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The Laryngoscope Mar 2021Bilateral myringotomy and tympanostomy tube placement (BMT) is the most common pediatric surgery in the United States. Intraoperative middle ear effusion (MEE) is a risk... (Comparative Study)
Comparative Study
OBJECTIVES/HYPOTHESIS
Bilateral myringotomy and tympanostomy tube placement (BMT) is the most common pediatric surgery in the United States. Intraoperative middle ear effusion (MEE) is a risk factor for future BMTs in children with recurrent acute otitis media (RAOM). However, the impact of the type of MEE is unknown. Here, we assess otologic outcomes based on intraoperative MEE type and indication for surgery.
STUDY DESIGN
Case series chart review.
METHODS
After institutional review board approval, we performed a review of children undergoing BMTs between 2008 and 2009. Included patients had their first BMT, preoperative visit, and an operative report. Patients with cleft palate or Down syndrome were excluded. Indications for surgery included RAOM and chronic otitis media with effusion (COME). Other variables evaluated were future BMT, acquired cholesteatoma, and otorrhea. Logistic regression was used for statistical analysis.
RESULTS
Out of 1,045 patients reviewed, 680 were included and underwent their first BMT. There were 619 patients who had RAOM. Serous effusions were present in 22.2%, mucoid in 31.3%, purulent in 12.9%, undocumented or bloody in 2.3% of patients, and 31.2% of patients had dry middle ears. Moreover, 22.7% of patients underwent future BMTs. In RAOM patients, serous effusions decreased odds of perforation (odds ratio [OR]: 0.195, 95% confidence interval [CI]: 0.0438-0.867, P = .032), and purulent effusions increased the odds of in-office otorrhea suctioning (OR: 2.13, 95% CI: 1.20-3.77, P = .010) compared to dry. Mucoid effusions had no significant effect on outcomes in COME or RAOM patients.
CONCLUSIONS
Intraoperative MEEs were noted in 68.7% of cases; purulent effusions increase the odds of in-office suctioning in RAOM patients.
LEVEL OF EVIDENCE
4 Laryngoscope, 131:E993-E997, 2021.
Topics: Adenoidectomy; Child, Preschool; Chronic Disease; Female; Humans; Infant; Male; Middle Ear Ventilation; Otitis Media; Otitis Media with Effusion; Otitis Media, Suppurative; Postoperative Complications; Recurrence; Reoperation; Time Factors; Treatment Outcome
PubMed: 32621539
DOI: 10.1002/lary.28860 -
Alzheimer's & Dementia (Amsterdam,... 2023Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is...
UNLABELLED
Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co-occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four-class solution (no symptoms, apathy, depression, and combined apathy/depression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathy/depression syndrome exists, supported by the model fit test with the four-class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy ). Using a data-driven method, we show distinct and statistically meaningful co-occurrence of apathy and depressive symptoms. There was evidence that these classes have different clinical associations, which may help inform diagnostic categories for research studies and clinical practice.
HIGHLIGHTS
We found four classes: no symptoms, apathy, depression and apathy/depression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms.
PubMed: 36777092
DOI: 10.1002/dad2.12398 -
Frontiers in Endocrinology 2021Defects in the insulin receptor () gene cause various severe insulin resistance conditions, including Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS) and type A...
OBJECTIVE
Defects in the insulin receptor () gene cause various severe insulin resistance conditions, including Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS) and type A insulin resistance (type A-IR). This study aimed to investigate the clinical characterization and molecular defects in three Chinese children with -related insulin resistance syndrome.
METHODS
We reviewed the clinical data of three Chinese children with -related insulin resistance syndrome from two unrelated kindreds. Genetic analysis was performed using whole-exome sequencing and the effects of the novel variants were further assessed by functional assays.
RESULTS
The proband with type A-IR presented with acanthosis nigricans, hypertrichosis, and euglycemia with mild insulin resistance in early childhood. His sister presented with features typical of type A-IR and was diagnosed with diabetes mellitus with severe insulin resistance at the age of 9.8 years. The proband with DS showed typical dysmorphic characteristics, severe intrauterine growth retardation, extreme insulin resistance, fasting hypoglycemia and postprandial hyperglycemia from birth. The heterozygote variants c.[3670G>A]; c.[3614C>T] were identified in both siblings with type A-IR; and c.[749_751del]; c.[3355C>T] in the patient with DS. studies showed that the novel variant c.749_751del [p.(Thr250del)] in the α-subunit, reduced expression of the mature INSR protein and severely impaired INSR function. In contrast, the novel variant c.3670G>A [p.(Val1224Met)] in the β-subunit had no effect on total protein expression and phosphorylation of INSR and Akt, suggesting that the variant p.Val1224Met appeared to be tolerated and was not responsible for the severe insulin resistance.
CONCLUSION
Our study detailed the clinical features of three patients with type A-IR and DS, and identified two novel variants in the gene. Functional assays indicated the novel variant p.Thr250del was pathogenic. In contrast, the novel variant p.Val1224Met was suggested to be tolerated by our experimental data, even though bioinformatics analyses predicted the variant as deleterious.
Topics: Acanthosis Nigricans; Animals; Antigens, CD; CHO Cells; Child; Child, Preschool; China; Cricetulus; DNA Mutational Analysis; Diabetes Complications; Donohue Syndrome; Family; Female; Humans; Insulin Resistance; Male; Metabolic Syndrome; Mutation, Missense; Patient Acuity; Pedigree; Receptor, Insulin; Syndrome
PubMed: 33995269
DOI: 10.3389/fendo.2021.606964 -
Molecular Biology Reports Mar 2016Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million life births. It represents the most severe form of insulin...
Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million life births. It represents the most severe form of insulin resistance due to mutations involving the insulin receptor (IR) gene "INSR". DS is characterized by pre- and postnatal growth retardation with failure-to-thrive, lipoatrophy, acanthosis nigricans, hypertrichosis, and dysmorphic features. An exhaustive INSR gene sequencing was performed after PCR amplification of coding exons and introns boundaries. Bioinformatic tools, including ESEfinder, MFOLD and Proter software were also used to predict the impact of INSR mutation on INSR on gene expression as well as on the protein structure and function. The results have shown a novel unusual c.3003_3012delinsGGAAG (p.S1001_D1004delinsRE) insertion/deletion (indel) mutation within the exon 16 in the three patients, which represent the fourth indel mutation within the INSR gene. The mutation modifies the secondary structure of DNA and RNA, as well as the composition of exonic splicing enhancers of exon 16. Moreover, despite the conservation of the secondary structure of the IR, the p.S1001_D1004delinsRE in-frame mutation is accompanied by the loss of four amino acids replaced by two residues of different nature and hydrophobicity level in the juxtamembrane domain of the receptor. The results have confirmed the role of the juxtamembrane domain of IR involved in a crucial interaction of the IR with cellular effectors essentially the IR substrate 1 (IRS-1), the SHC and the Nck proteins that ensure the signal mediated by the insulin transduction pathway in target cells. Our findings have also proven the genotype/phenotype correlation between INSR mutation and DS phenotype severity.
Topics: Adaptor Proteins, Signal Transducing; Africa; Amino Acid Sequence; Antigens, CD; Donohue Syndrome; Female; Gene Expression; Humans; INDEL Mutation; Infant; Infant, Newborn; Insulin Receptor Substrate Proteins; Male; Molecular Sequence Data; Oncogene Proteins; Protein Structure, Secondary; Receptor, Insulin; Sequence Alignment; Sequence Analysis, DNA; Shc Signaling Adaptor Proteins; Signal Transduction
PubMed: 26874853
DOI: 10.1007/s11033-016-3951-9 -
The New England Journal of Medicine Jan 2021Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.
METHODS
In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients.
RESULTS
Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.
CONCLUSIONS
In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).
Topics: Adult; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; COVID-19; Double-Blind Method; Drug Combinations; Female; Humans; Immunologic Factors; Least-Squares Analysis; Male; Middle Aged; Outpatients; Reverse Transcriptase Polymerase Chain Reaction; SARS-CoV-2; Viral Load; COVID-19 Drug Treatment
PubMed: 33332778
DOI: 10.1056/NEJMoa2035002 -
Pediatric Critical Care Medicine : a... May 2019Many hospitals aim to extubate children early after cardiac surgery, yet it remains unclear how this practice associates with extubation failure. We evaluated adjusted...
OBJECTIVES
Many hospitals aim to extubate children early after cardiac surgery, yet it remains unclear how this practice associates with extubation failure. We evaluated adjusted extubation failure rates and duration of postoperative mechanical ventilation across hospitals and assessed cardiac ICU organizational factors associated with extubation failure.
DESIGN
Secondary analysis of the Pediatric Cardiac Critical Care Consortium clinical registry.
SETTING
Pediatric Cardiac Critical Care Consortium cardiac ICUs.
PATIENTS
Patients with qualifying index surgical procedures from August 2014 to June 2017.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
We modeled hospital-level adjusted extubation failure rates using multivariable logistic regression. A previously validated Pediatric Cardiac Critical Care Consortium model was used to calculate adjusted postoperative mechanical ventilation. Observed-to-expected ratios for both metrics were derived for each hospital to assess performance. Hierarchical logistic regression was used to assess the association between cardiac ICU factors and extubation failure. Overall, 16,052 surgical hospitalizations were analyzed. Predictors of extubation failure (p < 0.05 in final case-mix adjustment model) included younger age, underweight, greater surgical complexity, airway anomaly, chromosomal anomaly/syndrome, longer cardiopulmonary bypass time, and other preoperative comorbidities. Three hospitals were better-than-expected outliers for extubation failure (95% CI around observed-to-expected < 1), and three hospitals were worse-than-expected (95% CI around observed-to-expected > 1). Two hospitals were better-than-expected outliers for both extubation failure and postoperative mechanical ventilation, and three were worse-than-expected for both. No hospital was an outlier in opposite directions. Greater nursing hours per patient day and percent nursing staff with critical care certification were associated with lower odds of extubation failure. Cardiac ICU factors such as fewer inexperienced nurses, greater percent critical care trained attendings, cardiac ICU-dedicated respiratory therapists, and fewer patients per cardiac ICU attending were not associated with lower odds of extubation failure.
CONCLUSIONS
We saw no evidence that hospitals trade higher extubation failure rates for shorter duration of postoperative mechanical ventilation after pediatric cardiac surgery. Increasing specialized cardiac ICU nursing hours per patient day may achieve better extubation outcomes and mitigate the impact of inexperienced nurses.
Topics: Airway Extubation; Cardiac Surgical Procedures; Child; Female; Hospitals; Humans; Infant; Infant, Newborn; Male; Nursing Staff, Hospital; Outcome Assessment, Health Care; Postoperative Period; Registries; Respiration, Artificial; Time Factors
PubMed: 30807544
DOI: 10.1097/PCC.0000000000001877 -
Journal of the Endocrine Society Nov 2017Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in...
CONTEXT
Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects.
PURPOSE
The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations.
METHODS
We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index <25 kg/m) who exhibited hyperinsulinemia (serum fasting immunoreactive insulin ≥15 µU/mL). Genetic analysis was performed for the insulin receptor gene in 11 nonobese subjects with hyperinsulinemia.
RESULTS
The prevalence of hyperinsulinemia without apparent diabetes in nonobese subjects was 0.4% (33/8630). In the 11 analyzed subjects, two novel heterozygous nonsense mutations were detected [c.2106 T>G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11).
CONCLUSIONS
To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia.
PubMed: 29264459
DOI: 10.1210/js.2017-00332 -
Diabetes Oct 2017The insulin receptor () gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient...
The insulin receptor () gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient with Donohue syndrome (DS) had a novel p.V657F mutation in the second fibronectin type III domain (FnIII-2), which contains the α-β cleavage site and part of the insulin-binding site. The mutant INSR was expressed in Chinese hamster ovary cells, revealing that it reduced insulin proreceptor processing and impaired activation of downstream signaling cascades. Using online databases, we analyzed 82 missense mutations and demonstrated that mutations causing DS were more frequently located in the FnIII domains than those causing the milder type A insulin resistance ( = 0.016). In silico structural analysis revealed that missense mutations predicted to severely impair hydrophobic core formation and stability of the FnIII domains all caused DS, whereas those predicted to produce localized destabilization and to not affect folding of the FnIII domains all caused the less severe Rabson-Mendenhall syndrome. These results suggest the importance of the FnIII domains, provide insight into the molecular mechanism of severe insulin resistance, will aid early diagnosis, and will provide potential novel targets for treating extreme insulin resistance.
Topics: Adolescent; Child, Preschool; Donohue Syndrome; Female; Genotype; Humans; Infant; Insulin Resistance; Male; Mutation; Mutation, Missense; Phenotype; Receptor, Insulin
PubMed: 28765322
DOI: 10.2337/db17-0301 -
The Journal of Infectious Diseases Jun 2023From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and...
From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and specimen collection for 14 days, 61% (43/70) of primary cases had culturable virus detected ≥6 days post-onset. Risk of secondary infection among household contacts tended to be greater when primary cases had culturable virus detected after onset. Regardless of duration of culturable virus, most secondary infections (70%, 28/40) had serial intervals <6 days, suggesting early transmission. These data examine viral culture as a proxy for infectiousness, reaffirm the need for rapid control measures after infection, and highlight the potential for prolonged infectiousness (≥6 days) in many individuals.
Topics: Humans; SARS-CoV-2; COVID-19; Tennessee; Family Characteristics; California
PubMed: 36705269
DOI: 10.1093/infdis/jiad018 -
International Journal of Radiation... 2021The purpose if this study was to develop a rabbit model of total body irradiation (TBI) -induced thrombocytopenia and coagulopathy across the dose-range which induces...
A New Zealand White rabbit model of thrombocytopenia and coagulopathy following total body irradiation across the dose range to induce the hematopoietic-subsyndrome of acute radiation syndrome.
PURPOSE
The purpose if this study was to develop a rabbit model of total body irradiation (TBI) -induced thrombocytopenia and coagulopathy across the dose-range which induces the hematopoietic subsyndrome of the acute radiation syndrome (H-ARS).
METHODS
Twenty male New Zealand White rabbits were assigned to arms to receive 6-MV of TBI at a dose of 6.5, 7.5, 8.5 or 9.5 Gy. Animals were treated with moderate levels of supportive care including buprenorphine for pain management, antibiotics, antipyretics for rectal body temperature >104.8 °F, and fluids for signs of dehydration. Animals were closelyfollowed for up to 45 days after TBI for signs of major morbidity/mortality. Hematology and serum chemistry parameters were routinely monitored. Hemostasis parameters were analyzed prior to TBI, 2 and 6 hours post-TBI, and at the time of euthanasia.
RESULTS
Animals developed the characteristic signs and symptoms of H-ARS during the first-week post TBI. Animals became thrombocytopenic with signs of severe acute anemia during the second week post TBI. Moribund animals presented with petechia and ecchymosis of the skin and generalized internal hemorrhage. Multiorgan dysfunction characterized by bone marrow failure, gastric ileus, acute renal toxicity, and liver abnormalities were common. Severe abnormalities in coagulation parameters were observed.
CONCLUSIONS
The presentation of bone marrow failure and multiorogan injury associated with ARS in the New Zealand White rabbit model is consistent with that described in the canine, swine, non-human primate, and in humans. The hemorrhagic syndrome associated with the ARS in rabbits is characterized by thrombocytopenia and hemostasis dysfunction, which appear to underlie the development of multiorgan dysfunction following TBI to rabbits. Taken together, the rabbit recapitulates the pathogenesis of ARS in humans, and may present an alternative small animal model for medical countermeasure pilot efficacy screening, dose-finding and schedule optimization studies prior to moving into large animal models of TBI-induced ARS.
Topics: Acute Radiation Syndrome; Anemia; Animals; Bone Marrow Failure Disorders; Dogs; Male; Rabbits; Swine; Thrombocytopenia; Whole-Body Irradiation
PubMed: 31526203
DOI: 10.1080/09553002.2019.1668981