Low-dose Induction of Buprenorphine in Pregnancy: A Case Series.

BACKGROUND: Because of a risk of precipitated withdrawal occurring from buprenorphine induction in people who use fentanyl, low-dose inductions are becoming increasingly common. However, little evidence exists on the use of this method in pregnant people. METHODS: We conducted a case series of all pregnant people treated for opioid use disorder with low-dose buprenorphine induction at the University of Maryland Medical Center between January 1, 2021, and August 22, 2022. Primary outcome was completion of induction regimen. Secondary outcomes were self-report of withdrawal, continuation of buprenorphine until delivery, and return to or continuation of illicit opioid use. RESULTS: Six pregnant people were prescribed a total of 10 buprenorphine inductions. Five of the 6 pregnant people (83.3%) completed at least 1 induction, none of whom experienced precipitated withdrawal. Two of 6 (33.3%) continued buprenorphine until the time of delivery, and 1 of 6 (16.7%) abstained from illicit opioid use. CONCLUSIONS: The low-dose buprenorphine induction regimen described was successful in 5 of 6 pregnant individuals. Further research, particularly regarding continuation rates, is needed.

The value of detailed first-trimester ultrasound in the era of noninvasive prenatal testing.

BACKGROUND: In 2020, the American College of Obstetricians and Gynecologists recommended noninvasive prenatal testing be offered to all patients. However, current societal guidelines in the United States do not universally recommend a detailed first-trimester ultrasound. OBJECTIVE: This study aimed to determine the additional findings identified through first-trimester ultrasound that would have otherwise been missed if noninvasive prenatal testing was used alone as a first-trimester screening method. STUDY DESIGN: This was a retrospective cohort study involving 2158 pregnant patients and 2216 fetuses that were seen at a single medical center between January 1, 2020, and December 31, 2022. All those included underwent both noninvasive prenatal testing and detailed first-trimester ultrasound between 11.0 and 13.6 weeks of gestation. Noninvasive prenatal testing results were categorized as low risk or high risk, and first-trimester ultrasound results were categorized as normal or abnormal. Abnormal first-trimester ultrasounds were further classified as first-trimester screening markers (increased nuchal translucency, absent nasal bone, tricuspid regurgitation, and ductus venosus reverse a-wave) or structural defects (the cranium, neck, heart, thorax, abdominal wall, stomach, kidneys, bladder, spine, and extremities). Descriptive statistics were used to report our findings. RESULTS: Of 2216 fetuses, 65 (3.0%) had a high-risk noninvasive prenatal testing result, whereas 2151 (97.0%) had a low-risk noninvasive prenatal testing result. Of those with a low-risk noninvasive prenatal testing result, 2035 (94.6%) had a normal first-trimester ultrasound, whereas 116 (5.4%) had at least 1 abnormal finding on first-trimester ultrasound. The most common screening marker detected within the low-risk noninvasive prenatal testing group was absent nasal bone (52/2151 [2.4%]), followed by reversed a-wave of the ductus venosus (30/2151 [1.4%]). The most common structural defect in this group was cardiac abnormality (15/2151 [0.7%]). Overall, 181 fetuses were identified as having "abnormal screening" through either a high-risk noninvasive prenatal testing result (n=65) or through a low-risk noninvasive prenatal testing result but abnormal first-trimester ultrasound (n=116). In summary, the incorporation of first-trimester ultrasound screening identified 116 additional fetuses (5.4%) that required further follow-up and surveillance than noninvasive prenatal testing alone would have identified. CONCLUSION: Detailed first-trimester ultrasound identified more fetuses with a potential abnormality than noninvasive prenatal testing alone. Therefore, first-trimester ultrasound remains a valuable screening method that should be used in combination with noninvasive prenatal testing.

Osteogenesis Imperfecta: The Impact of Genotype and Clinical Phenotype on Adiposity and Resting Energy Expenditure.

CONTEXT: Mutations in type I collagen or collagen-related proteins cause osteogenesis imperfecta (OI). Energy expenditure and body composition in OI could reflect reduced mobility or intrinsic defects in osteoblast differentiation increasing adipocyte development. OBJECTIVE: This study compares adiposity and resting energy expenditure (REE) in OI and healthy controls (HC), for OI genotype- and Type-associated differences. METHODS: We studied 90 participants, 30 with OI (11 COL1A1 Gly, 8 COL1A2 Gly, 4 COL1A1 non-Gly, 1 COL1A2 non-Gly, 6 non-COL; 8 Type III, 16 Type IV, 4 Type VI, 1 Type VII, 1 Type XIV) and 60 HC with sociodemographic characteristics/BMI/BMIz similar to the OI group. Participants underwent dual-energy x-ray absorptiometry to determine lean mass and fat mass percentage (FM%) and REE. FM% and REE were compared, adjusting for covariates, to examine the relationship of OI genotypes and phenotypic Types. RESULTS: FM% did not differ significantly in all patients with OI vs HC (OI: 36.6% ± 1.9%; HC: 32.7% ± 1.2%; P = 0.088). FM% was, however, greater than HC for those with non-COL variants (P = 0.016). FM% did not differ from HC among OI Types (P values > 0.05).Overall, covariate-adjusted REE did not differ significantly between OI and HC (OI: 1376.5 ± 44.7 kcal/d; HC: 1377.0 ± 96 kcal/d; P = 0.345). However, those with non-COL variants (P = 0.016) and Type VI OI (P = 0.04) had significantly lower REE than HC. CONCLUSION: Overall, patients with OI did not significantly differ in either extra-marrow adiposity or REE from BMI-similar HC. However, reduced REE among those with non-COL variants may contribute to greater adiposity.

Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia.

ABSTRACT: The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.

Sildenafil improves hippocampal brain injuries and restores neuronal development after neonatal hypoxia-ischemia in male rat pups.

The hippocampus is a fundamental structure of the brain that plays an important role in neurodevelopment and is very sensitive to hypoxia-ischemia (HI). The purpose of this study was to investigate the effects of sildenafil on neonatal hippocampal brain injuries resulting from HI, and on neuronal development in this context. HI was induced in male Long-Evans rat pups at postnatal day 10 (P10) by a left common carotid ligation followed by a 2-h exposure to 8% oxygen. Rat pups were randomized to vehicle or sildenafil given orally twice daily for 7 days starting 12 h after HI. Hematoxylin and eosin staining was performed at P30 to measure the surface of the hippocampus; immunohistochemistry was performed to stain neurons, oligodendrocytes, and glial cells in the hippocampus. Western blots of the hippocampus were performed at P12, P17, and P30 to study the expression of neuronal markers and mTOR pathway. HI caused significant hippocampal atrophy and a significant reduction of the number of mature neurons, and induced reactive astrocytosis and microgliosis in the hippocampus. HI increased apoptosis and caused significant dysregulation of the normal neuronal development program. Treatment with sildenafil preserved the gross morphology of the hippocampus, reverted the number of mature neurons to levels comparable to sham rats, significantly increased both the immature and mature oligodendrocytes, and significantly reduced the number of microglia and astrocytes. Sildenafil also decreased apoptosis and reestablished the normal progression of post-natal neuronal development. The PI3K/Akt/mTOR pathway, whose activity was decreased after HI in the hippocampus, and restored after sildenafil treatment, may be involved. Sildenafil may have both neuroprotective and neurorestorative properties in the neonatal hippocampus following HI.

Characterization of the adiponectin promoter + Cre recombinase insertion in the Tg(Adipoq-cre)1Evdr mouse by targeted locus amplification and droplet digital PCR.

The Tg(Adipoq-cre)1Evdr mouse has become an important tool in adipose tissue biology. However, the exact genomic transgene integration site has not been established. Using Targeted Locus Amplification (TLA) we found the transgene had integrated on mouse chromosome 9 between exons 6 and 7 of Tbx18. We detected transgene-transgene fusion; therefore, we used droplet digital polymerase chain reaction to identify Cre copy number. In two separate experiments, we digested with BAMHI and with HindIII to separate potentially conjoined Cre sequences. We found one copy of intact Cre present in each experiment, indicating transgene-transgene fusion in other parts of the BAC that would not contribute to tissue-specific Cre expression. Cre copy number for Tg(Adipoq-cre)1Evdr mice can be potentially used to identify homozygous mice.

Human pain genetics database: a resource dedicated to human pain genetics research.

The Human Pain Genetics Database (HPGDB) is a comprehensive variant-focused inventory of genetic contributors to human pain. After curation, the HPGDB currently includes 294 studies reporting associations between 434 distinct genetic variants and various pain phenotypes. Variants were then submitted to a comprehensive analysis. First, they were validated in an independent high-powered replication cohort by testing the association of each variant with 10 different pain phenotypes (n = 1320-26,973). One hundred fifty-five variants replicated successfully (false discovery rate 20%) in at least one pain phenotype, and the association P values of the HPGDB variants were significantly lower compared with those of random controls. Among the 155 replicated variants, 21 had been included in the HPGDB because of their association with analgesia-related and 13 with nociception-related phenotypes, confirming analgesia and nociception as pathways of vulnerability for pain phenotypes. Furthermore, many genetic variants were associated with multiple pain phenotypes, and the strength of their association correlated between many pairs of phenotypes. These genetic variants explained a considerable amount of the variance between different pairs of pain phenotypes, indicating a shared genetic basis among pain phenotypes. In addition, we found that HPGDB variants show many pleiotropic associations, indicating that genetic pathophysiological mechanisms are also shared among painful and nonpainful conditions. Finally, we demonstrated that the HPGDB data set is significantly enriched for functional variants that modify gene expression, are deleterious, and colocalize with open chromatin regions. As such, the HPGDB provides a validated data set that represents a valuable resource for researchers in the human pain field.