Neonatal Fever in the COVID-19 Pandemic: Odds of a Serious Bacterial Infection.

OBJECTIVES: A sepsis workup is recommended in young infants 56 days or younger with fever to rule out a serious bacterial infection (SBI). Given the reduction in non-severe acute respiratory syndrome - coronavirus 2 viral infections observed in multiple studies during the coronavirus diseases 2019 (COVID-19) pandemic, we sought to determine if the reduction in viral infections led to a change in the incidence of SBI in this vulnerable patient population. METHODS: We performed a multicenter, retrospective study of infants 56 days or younger presenting with fever to emergency departments of 6 community hospitals. We compared the incidence of SBIs, viral meningitis, and viral bronchiolitis during March 2020 to February 2021 (pandemic year) with the same calendar months in the 2 preceding years (prepandemic years). RESULTS: From March 2018 to February 2021, 543 febrile infants presented to the emergency departments, 95 during the pandemic year (March 2020 to February 2021) compared with 231 and 217 in the prepandemic years (March 2018 to February 2019 and March 2019 to February 2020, respectively).During the pandemic year, 28.4% of infants (27 of 95) were diagnosed with an SBI compared with 11.7% and 6.9% (P < 0.001) in the prepandemic years (27 of 231 and 15 of 217, respectively). Five patients were diagnosed with bacterial meningitis over the 3-year period, 4 of them during the pandemic year (4 of 95 [4.2%]). Positivity for viral cerebrospinal fluid polymerase chain reaction during the pandemic year was 6.4% (3 of 47) compared with 20.8% (25 of 120) and 20.4% (23 of 113) in prepandemic years (P = 0.070). During the pandemic year, 2.1% (2 of 95) febrile young infants were admitted with a comorbid diagnosis of bronchiolitis compared with 4.3% and 6.0% in the prepandemic years (P = 0.310). CONCLUSIONS: The COVID-19 pandemic led to an increase in the incidence of SBIs in febrile infants 56 days or younger, likely a result of reduction in non-severe acute respiratory syndrome - coronavirus 2 viral infections. Greater vigilance is thus warranted in the evaluation of febrile infants during the COVID-19 pandemic.

New polymorphism of ENPP1 (PC-1) is associated with increased risk of type 2 diabetes among obese individuals.

The K121Q polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is associated with type 2 diabetes and obesity. The possibility of other ENPP1 polymorphisms influencing these phenotypes has received little attention. Our aim was to examine the associations of tagging single nucleotide polymorphisms (SNPs) and haplotypes of the linkage disequilibrium (LD) block containing K121Q polymorphism with type 2 diabetes in a Polish population, controlling for any effect of obesity. We genotyped 426 type 2 diabetic case and 370 control subjects for seven SNPs in ENPP1. In the total group, neither type 2 diabetes nor obesity was significantly associated with any SNP. However, in obese subjects, two SNPs were significantly associated with type 2 diabetes: the Q allele of K121Q (odds ratio 1.6 [95% CI 1.003-2.6]) and T allele of rs997509 (4.7 [1.6-13.9]). In the LD block, four SNPs plus the K121Q polymorphism distinguished six haplotypes, three of which carried the Q allele. Interestingly, the T allele of rs997509 sufficed to distinguish a 121Q-carrying haplotype that was significantly more associated with type 2 diabetes than the other two (4.2 [1.3-13.5]). These other two 121Q-carrying haplotypes were not associated with type 2 diabetes. In conclusion, we found a new SNP, rs997509, in intron 1 that is strongly associated with risk of type 2 diabetes in obese individuals. The molecular mechanisms underlying this association are unknown.

Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5): a sex-specific effect.

Chemokines and their receptors have been implicated in the development of diabetic nephropathy. To determine whether the risk of diabetic nephropathy is influenced by two functional polymorphisms in the regulated upon activation normal T-cell expressed and secreted (RANTES) receptor gene (CCR5), we recruited patients with type 1 diabetes, including 496 case subjects with overt proteinuria or end-stage renal disease and 298 control subjects with normoalbuminuria. Male carriers of the 59029G allele, which is associated with diminished expression of CCR5 on the surface of immunocompetent cells, had significantly higher risk of developing diabetic nephropathy than noncarriers (OR [95% CI] 1.9 [1.2-3.0]). Similarly, male carriers of the 32-bp deletion, which causes truncation of the protein, had significantly higher risk of diabetic nephropathy than noncarriers (2.3 [1.3-4.2]). Combining both polymorphisms, three haplotypes were distinguished: one nonrisk haplotype carrying the 59029A allele and the 32-bp insertion and two risk haplotypes carrying the 59029A allele with the 32-bp deletion and carrying the 59029G allele with the 32-bp insertion. The distribution of these haplotypes differed significantly (P < 0.00001) in men with and without diabetic nephropathy but was not associated with diabetic nephropathy in women. In conclusion, two functional polymorphisms in CCR5 that decrease expression of the RANTES receptor on immunocompetent cells are associated with increased risk of diabetic nephropathy in type 1 diabetes, but only in men.

Methylenetetrahydrofolate reductase gene polymorphism and susceptibility to diabetic nephropathy in type 1 diabetes.

BACKGROUND: The T allele of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with elevated plasma homocysteine levels, and it has been postulated to be a risk factor for the development of diabetic nephropathy. We examined this hypothesis in both a case-control and a follow-up study in individuals with type 1 diabetes. METHODS: In the case-control study, the control group included 310 subjects with normoalbuminuria and diabetes duration of 15 years or greater, and the case group included 88 prevalent cases with end-stage renal disease (ESRD). The follow-up study included 235 subjects with overt proteinuria followed up for 6 years (on average), during which time ESRD developed in 69 subjects. DNA from each individual was genotyped for the C677T MTHFR polymorphism. RESULTS: The frequency of TT homozygotes did not vary significantly among the four groups: 10% in controls, 15% in prevalent cases of ESRD, 13% in cases with new-onset ESRD, and 11% in those who remained proteinuric during follow-up (P = 0.9, 6 df). Similarly, frequency of the T allele varied little among the same groups (range, 33% to 36%; P = 0.9, 3 df) During follow-up, 52 of 323 individuals with diabetic nephropathy died. Total mortality rates were 4.3/100 person-years in TT homozygotes, 2.4/100 person-years in CT heterozygotes, and 3.0/100 person-years in CC homozygotes (P = 0.55, 2 df). CONCLUSION: Using both a large case-control and a follow-up study, we found no evidence that the C677T MTHFR polymorphism has a significant role in the development of diabetic nephropathy in type 1 diabetes.

The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse beta cells.

Insufficient insulin secretion and reduced pancreatic beta cell mass are hallmarks of type 2 diabetes (T2DM). Here, we confirm that a previously identified polymorphism (rs2295490/Q84R) in exon 2 of the pseudokinase-encoding gene tribbles 3 (TRB3) is associated with an increased risk for T2DM in 2 populations of people of mixed European descent. Carriers of the 84R allele had substantially reduced plasma levels of C-peptide, the product of proinsulin processing to insulin, suggesting a role for TRB3 in beta cell function. Overexpression of TRB3 84R in mouse beta cells, human islet cells, and the murine beta cell line MIN6 revealed reduced insulin exocytosis, associated with a marked reduction in docked insulin granules visualized by electron microscopy. Conversely, knockdown of TRB3 in MIN6 cells restored insulin secretion and expression of exocytosis genes. Further analysis in MIN6 cells demonstrated that TRB3 interacted with the transcription factor ATF4 and that this complex acted as a competitive inhibitor of cAMP response element-binding (CREB) transcription factor in the regulation of key exocytosis genes. In addition, the 84R TRB3 variant exhibited greater protein stability than wild-type TRB3 and increased binding affinity to Akt. Mice overexpressing TRB3 84R in beta cells displayed decreased beta cell mass, associated with reduced proliferation and enhanced apoptosis rates. These data link a missense polymorphism in human TRB3 to impaired insulin exocytosis and thus increased risk for T2DM.

Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes.

OBJECTIVE: Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS: We genotyped approximately 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes-associated complications. RESULTS: A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P < 1 x 10(-5). The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 x 10(-7)). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 x 10(-6)). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression of both FRMD3 and CARS in human kidney. CONCLUSIONS: We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.