Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons.

BACKGROUND: Many pregnant persons in the United States are receiving messenger RNA (mRNA) coronavirus disease 2019 (Covid-19) vaccines, but data are limited on their safety in pregnancy. METHODS: From December 14, 2020, to February 28, 2021, we used data from the "v-safe after vaccination health checker" surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) to characterize the initial safety of mRNA Covid-19 vaccines in pregnant persons. RESULTS: A total of 35,691 v-safe participants 16 to 54 years of age identified as pregnant. Injection-site pain was reported more frequently among pregnant persons than among nonpregnant women, whereas headache, myalgia, chills, and fever were reported less frequently. Among 3958 participants enrolled in the v-safe pregnancy registry, 827 had a completed pregnancy, of which 115 (13.9%) resulted in a pregnancy loss and 712 (86.1%) resulted in a live birth (mostly among participants with vaccination in the third trimester). Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported. Although not directly comparable, calculated proportions of adverse pregnancy and neonatal outcomes in persons vaccinated against Covid-19 who had a completed pregnancy were similar to incidences reported in studies involving pregnant women that were conducted before the Covid-19 pandemic. Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases). CONCLUSIONS: Preliminary findings did not show obvious safety signals among pregnant persons who received mRNA Covid-19 vaccines. However, more longitudinal follow-up, including follow-up of large numbers of women vaccinated earlier in pregnancy, is necessary to inform maternal, pregnancy, and infant outcomes.

Gastrointestinal Computed Tomography Findings in Chronic Granulomatous Disease with Subgroup Clinicopathologic Analysis.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency which can lead to gastrointestinal (GI) complications including inflammatory bowel disease. Radiographic findings in this cohort have not been well described. AIMS: To describe the frequency and spectrum of gastrointestinal abnormalities seen on computed tomography (CT) in patients with CGD and determine whether radiography was predictive of endoscopic or histopathologic inflammatory findings. METHODS: A retrospective review was conducted on 141 consecutive CGD patients seen at the National Institutes of Health between 1988 and 2011. All corresponding CTs were reviewed for gastrointestinal abnormalities including wall thickening. Endoscopic and histopathologic findings were reviewed in subjects with documented endoscopy within 30 days of an imaging study. Findings were compared between patients with and without wall thickening on CT to determine whether bowel wall thickening was predictive of endoscopic or histologic inflammatory findings. RESULTS: Two hundred and ninety-two CTs were reviewed. GI wall thickening was present on CT in 61% of patients (n = 86). Among a subgroup of 20 patients who underwent endoscopy at the time of their imaging, there was a statistically significant correlation between radiographic gastrointestinal wall thickening and endoscopic inflammation in the same intestinal segment (p = 0.035). Additionally, there was a significant correlation between radiographic gastrointestinal wall thickening and inflammatory features on histopathology (p = 0.02). CONCLUSIONS: GI abnormalities are commonly observed on CT in CGD patients. Bowel wall thickening correlates with endoscopic and histopathologic evidence of inflammation. These findings may be used to better facilitate directed endoscopic assessment and histopathologic sampling in patients with CGD.

Use of COVID-19 Vaccines After Reports of Adverse Events Among Adult Recipients of Janssen (Johnson & Johnson) and mRNA COVID-19 Vaccines (Pfizer-BioNTech and Moderna): Update from the Advisory Committee on Immunization Practices - United States, July 2021.

In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for Pfizer-BioNTech and Moderna COVID-19 vaccines, and in February 2021, FDA issued an EUA for the Janssen (Johnson & Johnson) COVID-19 vaccine. After each EUA, the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for vaccine use; currently Pfizer-BioNTech is authorized and recommended for persons aged ≥12 years and Moderna and Janssen for persons aged ≥18 years (1-3). Both Pfizer-BioNTech and Moderna vaccines, administered as 2-dose series, are mRNA-based COVID-19 vaccines, whereas the Janssen COVID-19 vaccine, administered as a single dose, is a recombinant replication-incompetent adenovirus-vector vaccine. As of July 22, 2021, 187 million persons in the United States had received at least 1 dose of COVID-19 vaccine (4); close monitoring of safety surveillance has demonstrated that serious adverse events after COVID-19 vaccination are rare (5,6). Three medical conditions have been reported in temporal association with receipt of COVID-19 vaccines. Two of these (thrombosis with thrombocytopenia syndrome [TTS], a rare syndrome characterized by venous or arterial thrombosis and thrombocytopenia, and Guillain-Barré syndrome [GBS], a rare autoimmune neurologic disorder characterized by ascending weakness and paralysis) have been reported after Janssen COVID-19 vaccination. One (myocarditis, cardiac inflammation) has been reported after Pfizer-BioNTech COVID-19 vaccination or Moderna COVID-19 vaccination, particularly after the second dose; these were reviewed together and will hereafter be referred to as mRNA COVID-19 vaccination. ACIP has met three times to review the data associated with these reports of serious adverse events and has comprehensively assessed the benefits and risks associated with receipt of these vaccines. During the most recent meeting in July 2021, ACIP determined that, overall, the benefits of COVID-19 vaccination in preventing COVID-19 morbidity and mortality outweigh the risks for these rare serious adverse events in adults aged ≥18 years; this balance of benefits and risks varied by age and sex. ACIP continues to recommend COVID-19 vaccination in all persons aged ≥12 years. CDC and FDA continue to closely monitor reports of serious adverse events and will present any additional data to ACIP for consideration. Information regarding risks and how they vary by age and sex and type of vaccine should be disseminated to providers, vaccine recipients, and the public.

Association of Receipt of the Ad26.COV2.S COVID-19 Vaccine With Presumptive Guillain-Barré Syndrome, February-July 2021.

Importance: As part of postauthorization safety surveillance, the US Food and Drug Administration (FDA) has identified a potential safety concern for Guillain-Barré syndrome (GBS) following receipt of the Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccine. Objective: To assess reports of GBS received in the Vaccine Adverse Event Reporting System (VAERS) following Ad26.COV2.S vaccination. Design, Setting, and Participants: Reports of presumptive GBS were identified in a US passive reporting system (VAERS) February-July 2021 and characterized, including demographics, clinical characteristics, and relevant medical history. Exposures: Receipt of the Ad26.COV2.S vaccine; the comparator was the background rate of GBS in the general (unvaccinated) population that had been estimated and published based on a standardized case definition. Main Outcomes and Measures: Presumptive GBS; the reporting rate was analyzed, including calculation of the observed to expected ratio based on background rates and vaccine administration data. Because of limited availability of medical records, cases were not assessed according to the Brighton Collaboration criteria for GBS. Results: As of July 24, 2021, 130 reports of presumptive GBS were identified in VAERS following Ad26.COV2.S vaccination (median age, 56 years; IQR, 45-62 years; 111 individuals [86.0%] were < 65 years; 77 men [59.7%]). The median time to onset of GBS following vaccination was 13 days (IQR, 10-18 days), with 105 cases (81.4%) beginning within 21 days and 123 (95.3%) within 42 days. One hundred twenty-one reports (93.1%) were serious, including 1 death. With approximately 13 209 858 doses of vaccine administered to adults in the US, the estimated crude reporting rate was 1 case of GBS per 100 000 doses administered. The overall estimated observed to expected rate ratio was 4.18 (95% CI, 3.47-4.98) for the 42-day window, and in the worst-case scenario analysis for adults 18 years or older, corresponded to an estimated absolute rate increase of 6.36 per 100 000 person-years (based on a rate of approximately 8.36 cases per 100 000 person-years [123 cases per 1 472 162 person-years] compared with a background rate of approximately 2 cases per 100 000 person-years). For both risk windows, the observed to expected rate ratio was elevated in all age groups except individuals aged 18 through 29 years. Conclusions and Relevance: These findings suggest a potential small but statistically significant safety concern for Guillain-Barré syndrome following receipt of the Ad26.COV2.S vaccine. However, the findings are subject to the limitations of passive reporting systems and presumptive case definition, and they must be considered preliminary pending analysis of medical records to establish a definitive diagnosis.

Tumors displaying hybrid schwannoma and neurofibroma features in patients with neurofibromatosis type 2.

Although schwannoma and neurofibroma tumors are generally reported as distinct pathologic diagnoses, sporadic schwannoma/neurofibroma hybrid nerve sheath tumors have been reported in the general population with components of both entities. We report the clinicopathological features of these hybrid nerve sheath tumors in patients with neurofibromatosis type 2 (NF2). A retrospective review of nerve sheath tumor surgical specimens from patients with NF2 enrolled at the National Institutes of Health was performed. Those specimens reported to have schwannoma-like and neurofibromalike features were selected for further characterization by morphology, immunohistochemical panel (CD34, S100, neurofilament triplet protein (immunostain) (NFTP), epithelial membrane antigen (EMA)), and confirmation as hybrid tumors. Of 43 total NF2 patients undergoing resection of nerve sheath tumors, 11 specimens from 11 (26%) patients were found to be benign nerve sheath tumors exhibiting hybrid features of both neurofibroma and schwannoma. Immunohistochemical studies showed the schwannoma component to be S100+, CD 34- while the neurofibroma component was CD34+, variable S100+. Our experience emphasizes the importance of including this distinct tumor subtype, the schwannoma/neurofibroma hybrid tumor, in the differential diagnosis of nerve sheath tumors in NF2 patients and suggests that the relationship between neurofibroma and schwannoma tumors is closer than previously suspected..

Feasibility of Radio-Guided Surgery with 68Gallium-DOTATATE in Patients with Gastro-Entero-Pancreatic Neuroendocrine Tumors.

BACKGROUND: Surgery is the only definitive therapy for gastro-entero-pancreatic neuroendocrine tumors (GEPNETs), and achieving complete tumor resection is an important prognostic factor. Radiopharmaceuticals such as (68)Ga-DOTA peptides have been developed that offer superior accuracy for localization of GEPNETs. The study aim was to determine the feasibility of radio-guided surgery (RGS) using (68)Ga-DOTATATE in patients with primary and recurrent GEPNETs. METHODS: Fourteen patients with GEPNETs were enrolled onto a prospective study to determine the feasibility of RGS with (68)Ga-DOTATATE. Findings from preoperative imaging, intraoperative exploration, RGS, and pathology were analyzed. RESULTS: The median decay corrected target count rate was 172.6 (range 28.15-2341) for tumors, with a tumor-to-background ratio (TBR) of 4.46 (range 1.6-43.56). The median lesion size was 1.55 (range 0.5-15) cm. There was no significant correlation between preoperative imaging maximum standardized uptake value (SUVmax) of the lesions and TBR (Spearman r = - 0.01, p = 0.9), TBR and tumor size (Spearman r = 0.29, p = 0.14), and SUVmax and tumor size (Spearman r = 0.22, p = 0.28). The probe showed correct identification for gastric and small intestine neuroendocrine tumor (NET), including lymph node metastasis in 17 (81.0 %) of 21 cases, with a median TBR of 3.5 (1.6-40.2). For pancreatic NETs and lymph node metastasis, 16 (66.7 %) of 24 were correctly identified by RGS. CONCLUSIONS: Our study shows that RGS with (68)Ga-DOTATATE is feasible and correctly confirms bowel NETs and metastatic mesenteric lymph nodes. Further studies are needed to determine the benefit of RGS with (68)Ga-DOTATATE.

Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia.

Two-year-old purpose-bred beagles (n = 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7- or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P = .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P ≤ .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ~ 10 hours afterward (all P ≤ .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P = .03) noted at the infection site postmortem. Plasma cell­free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P ≤ .03). The low haptoglobin (r = 0.61; P = .003) and high NO consumption levels at 24 hours (r = −0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P = .03) and not associated with survival (P = NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion.

CXCR4/IgG-expressing plasma cells are associated with human gastrointestinal tissue inflammation.

BACKGROUND: We previously reported abnormalities in circulating B cells in patients with chronic granulomatous disease (CGD) and those with HIV infection. Gastrointestinal complications are common to both diseases and likely involve perturbation of immune cells, including plasma cells (PCs). IgA is the most abundant immunoglobulin in the human body, with roles in protection and maintenance of intestinal homeostasis. IgA is produced primarily by PCs residing in mucosal tissues that are also thought to circulate in the blood. OBJECTIVE: We sought to characterize and compare PCs in patients with infectious (HIV) and noninfectious (CGD and Crohn disease) diseases that have been associated with intestinal inflammation. METHODS: Phenotypic and transcriptional analyses were performed on cells isolated from the blood and colon. RESULTS: IgA-secreting CCR10-expressing PCs predominated in the guts of healthy subjects, whereas in patients with HIV, CGD, and Crohn disease, there was a significant increase in the proportion of IgG-secreting PCs. Where intestinal inflammation was present, IgG-secreting PCs expressed reduced levels of CCR10 and increased levels of CXCR4. The intensity of CXCR4 expression correlated with the frequency of IgG-expressing PCs and the frequency of CXCR4(+)/IgG(+) PCs was associated with the severity of intestinal inflammatory disease yet distinct from PCs and plasmablasts circulating in the blood. CONCLUSIONS: These findings suggest that regardless of the underlying disease, the presence of CXCR4(+)/IgG(+) PCs in the gut is a strong yet localized indicator of intestinal inflammation. Furthermore, our findings suggest that CXCR4(+)/IgG(+) PCs might play a role in immune cell homeostasis during inflammatory processes of the gut.

Paravertebral mushroom: identification of a novel species of Phellinus as a human pathogen in chronic granulomatous disease.

We describe a case of paravertebral abscess caused by a Phellinus sp. in a boy with chronic granulomatous disease. Sequence-based identification of this mold, a new agent of disease, suggests a close relation to Phellinus umbrinellus.

Transfusion of older stored blood worsens outcomes in canines depending on the presence and severity of pneumonia.

BACKGROUND: In experimental pneumonia we found that transfused older blood increased mortality and lung injury that was associated with increased in vivo hemolysis and elevated plasma cell-free hemoglobin (CFH), non-transferrin-bound iron (NTBI), and plasma labile iron (PLI) levels. In this study, we additionally analyze identically treated animals that received lower or higher bacterial doses. STUDY DESIGN AND METHODS: Two-year-old purpose-bred beagles (n = 48) challenged intrabronchially with Staphylococcus aureus (0 [n = 8], 1.0 × 10(9) [n = 8], 1.25 × 10(9) [n = 24], and ≥1.5 × 10(9) [n = 8] colony-forming units/kg) were exchange transfused with either 7- or 42-day-old canine universal donor blood (80 mL/kg in four divided doses). RESULTS: The greater increases in CFH with older blood over days after exchange proved relatively independent of bacterial dose. The lesser increases in CFH observed with fresher blood were bacterial dose dependent potentially related to bacterial hemolysins. Without bacterial challenge, levels of CFH, NTBI, and PLI were significantly higher with older versus fresher blood transfusion but there was no significant measurable injury. With higher-dose bacterial challenge, the elevated NTBI and PLI levels declined more rapidly and to a greater extent after transfusion with older versus fresher blood, and older blood was associated with significantly worse shock, lung injury, and mortality. CONCLUSION: The augmented in vivo hemolysis of transfused older red blood cells (RBCs) appears to result in excess plasma CFH and iron release, which requires the presence of established infection to worsen outcome. These data suggest that transfused older RBCs increase the risks from infection in septic subjects.

Healthcare providers' use of a concise summary to prescribe for lactating patients.

BACKGROUND: Most breastfeeding individuals take at least one prescription drug, yet limited data from lactation studies are available to inform the safety of these drugs during breastfeeding. As a result, healthcare providers (HCPs) rely on available information about safety of drugs used during pregnancy or on personal experiences to inform prescribing/counseling decisions for breastfeeding individuals. To improve risk communication regarding drugs used during lactation, the U.S. Food and Drug Administration published the Pregnancy and Lactation Labeling Rule (PLLR) in 2015, which added a narrative summary of available risk information to the lactation section of Prescribing Information (PI). Prior studies on labeling in PLLR format revealed that although HCPs found these details valuable, they regarded the narrative as too long to support decision-making during patient encounters. OBJECTIVE: This qualitative study's objective was to assess the utility of adding a concise summary to the Lactation subsection of PI to complement the narrative and succinctly communicate to busy HCPs a drug's risks when used during lactation. The concise summary consisted of a bolded headline, bulleted descriptions of available study findings and potential adverse reactions, and recommendations for risk mitigation. METHODS: Twenty-five online focus groups were conducted with five segments of HCPs to obtain their feedback on the concise summary and discuss their prescribing/counseling decisions for four fictitious prescription drugs including one vaccine. RESULTS: HCPs utilized the concise summary to make initial prescribing/counseling decisions. Many also used the labeling narrative for a comprehensive benefit-risk assessment. CONCLUSION: The findings indicate a need to continue to improve communication about safety of drugs used during lactation, and that the concise summary may help facilitate this communication. The study also highlights the need to educate HCPs about PI limitations when clinical data are lacking and the need to encourage clinical studies to be conducted to support actionable recommendations about use of prescription drugs during lactation.

A novel nomogram for peritoneal mesothelioma predicts survival.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare disease treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Estimation of personalized survival times can potentially guide treatment and surveillance. METHODS: We analyzed 104 patients who underwent CRS and cisplatin-based HIPEC for MPM. By means of 25 demographic, laboratory, operative, and histopathological variables, we developed a novel nomogram using machine-learned Bayesian belief networks with stepwise training, testing, and cross-validation. RESULTS: The mean peritoneal carcinomatosis index (PCI) was 15, and 66 % of patients had a completeness of cytoreduction (CC) score of 0 or 1. Eighty-seven percent of patients had epithelioid histology. The median follow-up time was 49 (1-195) months. The 3- and 5-year overall survivals (OS) were 58 and 46 %, respectively. The histological subtype, pre-CRS PCI, and preoperative serum CA-125 had the greatest impact on OS and were included in the nomogram. The mean areas under the receiver operating characteristic curve for the 10-fold cross-validation of the 3- and 5-year models were 0.77 and 0.74, respectively. The graphical calculator or nomogram uses color coding to assist the clinician in quickly estimating individualized patient-specific survival before surgery. CONCLUSIONS: Machine-learned Bayesian belief network analysis generated a novel nomogram predicting 3- and 5-year OS in patients treated with CRS and HIPEC for MPM. Pre-CRS estimation of survival times may potentially individualize patient care by influencing the use of systemic therapy and frequency of diagnostic imaging, and might prevent CRS in patients unlikely to achieve favorable outcomes despite surgical intervention.

Clinical, Endoscopic, and Histopathologic Gastrointestinal Disease in an American Cohort With Behçet's Disease.

INTRODUCTION: Behçet's disease (BD) is a chronic systemic vasculitis characterized by oral and genital ulcers, uveitis, and skin lesions. Patients with BD may develop gastrointestinal (GI) disease; however, characterization of GI disease in American cohorts is lacking. In this article, we present clinical, endoscopic, and histopathologic GI findings in an American cohort of patients with BD. METHODS: Patients with established BD were evaluated prospectively at the National Institutes of Health. Demographic and clinical data were collected including BD manifestations and GI symptoms. Endoscopy with histopathologic sampling was performed for both clinical and research indications with written consent. RESULTS: Eighty-three patients were evaluated. The majority were female (83.1%) and white (75.9%). Mean age was 36 ± 14.8 years. GI symptoms were reported in 75% of cohort with nearly half of reporting abdominal pain (48.2%) and significant numbers reporting acid reflux, diarrhea, and nausea/vomiting. Esophagogastroduodenoscopy was performed in 37 patients; erythema and ulcers were the most common found abnormalities. Colonoscopy was performed in 32 patients with abnormalities including polyps, erythema, and ulcers. Endoscopy was normal in 27% of esophagogastroduodenoscopies and 47% of colonoscopies. Vascular congestion was demonstrated on the majority of random biopsies throughout the GI tract. Inflammation was not highly prevalent on random biopsies except in the stomach. Wireless capsule endoscopy was performed on 18 patients; ulcers and strictures were the most common abnormalities. DISCUSSION: GI symptoms were common in this cohort of American patients with BD. Endoscopic examination was often normal; however, histopathologic examination demonstrated vascular congestion throughout the GI tract.

COVID-19 Vaccine Safety First Year Findings in Adolescents.

BACKGROUND AND OBJECTIVES: The Food and Drug Administration expanded Emergency Use Authorization for use of Pfizer-BioNTech (BNT-162b2) coronavirus disease 2019 vaccine to include people ages 12 years and older on May 10, 2021. We describe adverse events observed during the first full year of the US coronavirus disease 2019 vaccination program for adolescents ages 12 to 17 years. METHODS: We conducted descriptive analyses using data from 2 complementary US vaccine safety monitoring systems: v-safe, a voluntary smartphone-based system that monitors reactions and health impacts, and the Vaccine Adverse Event Reporting System (VAERS), the national spontaneous reporting system. We reviewed reports and calculated adverse event reporting rates using vaccine administration data. RESULTS: Among 172 032 adolescents ages 12 to 17 years enrolled in v-safe, most reported reactions following BNT-162b2 were mild to moderate, most frequently reported on the day after vaccination, and more common after dose 2. VAERS received 20 240 adverse event reports; 91.5% were nonserious. Among adverse events of interest, we verified 40 cases of multisystem inflammation syndrome in children (1.2 cases per million vaccinations), 34 (85%) of which had evidence of prior severe acute respiratory syndrome coronavirus 2 infection; and 570 cases of myocarditis (17.7 cases per million vaccinations), most of whom (77%) reported symptom resolution at the time of report. CONCLUSIONS: During the first year BNT-162b2 was administered to adolescents ages 12 to 17 years, most reported adverse events were mild and appeared self-limited. Rates of myocarditis were lower than earlier reports. No new serious safety concerns were identified.

Post-authorization surveillance of adverse events following COVID-19 vaccines in pregnant persons in the vaccine adverse event reporting system (VAERS), December 2020 - October 2021.

BACKGROUND: Pregnant persons are at increased risk of severe illness from COVID-19 infection, including intensive care unit admission, mechanical ventilation, and death compared with non-pregnant persons of reproductive age. Limited data are available on the safety of COVID-19 vaccines administered during and around the time of pregnancy. OBJECTIVE: To evaluate and summarize reports to the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system, in pregnant persons who received a COVID-19 vaccine to assess for potential vaccine safety problems. METHODS: We searched VAERS for US reports of adverse events (AEs) in pregnant persons who received a COVID-19 vaccine from 12/14/2020-10/31/2021. Clinicians reviewed reports and available medical records. Crude reporting rates for selected AEs were calculated, and disproportional reporting was assessed using data mining methods. RESULTS: VAERS received 3,462 reports of AEs in pregnant persons who received a COVID-19 vaccine; 1,831 (52.9%) after BNT162b2, 1,350 (38.9%) after mRNA-1273, and 275 (7.9%) after Ad26.COV2.S. Eight maternal deaths and 12 neonatal deaths were reported. Six-hundred twenty-one (17.9%) reports were serious. Pregnancy-specific outcomes included: 878 spontaneous abortions (<20 weeks), 101 episodes of vaginal bleeding, 76 preterm deliveries (<37 weeks), 62 stillbirths (≥20 weeks), and 33 outcomes with birth defects. Crude reporting rates for preterm deliveries and stillbirths, as well as maternal and neonatal mortality rates were below background rates from published sources. No disproportional reporting for any AE was observed. CONCLUSIONS: Review of reports to VAERS following COVID-19 vaccines in pregnant persons did not identify any concerning patterns of maternal or infant-fetal outcomes.

Reports of Injection Site Necrosis After 23-Valent Pneumococcal Vaccine Use.

This case series uses postmarketing data to evaluate the incidence of injection site necrosis after 23-valent pneumococcal vaccine use in the global market.

Neutral evolution of drug resistant colorectal cancer cell populations is independent of their KRAS status.

Emergence of tumor resistance to an anti-cancer therapy directed against a putative target raises several questions including: (1) do mutations in the target/pathway confer resistance? (2) Are these mutations pre-existing? (3) What is the relative fitness of cells with/without the mutation? We addressed these questions in patients with metastatic colorectal cancer (mCRC). We conducted an exhaustive review of published data to establish a median doubling time for CRCs and stained a cohort of CRCs to document mitotic indices. We analyzed published data and our own data to calculate rates of growth (g) and regression (d, decay) of tumors in patients with CRC correlating these results with the detection of circulating MT-KRAS DNA. Additionally we estimated mathematically the caloric burden of such tumors using data on mitotic and apoptotic indices. We conclude outgrowth of cells harboring intrinsic or acquired MT-KRAS cannot explain resistance to anti-EGFR (epidermal growth factor receptor) antibodies. Rates of tumor growth with panitumumab are unaffected by presence/absence of MT-KRAS. While MT-KRAS cells may be resistant to anti-EGFR antibodies, WT-KRAS cells also rapidly bypass this blockade suggesting inherent resistance mechanisms are responsible and a neutral evolution model is most appropriate. Using the above clinical data on tumor doubling times and mitotic and apoptotic indices we estimated the caloric intake required to support tumor growth and suggest it may explain in part cancer-associated cachexia.

SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma.

BACKGROUND: A staging/prognostic system has long been desired to better categorize pheochromocytoma/paraganglioma which can be very aggressive in the setting of SDHB mutations. METHODS: A retrospective analysis was conducted of clinical characteristics and outcomes including results of genetic testing, tumor recurrence/metastasis, Ki67/MIB1% staining, and tumor mitotic index in patients with pheochromocytoma/paraganglioma. RESULTS: Patients with SDHB mutation presented at younger age (33.0 years old vs 49.6 years old, P < .001), had increased local recurrence and distant metastases (47.6% vs 9.1%, P < .001, and 56.3% vs 9.1%, P < .001, respectively), and lesser median disease-free interval (89.8 months, 95% confidence interval 36.0-96.4 vs not reached, P < .001). SDHB mutation, greatest tumor diameter, and open operative resection were associated with a greater rate of local recurrence and distant metastases (P < .006 each). SDHB mutation and tumor diameter were independent risk factors for local recurrence (P ≤ .04 each) and metastases. Ki67% and mitotic index were not associated with SDHB mutation (P ≥ .09 each), local recurrence (P = .48, P = .066, respectively), metastases (P ≥ .22 each), or disease-free interval (P ≥ .19 each). CONCLUSION: SDHB status and primary tumor size are more predictive of patient outcome than Ki67% or mitotic index and should be part of any clinically relevant, prognostic scoring system.

Using Probabilistic Record Linkage of Structured and Unstructured Data to Identify Duplicate Cases in Spontaneous Adverse Event Reporting Systems.

INTRODUCTION: Duplicate case reports in spontaneous adverse event reporting systems pose a challenge for medical reviewers to efficiently perform individual and aggregate safety analyses. Duplicate cases can bias data mining by generating spurious signals of disproportional reporting of product-adverse event pairs. OBJECTIVE: We have developed a probabilistic record linkage algorithm for identifying duplicate cases in the US Vaccine Adverse Event Reporting System (VAERS) and the US Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: In addition to using structured field data, the algorithm incorporates the non-structured narrative text of adverse event reports by examining clinical and temporal information extracted by the Event-based Text-mining of Health Electronic Records system, a natural language processing tool. The final component of the algorithm is a novel duplicate confidence value that is calculated by a rule-based empirical approach that looks for similarities in a number of criteria between two case reports. RESULTS: For VAERS, the algorithm identified 77% of known duplicate pairs with a precision (or positive predictive value) of 95%. For FAERS, it identified 13% of known duplicate pairs with a precision of 100%. The textual information did not improve the algorithm's automated classification for VAERS or FAERS. The empirical duplicate confidence value increased performance on both VAERS and FAERS, mainly by reducing the occurrence of false-positives. CONCLUSIONS: The algorithm was shown to be effective at identifying pre-linked duplicate VAERS reports. The narrative text was not shown to be a key component in the automated detection evaluation; however, it is essential for supporting the semi-automated approach that is likely to be deployed at the Food and Drug Administration, where medical reviewers will perform some manual review of the most highly ranked reports identified by the algorithm.