The effect of different levothyroxine administration regimens on thyroid hormone levels: a systematic review, pairwise, and network meta-analysis.

INTRODUCTION: This systematic review aimed to compare the effect of alternative levothyroxine administration regimens on thyroid hormone levels and patient-reported outcomes (PROs) among adults with hypothyroidism. METHODS: We searched PubMed, Embase, CENTRAL, CINAHL, LILACS, SciELO, Scopus, Web of Science, OpenGrey, ProQuest, ClinicalTrials.gov, and ICTRP from inception to May/2023 for randomized controlled trials (RCTs). We assessed the risk of bias with Cochrane Risk of Bias 2.0 tool. We analyzed TSH levels by pairwise and network meta-analyses (NMA). The FT4 levels and PROs were qualitatively assessed. RESULTS: We included 14 RCTs (906 participants) comparing different regimens, as bedtime vs. before breakfast. A total of 12 RCTs were at high risk of bias. Seven RCTs were included in the TSH meta-analysis, where the mean difference (MD) and 95% confidence interval (CI) were as follows: bedtime vs before breakfast (4 RCTs) 0.69 (-1.67-3.04), I2 = 92%, very low certainty evidence; weekly dose vs before breakfast (2 RCTs) 1.68 (0.94-2.41), I2 = 0%, low certainty evidence; and at breakfast vs before breakfast (1 RCT) 0.65 (-1.11-2.41), very low certainty evidence. The NMA showed no evidence of differences in TSH level with different regimens. CONCLUSION: The evidence is insufficient to determine the most effective levothyroxine administration regimen for hypothyroidism. SYSTEMATIC REVIEW REGISTRATION: PROSPERO - CRD42021279375.

Linezolid does not improve bactericidal activity of rifampin-containing first-line regimens in animal models of TB meningitis.

Tuberculous meningitis (TB meningitis) is the most devastating form of tuberculosis (TB) and there is a critical need to optimize treatment. Linezolid is approved for multidrug resistant TB and has shown encouraging results in retrospective TB meningitis studies, with several clinical trials underway assessing its additive effects on high-dose (35 mg/kg/day) or standard-dose (10 mg/kg/day) rifampin-containing regimens. However, the efficacy of adjunctive linezolid to rifampin-containing first-line TB meningitis regimens and the tissue pharmacokinetics (PK) in the central nervous system (CNS) are not known. We therefore conducted cross-species studies in two mammalian (rabbits and mice) models of TB meningitis to test the efficacy of linezolid when added to the first-line TB regimen and measure detailed tissue PK (multicompartmental positron emission tomography [PET] imaging and mass spectrometry). Addition of linezolid did not improve the bactericidal activity of the high-dose rifampin-containing regimen in either animal model. Moreover, the addition of linezolid to standard-dose rifampin in mice also did not improve its efficacy. Linezolid penetration (tissue/plasma) into the CNS was compartmentalized with lower than previously reported brain and cerebrospinal fluid (CSF) penetration, which decreased further two weeks after initiation of treatment. These results provide important data regarding the addition of linezolid for the treatment of TB meningitis.

Clinical nursing care protocol for convalescent plasma transfusion in patients with COVID-19.

Introduction: The treatment of COVID-19 is still challenge. So convalescent plasma can be an important alternative of treatment. Protocols with nursing care during infusion is very important to guide an effective and safety care. Objective: to analyze the evidence in the literature on the action of convalescent plasma, of the use of protocols with nursing care to use convalescent plasma and build a nursing care protocol for transfusion in patients with COVID-19. Methods: Methodological study carried out in two stages: scoping review. The search was done using the descriptors: convalescent plasma transfusion, convalescent plasma, and acute respiratory syndromes or COVID-19, to found protocols and effectiveness of convalescent plasm. Beside was done a specialist panel to build the protocol. Results: Low-evidence studies have shown improvement in the clinical signs of COVID-19 using Convalescent Plasma, reduction or elimination of viral load, benefits in the production of lymphocytes, decreases C-reactive protein, increases titers of anti-SARS-CoV-2 antibodies, positive evolution in lung involvement identified by X-rays, decrease in hospitalization. No studies were found in the databases on the protocol for clinical nursing care in plasma transfusion. Therefore, a protocol was developed with the description of clinical nursing care to be performed before, during and after the transfusion by plasma: checking of vital signs and indicative signs of transfusion reaction, measurement of oxygen saturation, assessment of venous access and checking of the level of consciousness. Conclusion: There are no evidence studies to support the use of plasma, nor anything related to bundles.

Dynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies.

Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize 18F-pretomanid (chemically identical to the antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure pretomanid concentration-time profiles. Dynamic PET in mouse and rabbit models of TB meningitis demonstrates excellent CNS penetration of pretomanid but cerebrospinal fluid (CSF) levels does not correlate with those in the brain parenchyma. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis is substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18F-pretomanid PET in six healthy volunteers demonstrates excellent CNS penetration of pretomanid, with significantly higher levels in the brain parenchyma than in CSF. These data have important implications for developing new antibiotic treatments for TB meningitis.

High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis.

Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.

124I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection.

PURPOSE: Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with 124I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection. PROCEDURES: Pulmonary 124I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues. RESULTS: Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals (P < 0.01). Increased 124I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary 124I-iodo-DPA-713 PET activity was noted in male versus female hamsters (P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues (P = 0.02). CONCLUSION: 124I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, 124I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19.

Pharmacokinetics of high-titer anti-SARS-CoV-2 human convalescent plasma in high-risk children.

BACKGROUNDWhile most children who contract COVID-19 experience mild disease, high-risk children with underlying conditions may develop severe disease, requiring interventions. Kinetics of antibodies transferred via COVID-19 convalescent plasma early in disease have not been characterized.METHODSIn this study, high-risk children were prospectively enrolled to receive high-titer COVID-19 convalescent plasma (>1:320 anti-spike IgG; Euroimmun). Passive transfer of antibodies and endogenous antibody production were serially evaluated for up to 2 months after transfusion. Commercial and research ELISA assays, virus neutralization assays, high-throughput phage-display assay utilizing a coronavirus epitope library, and pharmacokinetic analyses were performed.RESULTSFourteen high-risk children (median age, 7.5 years) received high-titer COVID-19 convalescent plasma, 9 children within 5 days (range, 2-7 days) of symptom onset and 5 children within 4 days (range, 3-5 days) after exposure to SARS-CoV-2. There were no serious adverse events related to transfusion. Antibodies against SARS-CoV-2 were transferred from the donor to the recipient, but antibody titers declined by 14-21 days, with a 15.1-day half-life for spike protein IgG. Donor plasma had significant neutralization capacity, which was transferred to the recipient. However, as early as 30 minutes after transfusion, recipient plasma neutralization titers were 6.2% (range, 5.9%-6.7%) of donor titers.CONCLUSIONConvalescent plasma transfused to high-risk children appears to be safe, with expected antibody kinetics, regardless of weight or age. However, current use of convalescent plasma in high-risk children achieves neutralizing capacity, which may protect against severe disease but is unlikely to provide lasting protection.Trial registrationClinicalTrials.gov NCT04377672.FundingThe state of Maryland, Bloomberg Philanthropies, and the NIH (grants R01-AI153349, R01-AI145435-A1, K08-AI139371-A1, and T32-AI052071).

Kit-based synthesis of 2-deoxy-2-[18F]-fluoro-D-sorbitol for bacterial imaging.

Clinically available imaging tools for diagnosing infections rely on structural changes in the affected tissues. They therefore lack specificity and cannot differentiate between oncologic, inflammatory and infectious processes. We have developed 2-deoxy-2-[18F]fluoro-D-sorbitol (18F-FDS) as an imaging agent to visualize infections caused by Enterobacterales, which represent the largest group of bacterial pathogens in humans and are responsible for severe infections, often resulting in sepsis or death. A clinical study in 26 prospectively enrolled patients demonstrated that 18F-FDS positron emission tomography (PET) was safe, and could detect and localize infections due to drug-susceptible or multi-drug-resistant Enterobacterales strains as well as differentiate them from other pathologies (sterile inflammation or cancer). 18F-FDS is cleared almost exclusively through renal filtration and has also shown potential as a PET agent for functional renal imaging. Since most PET radionuclides have a short half-life, maximal clinical impact will require fast, on-demand synthesis with limited infrastructure and personnel. To meet this demand, we developed a kit-based solid phase method that uses commercially and widely available 2-deoxy-2-[18F]fluoro-D-glucose as the precursor and allows 18F-FDS to be produced and purified in one step at room temperature. The 18F-FDS kit consists of a solid-phase extraction cartridge packed with solid supported borohydride (MP-borohydride), which can be attached to a second cartridge to reduce pH. We evaluated the effects of different solid supported borohydride reagents, cartridge size, starting radioactivity, volumes and flow rates in the radiochemical yield and purity. The optimized protocol can be completed in <30 min and allows the synthesis of 18F-FDS in >70% radiochemical yield and >90% radiochemical purity.

Antidiabetic effects of Olea europaea L. leaves in diabetic rats induced by high-fat diet and low-dose streptozotocin.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, insulin resistance, and dyslipidemia. It has broad occurrence worldwide, affecting millions of people, and can cause serious complications. The olive (Olea europaea L.) has important pharmacological functions, including anti-inflammatory, antioxidant, and hypoglycemic activities. Olive leaves are used in traditional medicine for diabetes and hypertension. AIM OF THE STUDY: To evaluate the effect of the ethanolic extract of olive leaves (EEOL) on the metabolism of rats with diabetes induced by a high-fat diet and low dose of streptozotocin (STZ). MATERIALS AND METHODS: Male Wistar rats were either given normal feed or a high-fat diet (70% standard laboratory feed, 15% sucrose, 10% lard and 5% yolk powder) for four weeks, followed by administration of STZ (35 mg/kg, via ip). Animals with fasting glucose levels above 200 mg/dL were considered diabetic. Animals were divided into 5 groups, which received ethanol (10 mL/kg), metformin (250 mg/kg), or EEOL at doses of 200 and 400 mg/kg during 10 weeks by oral gavage. Blood samples were used to measure hematological and biochemical parameters, and kidneys were removed for posterior analysis. Body weight was recorded weekly. RESULTS: A significant decrease in body weight was observed among diabetic animals treated with ethanol and EEOL compared to the control group. Moreover, animals treated with EEOL showed an improvement in glucose levels and in levels of inflammatory and metabolic markers when compared to diabetic animals. CONCLUSIONS: The results indicate a potential anti-diabetic activity of olive leaves, however more studies are needed to validate clinical effects.

Acute toxicity and antimicrobial activity of leaf tincture Baccharis trimera (Less).

BACKGROUND: The present study aimed to evaluate the possible acute oral toxicity of Baccharistrimera leaf dye as well as its antimicrobial activity. METHOD: Organization for Economic co-operation and development (OECD) 423 was used to assess acute oral toxicity and as per protocol a dose of 2000 mg/kg of tincture was administered to Wistar rats, male and female, and observed for 14 days. Biochemical and hematological analyzes were performed with sample collected of rat. The dye was evaluated for antimicrobial activity by agar diffusion and microdilution methods, which allow to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) and antibiofilm potential. RESULTS: The results showed that there was no loss of animals and no significant changes in hematological and biochemical parameters after oral administration of 2000 mg/kg of tincture and was considered safe by the OECD, classified as category 5. The dyeing also showed an important antimicrobial activity against gram positive and gram negative bacteria also significantly decreased the microbial biofilm. CONCLUSION: The tincture of B.trimera leaf when given orally once can be considered safe and has a relevant antimicrobial potential that should be elucidated in subsequent research.

Impact of health professional training in breastfeeding on their knowledge, skills, and hospital practices: a systematic review.

OBJECTIVE: To identify the impact of training in breastfeeding on knowledge, skills, and professional and hospital practices. DATA SOURCE: The systematic review search was carried out through the MEDLINE, Scopus, and LILACS databases. Reviews, studies with qualitative methodology, those without control group, those conducted in primary care, with specific populations, studies that had a belief and/or professional attitude as outcome, or those with focus on the post-discharge period were excluded. There was no limitation of period or language. The quality of the studies was assessed by the adapted criteria of Downs and Black. SUMMARY OF DATA: The literature search identified 276 articles, of which 37 were selected for reading, 26 were excluded, and six were included through reference search. In total, 17 intervention articles were included, three of them with good internal validity. The studies were performed between 1992 and 2010 in countries from five continents; four of them were conducted in Brazil. The training target populations were nursing practitioners, doctors, midwives, and home visitors. Many kinds of training courses were applied. Five interventions employed the theoretical and practical training of the Baby-Friendly Hospital Initiative. All kinds of training courses showed at least one positive result on knowledge, skills, and/or professional/hospital practices, most of them with statistical significance. CONCLUSIONS: Training of hospital health professionals has been effective in improving knowledge, skills, and practices.

A autoimagem e a autoestima das pessoas com transtornos de pele: uma revisão integrativa da literatura baseada no modelo de Callista Roy / La autoimagen y la autoestima de las personas con trastornos de piel: una revisión integradora de la literatura basada en el modelo de Callista Roy / Self-Image and Self-Esteem in Persons with Skin Disorders: An Integrative Literature Review Based Callista Roy's Model

Objetivo: conhecer a relação entre os transtornos da pele e a alteração do autoconceito nas pessoas com afecção cutânea. Método: revisão integrativa da literatura a partir dos descritores: lesões, dermatologia e autoimagem. A busca se fez nas bases Lilacs, SciELO e PubMed, em artigos publicados entre 2000 e 2012. Resultados: a revisão integrativa mostrou os principais efeitos psicológicos causados pelas doenças da pele e confirmou que os fatores psicossociais relacionados com a autoimagem e a autoestima afetam a vida das pessoas. Conclusão: os transtornos da pele podem levar o indivíduo a buscar estratégias que vão desde o isolamento do corpo e o isolamento social, a negação da doença até o uso de maquiagem de camuflagem, como aparecem nas publicações. A escassez de estudos publicados que mostrem as estratégias a adotar pelos enfermeiros para lidar com os efeitos psicológicos causados pela doença cutânea evidenciam a necessidade de se pesquisar sobre o tema.

Objetivo: conocer la relación entre los trastornos de la piel y la alteración del autoconcepto en las personas con afección cutánea. Método: revisión integradora de la literatura desde los descriptores: lesiones, dermatología, y autoimagen. La búsqueda se hizo en las bases Lilacs, SciELO y PubMed, en artículos publicados entre el año 2000 y 2012. Resultados: La revisión integradora mostró los principales efectos psicológicos causados por las enfermedades de la piel y confirmó que los factores psicosociales relacionados con la autoimagen y la autoestima afectan la vida de las personas. Conclusión: los trastornos de la piel pueden llevar al individuo a buscar estrategias que van desde el aislamiento del cuerpo y el aislamiento social, la negación de la enfermedad y hasta el uso de maquillaje de camuflaje, como muestran las publicaciones. La escasez de estudios publicados que muestran las estrategias a adoptar por los enfermeros para lidiar con los efectos psicológicos causados por la enfermedad cutánea evidencia la necesidad de investigar sobre el tema.

Purpose: The purpose of this study is to understand the relationship between skin disorders and alteration of self-image in persons who suffer from skin problems. Method: An integrative literature review was done on the basis of three descriptors: lesions, dermatology, and self-image. The search centered on the Lilacs, SciELO and PubMed databases, among articles published between 2000 and 2012. Findings: The integrative review showed the major psychological effects caused by skin disorders and confirmed that psycho-social factors related to self-image and self-esteem impact a person's life. Conclusion: Skin disorders can prompt a person to resort to a variety of strategies ranging from physical seclusion and social isolation to denial of the aliment and even the use of camouflage makeup, as shown in publications. The scarcity of published studies showing the strategies adopted by nurses to deal with the psychological effects of skin disease demonstrate the need for research on the topic.

Impact of an interdisciplinary approach in children and adolescents with lower urinary tract dysfunction (LUTD).

INTRODUCTION: The lower urinary tract dysfunction (LUTD) corresponds to changes in the filling or emptying of urine caused by neurogenic, anatomical and functional alterations. OBJECTIVE: To evaluate the impact of treatment in children and adolescents with LUTD. METHODS: Historical cohort of 15 year follow-up with the participation of 192 patients (123F, 69M), aged 0.1 to 16.8 years, analyzed at admission (T0) and at final follow-up (T1). Most patients belong to a neurologic bladder dysfunction group (60.4%). The treatment was uroterapy with behavioral and cognitive intervention, timed voiding, oral hydration, laxative diet, biofeedback, sacral nerve stimulation, clean intermittent catheterization (CIC), anticholinergic therapy, rectal enema, treatment of urinary tract infection (UTI) and, in refractory cases, surgical procedures such as continent and incontinent urinary diversion (vesicostomy), bladder augmentation and conduit for performing antegrade colonic enema. RESULTS: The main symptoms were daytime urinary incontinence (82.3%), the non-monosymptomatic nocturnal enuresis (78.6%), fecal incontinence (54.2%) and constipation (47.9%). There was a significant reduction of urinary tract infection (p = 0.0027), daytime urinary incontinence (p < 0.001), nocturnal enuresis (p < 0.001), fecal incontinence (p = 0.010) and of vesicoureteral reflux (p = 0.01). There was significant increase in the use of CIC (p = 0.021), of anticholinergic therapy (p < 0.001) and decrease of chemoprophylaxis (p < 0.001). CONCLUSION: This study showed that treatment of LUTD in children must be individualized, and requires constant monitoring of clinical, laboratory and imaging to minimize the risk of kidney damage.

[Assisted hatching following embryo implantation failure]. / Eclosión asistida en pacientes con falla previa en la implantación embrionaria.

BACKGROUND: Assisted hatching in reproduction techniques has improved the successful implantation rates in certain groups of patients with poor prognosis. This study focuses on its effect in groups of patients with previous implantation failure and according to age groups. OBJECTIVE: Compare the pregnancy rates of patients who turned to this technique following an implantation failure using in vitro fertilization with those of patients who did not use assisted hatching before another attempt of in vitro fertilization and according to specific age groups. MATERIAL AND METHOD: Cases of patients using assisted hatching in our Center between January 2008 and December 2009 were studied. The results were compared in terms of age in three groups: group I, >35 years; group II, 35-39 years, and group III, > 40 years. RESULTS: Patients in group II had better pregnancy rate (30%) than those in groups I and III (16.98 and 20.83%, respectively). When comparing the results of the group of patients using assisted hatching with those of the group that did not, the first reported a 20% pregnancy rate versus no pregnancy in the other group.

Preservation of lysozyme structure and function upon encapsulation and release from poly(lactic-co-glycolic) acid microspheres prepared by the water-in-oil-in-water method.

When proteins are encapsulated in bioerodible polymers by water-in-oil-in-water (w/o/w) encapsulation techniques, inactivation and aggregation are serious drawbacks hampering their sustained delivery. Hen egg-white lysozyme was employed to investigate whether stabilizing it towards the major stress factors in the w/o/w encapsulation procedure would allow for the encapsulation and release of structurally unperturbed, non-aggregated, and active protein. When it was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres without stabilizing additives, lysozyme showed substantial loss in activity and aggregation. It has been shown that by co-dissolving various sugars and polyhydric alcohols with lysozyme in the first aqueous buffer, interface-induced lysozyme aggregation and inactivation can be minimized in the first emulsification step [J. Pharm. Pharmacol. 53 (2001) 1217]. Herein, it was found that those excipients, which were efficient in preventing interface-induced structural perturbations, were also efficient in minimizing lyophilization-induced structural perturbations (e.g. lactulose). The efficient excipients identified also reduced structural perturbations upon lysozyme encapsulation in PLGA microspheres and this led to reduced lysozyme inactivation and aggregation. However, the data obtained also show that later steps in the encapsulation procedure are detrimental to lysozyme activity. Lysozyme inactivation was completely prevented only by employing the efficient excipients in the second aqueous phase also. In summary, protein aggregation and inactivation were minimized by rationally selecting excipients efficient in stabilizing lysozyme against the major stress factors of w/o/w encapsulation.