Response to the US FDA LeadCare Testing Systems Recall and CDC Health Alert.

On May 17, 2017, the Food and Drug Administration issued a safety recall for the Magellan Diagnostics' LeadCare Testing Systems due to the potential for inaccurately low blood lead test results when used with venous blood samples. Concurrently, the Centers for Disease Control and Prevention (CDC) issued a health alert with retesting recommendations for specific high-risk populations. The purpose of the CDC retesting recommendations was to help identify high-risk individuals so that those potentially impacted by falsely low test results could be retested and receive appropriate follow-up care. The CDC's Lead Poisoning Prevention Program sought to understand how the recall and recommendations impacted state and local public health agencies. Childhood lead poisoning prevention programs (CLPPPs) in state and local public health agencies collect blood lead test results for children and had a lead role in identifying children for retesting. Case studies are presented that highlight the experiences of 4 state CLPPPs in responding to the recall and recommendations. Collectively, the case studies point to several lessons learned, including the importance of (1) having a well-functioning surveillance system in place prior to a serious incident; (2) having a clear understanding of the roles partners play in the continuum of care for children potentially exposed to lead; and (3) ensuring effective communications with all staff, both internal and external, to public health agencies that have a role in responding to a serious incident. The ability to respond to public health emergencies or other serious incidents takes the combined effort of federal, state, and local public health agencies as well as others in the health care delivery system. The CDC will continue to support state and local lead poisoning prevention programs so that they have the information and tools they need to address and prevent the health effects of lead exposures in communities.

CBCT evaluation of buccal bone regeneration in postmenopausal women with and without osteopenia or osteoporosis undergoing dental implant therapy.

STATEMENT OF PROBLEM: Because alveolar bone augmentation in women with osteoporosis/osteopenia has an uncertain prognosis, objective and reliable methods should be used to study standard surgical approaches. PURPOSE: The purpose of this clinical study was to evaluate bone regeneration 9 months after bone augmentation and implant placement in postmenopausal women with different levels of systemic bone health by using cone beam computed tomography (CBCT) and to test proof of concept for this measurement approach. MATERIAL AND METHODS: A subset of 14 participants was analyzed in a best practice study of postmenopausal women receiving dental implants and simultaneous horizontal ridge augmentation. Women were categorized as osteopenic/osteoporotic or normal based on the results of preoperative dual-energy x-ray absorptiometry. All implant study sites received a particulate graft and/or buccal plate expansion. The study sites were evaluated with CBCT preoperatively, immediately postoperatively, and 9 months postoperatively. Nonparametric statistics were used for all analyses. The related samples Wilcoxon signed rank test was used to assess the differences in bone width between time points (α=.05 for all tests). RESULTS: After 9 months, 13 out of 14 participants showed increased bone width compared to the preoperative baseline measurements. The increase was statistically significant for the participants with osteoporosis/osteopenia (P=.007), but not for those with normal bone health (P=.066). The CBCT scans showed that mineralized tissue buccal to the implant surface had the radiographic appearance of mature bone. CONCLUSIONS: CBCT showed evidence of bone regeneration, with an increase in alveolar ridge width in postmenopausal osteopenic/osteoporotic women subsequent to surgical reconstruction.

The relationship between implant stability and bone health markers in post-menopausal women with bisphosphonate exposure.

OBJECTIVES: The authors assessed the relationship between implant stability and bone turnover markers in patients with and without a history of bisphosphonate (BP) exposure for treatment of osteopenia/osteoporosis. MATERIALS AND METHODS: One dental implant site was evaluated in 58 post-menopausal women with a spectrum of bone health in a "best practice" prospective cohort study. Each site had a previous or simultaneous bone augmentation procedure. BP exposure at enrollment was categorized as "never" or "past/current" exposure. Implant stability was assessed by resonance frequency analysis (RFA ISQ) at surgery and 8 weeks post-implant. Bone turnover markers, C-telopeptide collagen crosslinks (sCTX) and procollagen -1 N-terminal telopeptide (P1NP), were measured pre-treatment, 1, and 8 weeks following implant surgery. RESULTS: Mean age was 62.4 ± 6.8 years; 66 % were osteopenic/osteoporotic. Average RFA ISQ at placement for all participants was 63.5 ± 11.3, at 8 weeks post-surgery 74.2 ± 9.4 (p < 0.01). Among "past/current" BP users, there was a significant negative correlation between RFA ISQ values at 8 weeks post-implant placement and sCTX and P1NP values at 1 week (ρ = -.65 and ρ = -.55, respectively; p < 0.01) and 8 weeks (ρ = -.64 and ρ = -.52, respectively; p < 0.05). CONCLUSION: RFA ISQ values increased between implant placement and 8 weeks post-surgery demonstrating successful osseointegration. Lower bone turnover was associated with better implant stability among patients with a history of BP exposure. CLINICAL RELEVANCE: Further investigation of the relationship between BP exposure and implant stability is warranted in a larger population, as results may strongly impact on clinical practice decisions.

Evaluation of self-collected nasal, urine, and saliva samples for molecular detection of SARS-CoV-2 using an EUA approved RT-PCR assay and a laboratory developed LAMP SARS-CoV-2 test.

As the SARS-CoV-2 virus spread throughout the world, millions of positive cases of COVID-19 were registered and, even though there are millions of people already vaccinated against SARS-CoV-2, a large part of the global population remains vulnerable to contracting the virus. Massive nasopharyngeal sample collection in Puerto Rico at the beginning of the pandemic was limited by the scarcity of trained personnel and testing sites. To increase SARS-CoV-2 molecular testing availability, we evaluated the diagnostic accuracy of self-collected nasal, saliva, and urine samples using the TaqPath reverse transcription polymerase chain reaction (RT-PCR) COVID-19 kit to detect SARS-CoV-2. We also created a colorimetric loop-mediated isothermal amplification (LAMP) laboratory developed test (LDT) to detect SARS-CoV-2, as another strategy to increase the availability of molecular testing in community-based laboratories. Automated RNA extraction was performed in the KingFisher Flex instrument, followed by PCR quantification of SARS-CoV-2 on the 7500 Fast Dx RT-PCR using the TaqPath RT-PCR COVID-19 molecular test. Data was interpreted by the COVID-19 Interpretive Software from Applied Biosystems and statistically analyzed with Cohen's kappa coefficient (k). Cohen's kappa coefficient (k) for paired nasal and saliva samples showed moderate agreement (0.52). Saliva samples exhibited a higher viral load. We also observed 90% concordance between LifeGene-Biomarks' SARS-CoV-2 Rapid Colorimetric LAMP LDT and the TaqPath RT-PCR COVID-19 test. Our results suggest that self-collected saliva is superior to nasal and urine samples for COVID-19 testing. The results also suggest that the colorimetric LAMP LDT is a rapid alternative to RT-PCR tests for the detection of SARS-CoV-2. This test can be easily implemented in clinics, hospitals, the workplace, and at home; optimizing the surveillance and collection process, which helps mitigate global public health and socioeconomic upheaval caused by airborne pandemics.

Implant-guided vertical bone growth in the mini-pig.

OBJECTIVE: To attain and describe guided vertical bone regeneration around titanium (Ti) and titanium zirconium (Ti-Zr) dental implants utilizing non-glycosylated recombinant human bone morphogenetic protein-2 (ng/rhBMP-2), biomaterial scaffolds and a scaffold retainer. MATERIALS AND METHODS: Thirty-two modified Straumann TE implants were partially embedded in the mandibles of eight adult mini-pigs. Pre-shaped resorbable scaffolds were placed around the implant and shielded and stabilized with a newly developed Ti custom scaffold retainer (umbrella) or wide-neck (WN) healing caps to stabilize the scaffold. Ng/rhBMP-2 (50 µg) was applied to the supracrestal portion of the implant or incorporated within the scaffold. At 9 weeks, soft tissue healing was assessed. Vertical bone regeneration outcomes including bone height, bone-to-implant contact (BIC) and bone volume were assessed by micro-computed tomography and histology. RESULTS: Soft tissue healing at the test sites (+ng/rhBMP-2/+scaffold) appeared to be substantially better than the control sites (-ng/rhBMP-2/-scaffold). Bone height, BIC percentage and bone volume were all similar regardless of whether WN healing caps or umbrella scaffold stabilization was used for all biomaterial scaffolds tested. WN healing cap test sites showed greater new bone height and BIC as compared with aggregate data from the control sites (P=0.05). Comparison of aggregate data from the umbrella test sites showed greater BIC and new bone volume as compared with aggregate data from the control sites(P=0.05). CONCLUSION: Vertical bone regeneration was successfully attained utilizing ng/rhBMP-2, biomaterial scaffolds and a scaffold retainer.

Precision health diagnostic and surveillance network uses S gene target failure (SGTF) combined with sequencing technologies to track emerging SARS-CoV-2 variants.

INTRODUCTION: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic revealed a worldwide lack of effective molecular surveillance networks at local, state, and national levels, which are essential to identify, monitor, and limit viral community spread. SARS-CoV-2 variants of concern (VOCs) such as Alpha and Omicron, which show increased transmissibility and immune evasion, rapidly became dominant VOCs worldwide. Our objective was to develop an evidenced-based genomic surveillance algorithm, combining reverse transcription polymerase chain reaction (RT-PCR) and sequencing technologies to quickly identify highly contagious VOCs, before cases accumulate exponentially. METHODS: Deidentified data were obtained from 508,969 patients tested for coronavirus disease 2019 (COVID-19) with the TaqPath COVID-19 RT-PCR Combo Kit (ThermoFisher) in four CLIA-certified clinical laboratories in Puerto Rico (n = 86,639) and in three CLIA-certified clinical laboratories in the United States (n = 422,330). RESULTS: TaqPath data revealed a frequency of S Gene Target Failure (SGTF) > 47% for the last week of March 2021 in both, Puerto Rico and US laboratories. The monthly frequency of SGTF in Puerto Rico steadily increased exponentially from 4% in November 2020 to 47% in March 2021. The weekly SGTF rate in US samples was high (>8%) from late December to early January and then also increased exponentially through April (48%). The exponential increase in SGFT prevalence in Puerto Rico was concurrent with a sharp increase in VOCs among all SARS-CoV-2 sequences from Puerto Rico uploaded to Global Influenza Surveillance and Response System (GISAID) (n = 461). Alpha variant frequency increased from <1% in the last week of January 2021 to 51.5% of viral sequences from Puerto Rico collected in the last week of March 2021. CONCLUSIONS: According to the proposed evidence-based algorithm, approximately 50% of all SGTF patients should be managed with VOCs self-quarantine and contact tracing protocols, while WGS confirms their lineage in genomic surveillance laboratories. Our results suggest this workflow is useful for tracking VOCs with SGTF.

Seroprevalence of Varicella in Pregnant Women and Newborns in a Region of Colombia.

We estimate the seroprevalence of IgG antibodies to varicella zoster virus (VZV) based on the first serological study in a cohort of pregnant women and newborns from the Aburrá Valley (Antioquia-Colombia) who attended delivery in eight randomly chosen hospitals. An indirect enzyme immunoassay was used to determine anti-VZV IgG antibodies. Generalized linear models were constructed to identify variables that modify seropositivity. In pregnant women, seropositivity was 85.8% (95% CI: 83.4-85.9), seronegativity was 12.6% (95% CI: 10.8-14.6), and concordance with umbilical cord titers was 90.0% (95% CI: 89-91). The seropositivity of pregnant women was lower in those who lived in rural areas (IRR: 0.4, 95% CI: 0.2-0.7), belonged to the high socioeconomic status (IRR: 0.4, 95% CI: 0.2-0.7), and had studied 11 years or more (IRR: 0.6, 95% CI: 0.4-0.8). Among newborns, seropositivity was lower in those who weighed less than 3000 g (IRR: 0.8, 95% CI: 0.6-1.0). The high seropositivity and seronegativity pattern indicates the urgent need to design preconception consultation and vaccination reinforcement for women of childbearing age according to their sociodemographic conditions, to prevent infection and complications in the mother and newborn.

A novel rapamycin analog is highly selective for mTORC1 in vivo.

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.

Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins.

The mechanism by which the drug rapamycin inhibits the mechanistic target of rapamycin (mTOR) is of intense interest because of its likely relevance in cancer biology, aging, and other age-related diseases. While rapamycin acutely and directly inhibits mTORC1, only chronic administration of rapamycin can inhibit mTORC2 in some, but not all, cell lines or tissues. The mechanism leading to cell specificity of mTORC2 inhibition by rapamycin is not understood and is especially important because many of the negative metabolic side effects of rapamycin, reported in mouse studies and human clinical trials, have been attributed recently to mTORC2 inhibition. Here, we identify the expression level of different FK506-binding proteins (FKBPs), primarily FKBP12 and FKBP51, as the key determinants for rapamycin-mediated inhibition of mTORC2. In support, enforced reduction of FKBP12 completely converts a cell line that is sensitive to mTORC2 inhibition to an insensitive cell line, and increased expression can enhance mTORC2 inhibition. Further reduction of FKBP12 in cell lines with already low FKBP12 levels completely blocks mTORC1 inhibition by rapamycin, indicating that relative FKBP12 levels are critical for both mTORC1 and mTORC2 inhibition, but at different levels. In contrast, reduction of FKBP51 renders cells more sensitive to mTORC2 inhibition. Our findings reveal that the expression of FKBP12 and FKBP51 is the rate limiting factor that determines the responsiveness of a cell line or tissue to rapamycin. These findings have implications for treating specific diseases, including neurodegeneration and cancer, as well as targeting aging in general.

Bone quality evaluation: comparison of cone beam computed tomography and subjective surgical assessment.

PURPOSE: To examine the relationship between dental cone beam computed tomography (CBCT) gray scale values and Hounsfield units (HU), and whether the gray values of edentulous sites correlate with the subjective clinical bone quality assessed at surgery. MATERIALS AND METHODS: Two radiographic phantoms containing varying concentrations of either dipotassium hydrogen phosphate or calcium hydroxyapatite (HA) were imaged using multislice CT or CBCT. Reconstructed DICOM data were analyzed to examine the relationship between CBCT gray values and HU. Presurgical CBCT scans from 52 patients who underwent implant placement in the posterior sextants were used. The gray values of the edentulous implant sites were measured and compared with the subjective bone quality assessed at surgery. RESULTS: There was a strong correlation between CBCT gray values and HU. CBCT gray values increased linearly with increasing calcium HA or bone equivalent density material. CBCT gray values measured at edentulous implant sites ranged from -455 to 642, with a trend of decreasing gray values with bone quality type. The median gray values for the four subjective bone types were: 362 (type 1), 214 (type 2), 76 (type 3), and -454 (type 4). CONCLUSIONS: CBCT gray values can be used to infer bone density and may provide a valuable aid to predict bone quality at potential implant sites.