reviewed to ascertain the cause of euthanasia. Each explanatory variable was individually investigated by univariable penalized maximum likelihood logistic regression, followed by multivariable analysis. Statistical significance was set at p < 0.05. RESULTS: Perianesthetic mortality was 7.3%, but was 3.4% when considering only goats undergoing elective procedures. Multivariable analysis showed that gastrointestinal surgeries [odds ratio (OR) 19.17, standard error (SE) 12.99, 95% confidence interval (CI) 5.08-72.33; p < 0.01] and requirement for perianesthetic norepinephrine infusion (OR 10.85, SE 8.82, 95% CI 2.21-53.33; p < 0.01) were associated with increased mortality. Maintaining other variables equal, the use of perianesthetic ketamine infusion was associated with decreased mortality (OR 0.09, SE 0.09, 95% CI 0.01-0.73; p = 0.02). Anesthesia-related or anesthesia-contributory complications included hypothermia (52.4%), bradycardia (38.1%), hypotension (35.3%), hypoxemia (14.8%), regurgitation/aspiration (7.3%), azotemia/acute renal failure (4.6%), myopathies/neuropathies (4.1%) and fever of unknown origin (2.7%). CONCLUSIONS AND CLINICAL RELEVANCE: In this population, gastrointestinal surgeries and the requirement for perianesthetic norepinephrine infusion were associated with increased mortality in goats undergoing general anesthesia, while ketamine infusion may have a protective effect.

Physiological status of House Sparrows (Passer domesticus) along an ozone pollution gradient.

Mexico City is one of the most polluted cities in the world, and one in which air contamination is considered a public health threat. Numerous studies have related high concentrations of particulate matter and ozone to several respiratory and cardiovascular diseases and a higher human mortality risk. However, almost all of those studies have focused on human health outcomes, and the effects of anthropogenic air pollution on wildlife species is still poorly understood. In this study, we investigated the impacts of air pollution in the Mexico City Metropolitan Area (MCMA) on house sparrows (Passer domesticus). We assessed two physiological responses commonly used as biomarkers: stress response (the corticosterone concentration in feathers), and constitutive innate immune response (the concentration of both natural antibodies and lytic complement proteins), which are non-invasive techniques. We found a negative relationship between the ozone concentration and the natural antibodies response (p = 0.003). However, no relationship was found between the ozone concentration and the stress response or the complement system activity (p > 0.05). These results suggest that ozone concentrations in air pollution within MCMA may constrain the natural antibody response in the immune system of house sparrows. Our study shows, for the first time, the potential impact of ozone pollution on a wild species in the MCMA presenting the Nabs activity and the house sparrow as suitable indicators to assess the effect of air contamination on the songbirds.

Lumbosacral plexus block using a combination of ultrasound-guided lateral pre-iliac and parasacral approaches in cats.

OBJECTIVE: To describe an ultrasound-guided lateral pre-iliac (LPI) and parasacral (PS) approach in feline cadavers (phase I) and compare the perioperative analgesic use and complications in cats administered LPI and PS blocks (group PNB) or epidural anesthesia (group EPI) for pelvic limb surgery (phase II). STUDY DESIGN: Experimental uncontrolled, anatomic and retrospective cohort study. ANIMALS: A group of eight feline cadavers and 52 medical records. METHODS: Bilateral LPI and PS approaches with 0.1 mL kg-1 of dye to stain the femoral and obturator nerves and the lumbosacral trunk, respectively, were performed on each cadaver. Nerve staining effect was evaluated upon dissections (phase I). Perioperative analgesics use, and complication rates were retrospectively compared between groups PNB and EPI (phase II). Continuous data were compared using the Mann-Whitney U test and the prevalence of events with Fisher's exact test. Differences were considered significant when p < 0.05. RESULTS: Dissections revealed that the LPI approach stained 94% and 75% of the femoral and obturator nerves, respectively. The PS approach stained 100% of the lumbosacral trunks. Cats enrolled in group PNB (n = 23) were administered lower doses of intraoperative opioids than those in group EPI (n = 25) (p = 0.006). Intraoperative rescue analgesia was required in 60% and 17.4% of cats enrolled in groups EPI and PNB, respectively (p = 0.003). Group PNB required more intraoperative anticholinergics than group EPI (p = 0.02). There were no differences in postoperative pain scores, analgesic use and complication rates. CONCLUSIONS AND CLINICAL RELEVANCE: The ultrasound-guided LPI and PS approach stained the femoral/obturator nerves and the lumbosacral trunk, respectively, in feline cadavers. Furthermore, PNB was associated with lower intraoperative opioid use and similar postoperative pain and analgesic use compared with epidural anesthesia in a cohort of cats undergoing surgery of the pelvic limb.

Immunoendocrine abnormalities in the female reproductive system, and lung steroidogenesis during experimental pulmonary tuberculosis.

INTRODUCTION: Tuberculosis (TB) caused by Mycobacterium tuberculosis mainly affects the lungs, but can spread to other organs. TB chronically activates the immune and endocrine systems producing remarkable functional changes.So far, it is unknown whether pulmonary non-disseminated TB cause changes in the female reproductive system and lung endocrinology. OBJECTIVE: To investigate whether pulmonary TB produces immunoendocrine alterations of the female mice reproductive organs, and lung estradiol synthesis. METHODS: BALB/c mice were infected intratracheally with Mycobacterium tuberculosis (Mtb) strain H37Rv. Groups of six non-infected and infected animals were euthanized on different days. Bacillary loads were determined in the lungs, ovaries and uterus. Immunohistochemistry and morphometry studies were performed in histological sections. Serum estradiol wasassayed, and supernatantfrom cultured lung cells was analyzed by Thin Layer Chromatography (TLC). RESULTS: Mtb only grew in lung tissue. Histopathology revealed abnormal folliculogenesis and decreased corpora lutea. Altered ovarian expression of IL-6, IL-1ß was found. The infection increased serum estradiol. Estradiol synthesis by infected lung cells triplicate after 30 pi days.Aromatase immunostaining was found in the alveolar and bronchial epithelium, being stronger in the infected lungs, mainly in macrophages. CONCLUSION: Pulmonary TB affects the histophysiology of the female reproductive system in absence of its local infection, and disturbslung endocrinology.

Sex difference in innate inflammatory response and macrophage polarization in Streptococcus agalactiae-induced pneumonia and potential role of microRNA-223-3p.

While number of studies have shown that biological sex is a risk factor in the incidence and severity of infection-induced inflammatory diseases, the underlying mechanisms are still poorly understood. In this study, we compared the innate inflammatory response in male and female mice with group B streptococcal (GBS)-induced pneumoniae. Although male and female mice displayed similar bacterial burdens, males exhibited more innate inflammatory cytokines and chemokines and a higher proportion of infiltrating monocytes/macrophages. The analysis of the distribution of macrophage subtypes M1 (pro-inflammatory) versus M2 (anti-inflammatory) yielded a higher M1/M2 ratio in infected males compared with females. Given the importance of the chromosome X-linked microRNA-223-3p (miR-223-3p) in modulating the inflammatory process and macrophage polarization, we investigated its potential contribution in sex bias of GBS-induced innate inflammatory response. Knock-down of miR-223-3p with specific antagomiR resulted in increased inflammatory response and higher M1/M2 ratio following GBS infection. Notably, compared to male mice, we detected higher amount of miR-223-3p in macrophages from females that correlated negatively with M1 phenotype. These results suggest that differential expression of miR-233-3p may impact macrophage polarization, thereby contributing to fine-tune sex differences in inflammatory response.

Towards the development of an epitope-focused vaccine for SARS-CoV-2.

The rapid spread of COVID-19 on all continents and the mortality induced by SARS-CoV-2 virus, the cause of the pandemic coronavirus disease 2019 (COVID-19) has motivated an unprecedented effort for vaccine development. Inactivated viruses as well as vaccines focused on the partial or total sequence of the Spike protein using different novel platforms such us RNA, DNA, proteins, and non-replicating viral vectors have been developed. The high global need for vaccines, now and in the future, and the emergence of new variants of concern still requires development of accessible vaccines that can be adapted according to the most prevalent variants in the respective regions. Here, we describe the immunogenic properties of a group of theoretically predicted RBD peptides to be used as the first step towards the development of an effective, safe and low-cost epitope-focused vaccine. One of the tested peptides named P5, proved to be safe and immunogenic. Subcutaneous administration of the peptide, formulated with alumina, induced high levels of specific IgG antibodies in mice and hamsters, as well as an increase of IFN-γ expression by CD8+ T cells in C57 and BALB/c mice upon in vitro stimulation with P5. Neutralizing titers of anti-P5 antibodies, however, were disappointingly low, a deficiency that we will attempt to resolve by the inclusion of additional immunogenic epitopes to P5. The safety and immunogenicity data reported in this study support the use of this peptide as a starting point for the design of an epitope restricted vaccine.

Erector spinae plane block at the thoracolumbar spine: a canine cadaveric study.

OBJECTIVE: To investigate the injectate spread and nerve staining of ultrasound-guided erector spinae plane (ESP) injections at the thoracolumbar spine in canine cadavers. STUDY DESIGN: Prospective, randomized, descriptive, anatomic study. ANIMALS: A total of 15 canine cadavers. METHODS: The location of the medial and lateral branches of the dorsal branches of the spinal nerves (DBSN) from the tenth thoracic (T10) to the third lumbar vertebra (L3) were identified by dissection of three cadavers. ESP injections of dye (0.5 mL kg-1) were performed in seven cadavers using as landmarks the T12 transverse process (ESPTp) on one side and the lateral aspect of the T12 mammillary process (ESPMp) on the opposite side. Additionally, five cadavers were injected with dye (0.5 mL kg-1) bilaterally on the lateral aspect of the L2 mammillary process (ESPMp_L2). Nerve staining effect was analyzed after gross anatomic dissections. The number of stained nerves was analyzed using the Mann-Whitney U test. RESULTS: Gross anatomic dissections showed that the medial and lateral branches of the DBSN change their path in relation to the epaxial muscles caudal to T11. Approaches ESPTp and ESPMp at T12 stained 2 (0-2) and 3 (2-4) medial (p = 0.01) and 3 (3-4) and 2 (0-2) lateral (p = 0.03) branches, respectively. Injection ESPMp_L2 stained 3 (2-4) medial and 2 (0-3) lateral branches. Injections ESPMp and ESPMp_L2 produced a preferential cranial spread from the injection site. No ventral branches of the spinal nerves were stained with either technique. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that the mammillary process should be used as anatomic landmark to perform ultrasound-guided ESP blocks in the thoracolumbar spine caudal to T11 when targeting the medial branches of the DBSN. Injections should be performed one spinal segment caudal to the level intended to desensitize.

Pericapsular hip desensitization in dogs: a cadaveric study and case series.

OBJECTIVE: To develop and assess the efficacy of an ultrasound (US)-guided pericapsular hip desensitization (PHD) technique in dogs. STUDY DESIGN: Prospective, randomized, anatomical study and a case series. ANIMALS: A total of 30 healthy dogs, eight canine cadavers and seven dogs with hip osteoarthritis. METHODS: After studying the US anatomy of the medial aspect of the coxofemoral joint and determining an acoustic window to perform an US-guided PHD in healthy dogs, the US-guided PHD was performed bilaterally in canine cadavers. A low [(LV) 0.1 mL kg-1] and high [(HV) 0.2 mL kg-1] volume of dye was injected per hip on each cadaver. The staining of the pericapsular nerves was assessed by anatomical dissection, and comparison between LV and HV was assessed using Fisher's exact test. Then, the US-guided PHD was performed using a triamcinolone-bupivacaine solution in dogs with hip osteoarthritis. Dynamic pain response was assessed before and after injection. The canine brief pain inventory (CBPI) questionnaire was used to assess treatment efficacy and duration. RESULTS: The US-guided PHD could be performed by inserting the needle between the iliopsoas muscle and the periosteum of the ilium. The articular branches of the femoral and obturator nerves were stained in all cadavers using both volumes. The main femoral nerve was never stained, but the main obturator nerve was stained in 37.5% and 100% of injections using LV and HV, respectively (p = 0.026). Treated animals showed decreased dynamic pain response after the injection. Compared with baseline, CBPI scores were reduced by ≥ 50% for ≥ 12 weeks in all but one dog. CONCLUSIONS AND CLINICAL SIGNIFICANCE: The US-guided PHD with both 0.1 and 0.2 mL kg-1 volumes stained the articular branches of the femoral and obturator nerves in canine cadavers and was associated with clinical improvement in dogs with hip osteoarthritis.

Efficacy and safety of camostat mesylate in early COVID-19 disease in an ambulatory setting: a randomized placebo-controlled phase II trial.

OBJECTIVES: This study aimed to assess the efficacy and safety of 300 mg camostat mesylate three times daily in a fasted state to treat early phase COVID-19 in an ambulatory setting. METHODS: We conducted a phase II randomized controlled trial in symptomatic (maximum 5 days) and asymptomatic patients with confirmed COVID-19 infection. Patients were randomly assigned in a 2:1 ratio to receive either camostat mesylate or a placebo. Outcomes included change in nasopharyngeal viral load, time to clinical improvement, the presence of neutralizing antibodies, and safety. RESULTS: Of 96 participants randomized between November 2020 and June 2021, analyses were performed on the data of 90 participants who completed treatment (N = 61 camostat mesylate, N = 29 placebo). The estimated mean change in cycle threshold between day 1 and day 5 between the camostat and placebo group was 1.183 (P = 0.511). The unadjusted hazard ratio for clinical improvement in the camostat group was 0.965 (95% confidence interval, 0.480-1.942, P = 0.921 by Cox regression). The percentage distribution of the 50% neutralizing antibody titer at day 28 visit and frequency of adverse events were similar between the two groups. CONCLUSION: Under this protocol, camostat mesylate was not found to be effective as an antiviral drug against SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov NCT04625114; November 12, 2020.

Intranasal dexamethasone: a new clinical trial for the control of inflammation and neuroinflammation in COVID-19 patients.

BACKGROUND: By end December of 2021, COVID-19 has infected around 276 million individuals and caused over 5 million deaths worldwide. Infection results in dysregulated systemic inflammation, multi-organ dysfunction, and critical illness. Cells of the central nervous system are also affected, triggering an uncontrolled neuroinflammatory response. Low doses of glucocorticoids, administered orally or intravenously, reduce mortality among moderate and severe COVID-19 patients. However, low doses administered by these routes do not reach therapeutic levels in the CNS. In contrast, intranasally administered dexamethasone can result in therapeutic doses in the CNS even at low doses. METHODS: This is an approved open-label, multicenter, randomized controlled trial to compare the effectiveness of intranasal versus intravenous dexamethasone administered in low doses to moderate and severe COVID-19 adult patients. The protocol is conducted in five health institutions in Mexico City. A total of 120 patients will be randomized into two groups (intravenous vs. intranasal) at a 1:1 ratio. Both groups will be treated with the corresponding dexamethasone scheme for 10 days. The primary outcome of the study will be clinical improvement, defined as a statistically significant reduction in the NEWS-2 score of patients with intranasal versus intravenous dexamethasone administration. The secondary outcome will be the reduction in mortality during hospitalization. CONCLUSIONS: This protocol is currently in progress to improve the efficacy of the standard therapeutic dexamethasone regimen for moderate and severe COVID-19 patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04513184 . Registered November 12, 2020. Approved by La Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS) with identification number DI/20/407/04/36. People are currently being recruited.

The Influence of Holder Pasteurization on the Diversity of the Human Milk Bacterial Microbiota Using High-Throughput DNA Sequencing.

BACKGROUND: Human milk is the best food for infants; however, when breastfeeding is not possible, pasteurized milk from human milk banks is the best alternative. Little has been reported about variations in the bacterial microbiota composition of human milk after pasteurization. RESEARCH AIM: To characterize and compare the bacterial microbiota composition and diversity within human milk among Mexican mothers before and after the Holder pasteurization process. METHODS: A cross-sectional, observational, and comparative design was used. The effect of the pasteurization process on the bacterial composition and diversity of human milk samples of donors (N = 42) from a public milk bank was assessed before and after pasteurization by high throughput deoxyribonucleic acid sequencing of V3-16S rRNA gene libraries. Sequencing data were examined using the Quantitative Insights into Microbial Ecology software and Phyloseq in R environment. RESULTS: A varied community of bacteria was found in both raw and pasteurized human milk. The bacterial diversity of the milk samples was increased by the pasteurization, where some thermoduric bacteria of the phyla Proteobacteria, Firmicutes, and Actinobacteria were more abundant. The source tracker analysis indicated that at most 1.0% of bacteria may have come from another source, showing the safety of the process used to treat milk samples. CONCLUSION: The pasteurization process increased the bacterial diversity. We selected taxa capable of surviving the process, which could proliferate after the treatment without being a risk for infants.

Early high antibody titre convalescent plasma for hospitalised COVID-19 patients: DAWn-plasma.

BACKGROUND: Several randomised clinical trials have studied convalescent plasma for coronavirus disease 2019 (COVID-19) using different protocols, with different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralising antibody titres, at different time-points and severities of illness. METHODS: In the prospective multicentre DAWn-plasma trial, adult patients hospitalised with COVID-19 were randomised to 4 units of open-label convalescent plasma combined with standard of care (intervention group) or standard of care alone (control group). Plasma from donors with neutralising antibody titres (50% neutralisation titre (NT50)) ≥1/320 was the product of choice for the study. RESULTS: Between 2 May 2020 and 26 January 2021, 320 patients were randomised to convalescent plasma and 163 patients to the control group according to a 2:1 allocation scheme. A median (interquartile range) volume of 884 (806-906) mL) convalescent plasma was administered and 80.68% of the units came from donors with neutralising antibody titres (NT50) ≥1/320. Median time from onset of symptoms to randomisation was 7 days. The proportion of patients alive and free of mechanical ventilation on day 15 was not different between both groups (convalescent plasma 83.74% (n=267) versus control 84.05% (n=137)) (OR 0.99, 95% CI 0.59-1.66; p=0.9772). The intervention did not change the natural course of antibody titres. The number of serious or severe adverse events was similar in both study arms and transfusion-related side-effects were reported in 19 out of 320 patients in the intervention group (5.94%). CONCLUSIONS: Transfusion of 4 units of convalescent plasma with high neutralising antibody titres early in hospitalised COVID-19 patients did not result in a significant improvement of clinical status or reduced mortality.