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Journal of Clinical Oncology : Official... Jan 2021As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study... (Comparative Study)
Comparative Study
PURPOSE
As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway.
PATIENTS AND METHODS
This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation).
RESULTS
Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76).
CONCLUSION
Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.
Topics: Aged; Aged, 80 and over; COVID-19; Cohort Studies; Critical Care; Elective Surgical Procedures; Epidemics; Female; Humans; International Cooperation; Logistic Models; Male; Middle Aged; Neoplasms; Outcome Assessment, Health Care; Postoperative Complications; SARS-CoV-2
PubMed: 33021869
DOI: 10.1200/JCO.20.01933 -
Journal of Clinical Research in... Apr 2023Homozygous or compound heterozygous mutations in insulin receptor gene (INSR) lead to marked insulin resistance and hyperglycaemia in Donohue syndrome and...
Homozygous or compound heterozygous mutations in insulin receptor gene (INSR) lead to marked insulin resistance and hyperglycaemia in Donohue syndrome and Rabson-Mendenhall syndrome, conditions which are associated with significant morbidity early in life. On the other hand, heterozygous INSR gene mutations result in milder phenotype known as type A insulin resistance syndrome. While presentation in adults with this condition is well reported, phenotypes in infant are less well-characterized. We herein report an infant presenting with hyperinsulinemic hypoglycaemia who did not respond to diazoxide therapy. She was subsequently found to carry heterozygous INSR gene mutation. Our patient was a female infant born at 29 weeks of gestation who developed recurrent hypoglycaemia in early infancy. Workup showed hyperinsulinism and she was started on first-line therapy with diazoxide and high-calorie feeds. However, continuous blood glucose monitoring showed post-prandial hyperglycaemia followed by rapid fall to hypogylcaemia. Whole exome sequencing was performed to investigate for diazoxide-unresponsive hyperinsulinism, which revealed a likely pathogenic mutation in the INSR gene c.1246C>T p. (R416X). This nonsense mutation was inherited from the father. With the molecular diagnosis, diazoxide was stopped and she followed a diet with low glycaemic-index food. Subsequent monitoring showed stable glucose profile. Our case highlights the importance to consider type A insulin resistance syndrome when no mutation could be identified in the ABCC8/KCNJ11 genes in diazoxide-unresponsive hyperinsulinism. With autosomal dominant inheritance, cascade screening should be performed in family members to identify those harbouring the mutation as they are at risk of early onset diabetes.
PubMed: 37074094
DOI: 10.4274/jcrpe.galenos.2023.2022-12-10 -
Pediatric Research Jan 2023We hypothesised that the clinical characteristics of hospitalised children and young people (CYP) with SARS-CoV-2 in the UK second wave (W2) would differ from the... (Observational Study)
Observational Study
BACKGROUND
We hypothesised that the clinical characteristics of hospitalised children and young people (CYP) with SARS-CoV-2 in the UK second wave (W2) would differ from the first wave (W1) due to the alpha variant (B.1.1.7), school reopening and relaxation of shielding.
METHODS
Prospective multicentre observational cohort study of patients <19 years hospitalised in the UK with SARS-CoV-2 between 17/01/20 and 31/01/21. Clinical characteristics were compared between W1 and W2 (W1 = 17/01/20-31/07/20,W2 = 01/08/20-31/01/21).
RESULTS
2044 CYP < 19 years from 187 hospitals. 427/2044 (20.6%) with asymptomatic/incidental SARS-CoV-2 were excluded from main analysis. 16.0% (248/1548) of symptomatic CYP were admitted to critical care and 0.8% (12/1504) died. 5.6% (91/1617) of symptomatic CYP had Multisystem Inflammatory Syndrome in Children (MIS-C). After excluding CYP with MIS-C, patients in W2 had lower Paediatric Early Warning Scores (PEWS, composite vital sign score), lower antibiotic use and less respiratory and cardiovascular support than W1. The proportion of CYP admitted to critical care was unchanged. 58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year), had lower PEWS, shorter length of stay and less respiratory support.
CONCLUSIONS
We found no evidence of increased disease severity in W2 vs W1. A large proportion of hospitalised CYP had no comorbidity.
IMPACT
No evidence of increased severity of COVID-19 admissions amongst children and young people (CYP) in the second vs first wave in the UK, despite changes in variant, relaxation of shielding and return to face-to-face schooling. CYP with no comorbidities made up a significant proportion of those admitted. However, they had shorter length of stays and lower treatment requirements than CYP with comorbidities once those with MIS-C were excluded. At least 20% of CYP admitted in this cohort had asymptomatic/incidental SARS-CoV-2 infection. This paper was presented to SAGE to inform CYP vaccination policy in the UK.
Topics: Humans; Child; Adolescent; SARS-CoV-2; COVID-19; Pandemics; Prospective Studies; Coronavirus Infections; United Kingdom
PubMed: 35449394
DOI: 10.1038/s41390-022-02052-5 -
American Journal of Medical Genetics.... Jan 2021Genetic diseases are a major cause of neonatal morbidity and mortality. The clinical differential diagnosis in severely ill neonates, especially in premature infants, is...
Genetic diseases are a major cause of neonatal morbidity and mortality. The clinical differential diagnosis in severely ill neonates, especially in premature infants, is challenging. Next generation sequencing (NGS) diagnostics is a valuable tool, but the turnaround time is often too long to provide a diagnosis in the time needed for clinical guidance in newborn intensive care units (NICU). To minimize turnaround time, we developed an ultra-rapid whole genome sequencing pipeline and tested it in clinical practice. Our pilot case, was a preterm infant presenting with several crises of dehydration, hypoglycaemia and hyponatremia together with nephrocalcinosis and hypertrophic cardiomyopathy. Whole genome sequencing was performed using a paired-end 2x75bp protocol. Sequencing data were exported after 50 sequencing cycles for a first analysis. After run completion, the rapid-sequencing protocol, a second analysis of the 2 x 75 paired-end run was performed. Both analyses comprised read-mapping and SNP-/indel calling on an on-site Edico Genome DRAGEN server, followed by functional annotation and pathogenicity prediction using in-house scripts. After the first analysis within 17 h, the emergency ultra-rapid protocol identified two novel compound heterozygous variants in the insulin receptor gene (INSR), pathogenic variants in which cause Donohue Syndrome. The genetic diagnosis could be confirmed by detection of hyperinsulinism and patient care adjusted. Nonetheless, we decided to pursue RNA studies, proving the functional effect of the novel splice variant and reduced expression levels of INSR in patients skin fibroblasts.
Topics: Antigens, CD; Dehydration; Female; Genetic Diseases, Inborn; High-Throughput Nucleotide Sequencing; Humans; Hypoglycemia; Infant; Infant Mortality; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Male; Molecular Sequence Annotation; Polymorphism, Single Nucleotide; Protein Isoforms; Receptor, Insulin; Whole Genome Sequencing
PubMed: 33048476
DOI: 10.1002/ajmg.a.61917 -
Journal of Pediatric Endocrinology &... Nov 2022Rabson Mendenhall syndrome (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate...
OBJECTIVES
Rabson Mendenhall syndrome (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate point on spectrum of insulin resistance with Donohue syndrome flanking the severe and Type A insulin resistance at the mild end. We are reporting a 3.5-month-old boy with RMS along with its management challenges in a resource limited country.
CASE PRESENTATION
An infant presented at 3.5-month of an age with failure to thrive and fluctuating blood glucose level (hyperglycaemia and hypoglycaemia) along with clinical features of insulin resistance. He was found to have raised HbA1C, high insulin and C peptide level and a homozygous mutation in gene c.1049C>T, (p.Ser350 Leu) confirming the diagnosis of RMS. He was managed with long-acting insulin (Detemir) along with frequent feeding.
CONCLUSIONS
RMS in resource limited countries could be managed with frequent feeding along with insulin. Early diagnosis and management can improve long term outcome.
Topics: Infant; Male; Humans; Donohue Syndrome; Insulin Resistance; Receptor, Insulin; Insulin; Mutation
PubMed: 36106528
DOI: 10.1515/jpem-2022-0214 -
Journal of Clinical Research in... Aug 2023Mutations in the gene result in rare inherited syndromes causing insulin resistance, such as leprechaunism (Donohue syndrome), Rabson-Mendenhall syndrome and insulin...
Mutations in the gene result in rare inherited syndromes causing insulin resistance, such as leprechaunism (Donohue syndrome), Rabson-Mendenhall syndrome and insulin resistance type A. Leprechaunism is an autosomal recessive disorder associated with extreme insulin resistance that leads to hyperinsulinemia, impaired glucose homeostasis, fasting hypoglycemia and postprandial hyperglycemia. Impaired insulin action causes prenatal and postnatal growth retardation. Lipoatrophy, dysmorphic facies, hypertrichosis, macrogenitosomia and hypertrophy of internal organs are also present. A male infant with congenital insulin resistance was born at term after a normal pregnancy with a weight of 1905 g (<3 c), a length of 48 cm (<3 c), and an Apgar score of 10. Intrauterine growth retardation, transient hypoglycemia, pneumonia, urinary tract infection and heart defects [patent foramen ovale (PFO); patent ductus arteriosus (PDA)] were diagnosed after birth. At 5 weeks of age, he was admitted to the regional hospital with severe fever, diarrhea and dehydration. Hyperglycemia was observed (672 mg/dL), and insulin was administered. He was referred to a hospital at 7 weeks of age for suspected neonatal diabetes and hypertrophic cardiomyopathy. The physical examination revealed a loud systolic heart murmur, tachycardia, tachypnea, dysmorphic facies, hypertrichosis, acanthosis nigricans, hypotonia, swollen nipples and enlarged testicles. Glycemic fluctuations (50-250 mg/dL) were observed. The serum insulin concentration was high (maximum 1200 IU/mL) at normoglycemia. Ultrasound of the heart confirmed progressive hypertrophic cardiomyopathy. Leprechaunism was confirmed by genetic analysis of , in which a novel c.320C>G; p. Thr107Arg homozygous missense mutation was found in exon 2.
Topics: Female; Humans; Infant; Infant, Newborn; Male; Antigens, CD; Cardiomyopathy, Hypertrophic; Diabetes Mellitus; Donohue Syndrome; Facies; Hyperglycemia; Hypertrichosis; Hypoglycemia; Insulin; Insulin Resistance; Mutation; Receptor, Insulin
PubMed: 34965699
DOI: 10.4274/jcrpe.galenos.2021.2021.0256 -
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 -
Journal of Addiction MedicineState Medicaid programs are the largest single provider of healthcare for pregnant persons with opioid use disorder (OUD). Our objective was to provide comparable,...
OBJECTIVES
State Medicaid programs are the largest single provider of healthcare for pregnant persons with opioid use disorder (OUD). Our objective was to provide comparable, multistate measures estimating the burden of OUD in pregnancy, medication for OUD (MOUD) in pregnancy, and related neonatal and child outcomes.
METHODS
Drawing on the Medicaid Outcomes Distributed Research Network (MODRN), we accessed administrative healthcare data for 1.6 million pregnancies and 1.3 million live births in 9 state Medicaid populations from 2014 to 2017. We analyzed within- and between-state prevalences and time trends in the following outcomes: diagnosis of OUD in pregnancy, initiation, and continuity of MOUD in pregnancy, Neonatal Opioid Withdrawal Syndrome (NOWS), and well-child visit utilization among children with NOWS.
RESULTS
OUD diagnosis increased from 49.6 per 1000 to 54.1 per 1000 pregnancies, and the percentage of those with any MOUD in pregnancy increased from 53.4% to 57.9%, during our study time period. State-specific percentages of 180-day continuity of MOUD ranged from 41.2% to 84.5%. The rate of neonates diagnosed with NOWS increased from 32.7 to 37.0 per 1000 live births. State-specific percentages of children diagnosed with NOWS who had the recommended well-child visits in the first 15 months ranged from 39.3% to 62.5%.
CONCLUSIONS
Medicaid data, which allow for longitudinal surveillance of care across different settings, can be used to monitor OUD and related pregnancy and child health outcomes. Findings highlight the need for public health efforts to improve care for pregnant persons and children affected by OUD.
Topics: Analgesics, Opioid; Delivery of Health Care; Female; Humans; Infant, Newborn; Medicaid; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Pregnant Women; United States
PubMed: 33560699
DOI: 10.1097/ADM.0000000000000780 -
Primary Care Diabetes Feb 2021To report on Rabson-Mendenhall Syndrome (RMS) diagnosed in Kuwait.
AIM
To report on Rabson-Mendenhall Syndrome (RMS) diagnosed in Kuwait.
METHODS
A toddler (18 months old) was referred with high plasma insulin and dysmorphic features suggestive of RMS including coarse facial features with globular nose, full lips and furrowed tongue. His skin was hyperkeratotic with hypertrichosis. His sister (aged 13.5 years) was diagnosed with diabetes at 9 years of age and treated with metformin and insulin. She presented with similar dysmorphic features, extensive acanthosis nigricans, dental abnormalities and bilateral nephrocalcinosis. The children were born to non-consanguineous parents. Blood samples were sent for genetic testing in a reference laboratory.
RESULTS
Both children were found to be homozygous for the p.Arg141Trp missense variant (p.Arg114Trp if numbered according to pro-receptor sequence) in the alpha subunit of the insulin receptor.
CONCLUSIONS
These cases demonstrate the importance of raising awareness among healthcare professionals to ensure rapid referral of patients with characteristic physical features of RMS and severe insulin resistance for genetic testing. Unfortunately, treatment of RMS patients remains a challenge with poor prognosis and short life expectancy usually caused by diabetes-related complications. Genetic testing confirms the diagnosis and allows informed genetic counseling of parents considering future pregnancies.
Topics: Acanthosis Nigricans; Donohue Syndrome; Female; Follow-Up Studies; Humans; Infant; Insulin Resistance; Kuwait; Male; Siblings
PubMed: 32843252
DOI: 10.1016/j.pcd.2020.07.012 -
Pediatric Diabetes Mar 2021
Topics: Donohue Syndrome; Humans; Legendary Creatures; Terminology as Topic
PubMed: 32981189
DOI: 10.1111/pedi.13127