Prevalence and correlates of alcohol and drug harms to others: Findings from the 2020 U.S. National Alcohol Survey.

OBJECTIVE: Measure prevalence and overlap of secondhand harms from other people's use of alcohol, cannabis, opioid, or other drugs and examine sociodemographic and other correlates of these secondhand harms. METHODS: This cross-sectional analysis used data from 7,799 respondents (51.6% female; 12.9% Black, 15.6% Hispanic/Latiné; mean age: 47.6) in the 2020 U.S. National Alcohol Survey. Secondhand harms included family/marriage difficulties, traffic accidents, vandalism, physical harm, and financial difficulties. Weighted prevalence estimates provided nationally representative estimates of these harms. Logistic regression assessed associations between individual characteristics and secondhand harms. RESULTS: Lifetime prevalence of secondhand harms from alcohol, cannabis, opioid, or other drugs was 34.2%, 5.5%, 7.6%, and 8.3%, respectively. There was substantial overlap among lifetime harms: almost 30% of those reporting secondhand alcohol harms also reported secondhand drug harms. Significant correlates of secondhand substance harms included female sex (alcohol, other drug); white (alcohol, opioid), American Indian/Alaska Native (opioid), and Black (cannabis) race/ethnicity; and separated/divorced/widowed marital status (opioid). Those reporting family history of alcohol problems had significantly higher odds of reporting secondhand harms across substance types. Individuals who reported frequent cannabis use had higher odds of reporting secondhand alcohol and opioid harms compared to those with no cannabis use, (aOR=1.55; aOR=2.38), but lower odds of reporting secondhand cannabis harms (aOR=0.51). CONCLUSIONS: Although less prevalent than secondhand alcohol harms, 14% of participants reported secondhand harms from someone else's drug use and frequently experienced secondhand harms attributed to multiple substances. Population-focused interventions are needed to reduce the total burden of alcohol and drug use.

Ultrasound-controlled transthoracic true-cut needle biopsy in pulmonary nodular amyloidosis.

The current case report presents a 59-year-old man with imaging studies of the thorax showing nodular lesions in the lungs bilaterally. Based on radiographic and CT images, preliminary diagnoses for possible granulomatosis (tuberculosis) or pulmonary metastatic dissemination of a neoplastic process were made. An ultrasound-controlled transthoracic true-cut needle biopsy of a subpleural lesion was performed. Special staining with Congo red and examination with a polarizing light microscope for detection of amyloid confirmed the diagnosis of 'pulmonary nodular amyloidosis' by visualizing green birefringence.

Dental intervention for the irradiated patient: time to re-evaluate dental treatment algorithms?

Modern radiotherapy delivery systems and treatment strategies are aimed at limiting the irradiation of healthy structures in the head and neck. This seeks to mitigate post-treatment toxicities and complications such as osteoradionecrosis of the jaw. Given the changes to radiotherapy, conventional workflows for the management of patients requiring dentoalveolar surgery may no longer be suitable. It may therefore be appropriate to revisit current treatment algorithms for the management of patients with radiotherapy to the jaws who require dentoalveolar surgery. At present, there are poor data on this. Development of a randomised trial may be warranted to establish the true relative risk for extraction of teeth in the setting of modern radiation therapy delivery systems.

Characterization of on-target adverse events caused by TRK inhibitor therapy.

BACKGROUND: The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. PATIENTS AND METHODS: Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. RESULTS: Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%-62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. CONCLUSIONS: TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

Circulating microRNAs in extracellular vesicles as potential biomarkers for psoriatic arthritis in patients with psoriasis.

BACKGROUND: Psoriatic arthritis (PsA) develops in ~30% of patients with psoriasis. The diagnosis of PsA is challenging, and there are no reliable molecular markers in clinical use. MicroRNAs are short non-coding regulatory RNAs, which can be actively packaged into extracellular vesicles (EVs) and secreted to the circulation. OBJECTIVES: To explore whether plasma-derived EV microRNAs may serve as biomarkers for PsA in patients with psoriasis. METHODS: Plasma samples were obtained from patients with cutaneous-only psoriasis (PsC) and patients with psoriasis and PsA. Plasma EVs were isolated using miRCURY™ Exosome Isolation Kit. RNA sequencing was used to identify differentially expressed EV miRNAs in the discovery phase (PsC, n = 15; PsA, n = 14). In the validation phase (PsC, n = 29; PsA, n = 28), 41 selected miRNAs were analysed in plasma EVs by qPCR. The association of the identified miRNAs with PsA was assessed by logistic regression analysis. RESULTS: RNA sequencing identified 19 plasma EV miRNAs with significantly different levels between PsA and PsC in the discovery cohort. Significantly lower levels of plasma EV let-7b-5p and miR-30e-5p in PsA vs. PsC were confirmed in the validation cohort, and their decreased levels were found to be associated with the presence of PsA. ROC analysis revealed an AUC of 0.68 (95% CI 0.53-0.83) for let-7b-5p and 0.69 (95% CI 0.55-0.84) for miR-30e-5p. CONCLUSIONS: Circulating EV microRNA levels are altered in patients with PsA as compared with PsC. Findings of this exploratory study suggest that circulating EV microRNAs may serve as biomarkers for arthritis in psoriasis patients.

Urinary oxidative stress biomarker levels and reproductive outcomes among couples undergoing fertility treatments.

STUDY QUESTION: Are urinary levels of oxidative stress biomarkers associated with reproductive outcome success following fertility treatments? SUMMARY ANSWER: Levels of oxidative stress in the middle tertile for women are associated with the highest levels of reproductive success while no associations were noted for men. WHAT IS KNOWN ALREADY: Oxidative stress may contribute to adverse fertility outcomes in the general population, but findings from couples undergoing fertility treatments are sparse. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 481 women and 249 of their male partners undergoing fertility treatments from 2007 to 2015, from the Environment and Reproductive Health (EARTH) study in Boston, MA. PARTICIPANTS/MATERIALS, SETTING, METHODS: One urine sample per participant was collected at each cycle and analysed for two oxidative stress markers: 8-isoprostane-PGF2α (8-iso-PGF2α) and 8-isoprostane-PGF2α metabolite (F2-isoP-M). Reproductive outcomes were abstracted from medical records and included the fertilization rate, for IVF (oocytes fertilized/mature oocytes retrieved), and rates of implantation, clinical pregnancy and live birth, for both IVF and IUI. Cluster-weighted generalized estimating equations were used to analyse adjusted associations between exposure tertiles and outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Levels of F2-isoP-M in the middle tertile were associated with the most success among women. Women in the upper tertile of F2-isoP-M had an adjusted mean live birth rate after IVF and IUI of 23% (95% CI: 17, 29) compared to 38% (95% CI: 31, 45) for women in the middle tertile and 27% (95% CI: 21, 34) in the lower tertile. The fertilization rate during IVF was higher for women with 8-iso-PGF2α in the middle tertile (0.77 [95% CI: 0.73, 0.80]) compared to women in the lower (0.69 [95% CI: 0.64, 0.73]) or upper tertiles (0.66 [95% CI: 0.61, 0.71]). No significant associations were found for other measured outcomes with 8-iso-PGF2α, or between any oxidative stress biomarker in men and reproductive outcomes in their partners. LIMITATIONS, REASONS FOR CAUTION: Isoprostanes are short-lived biomarkers and this study may not have captured the most relevant window of susceptibility for oxidative stress on the outcomes of interest. Findings from this study may not be generalizable to couples attempting conception without fertility assistance. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that a non-linear association may exist between oxidative stress and reproductive outcomes in a population undergoing fertility treatment, a finding not previously identified in the literature. Oxidative stress may represent the mechanism through which environmental chemicals are associated with adverse reproductive outcomes. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research Program of the National Institutes of Environmental Health Sciences (NIEHS) (ZIA ES103314) and by NIEHS grants R01ES022955, R01ES009718 and R01ES00002. There are no competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

ALK Mutation Status in EGFR-negative Non-small-cell Lung Cancer Patients in Bulgaria.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement mutation are found to be 3-13%. AIM: To evaluate the prevalence of ALK mutations in EGFR-negative NSCLC patients in Bulgaria. MATERIALS AND METHODS: One hundred and thirty-two patients with EGFR-negative NSCLC were examined for ALK mutation analysis between January and June 2016. Data were obtained from patients' register of four major oncological hospitals in Bulgaria. RESULTS: Data were available for 124 (93.9%) patients, tumor mass was insufficient for analysis in 8 (6.1%) patients. Most of the patients were with adenocarcinoma (82 patients, 62.1%); 11 patients (8.3%) were with squamous histology and 2 patients (1.5%) were with other type of NSCLC. Histology data were missing in 37 patients (28.0%). ALK mutation was confirmed in 5 patients (3.8%), 119 (90.2%) patients had ALK wild type. ALK positive patients were with adenocarcinoma (n=3), squamous cell carcinoma (n=1) and other type (n=1) NSCLC. All ALK mutations were observed in never smokers (n=3) and former smokers (n=2). CONCLUSION: The present study is the first of this kind in Bulgaria - it investigates the prevalence of ALK mutation rate in EGFR-negative NSCLC patients, which was found to be 3.8%. The presence of EGFR, ALK or other driver mutations is a prerequisite for targeted therapy and thus needs to be accurately assessed in NSCLC.

Diagnostic exome sequencing in children: A survey of parental understanding, experience and psychological impact.

Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and psychological impact of CES by conducting a survey study of English-speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to have CES. Most (65%) reported complete satisfaction with the genetic counseling experience, and satisfaction was positively associated with years of genetic counselor (GC) experience. The psychological impact of CES was greatest for parents of children with positive results and for parents with anxiety or depression. The results of this study are important for helping clinicians to prepare families for the possible results and variable psychological impact of CES. The frequency of parental misinterpretation of test results indicates the need for additional clarity in the communication of results. Finally, while the majority of patients were satisfied with their genetic counseling, satisfaction was lower for new GCs, suggesting a need for targeted GC training for genomic testing.

Chronic Obstructive Pulmonary Disease and Hepatitis C.

Chronic obstructive pulmonary disease (COPD) is a preventable, treatable disease with significant extrapulmonary manifestations that could affect negatively its course in some patients. Hepatitis C virus infection (HCV), on the other hand, is associated with a number of extrahepatic manifestations. COPD patients have increased prevalence of HCV and patients with HCV, especially older ones, have increased prevalence and faster progression of COPD. HCV infection exerts long-term effects on lung tissue and is an additional risk factor for the development of COPD. The presence of HCV is associated with an accelerated loss of lung function in COPD patients, especially in current smokers. COPD could represent extrahepatic manifestation associated with HCV infection. The aim of this article was to review the literature on prevalence of HCV in COPD and vice versa, pathogenetic link and the consequences of their mutual existence.

Modern surgical endodontic treatment of altered sensation following extrusion of endodontic filling materials.

AIM: This study presents the use of a modern surgical endodontic technique for the treatment of altered sensation following extrusion of endodontic filling materials. CASE PRESENTATION: A patient presented with an altered sensation following a root canal treatment and extrusion of root filling material at the mandibular canine and lateral incisor. She was treated using a modern surgical technique that included removal of the extruded filling materials followed by root-end management and obturation. The treatment resulted in complete periapical and neurosensory healing. CONCLUSIONS: Modern endodontic surgery may be beneficial for patients with nerve injury due to extruded endodontic filling materials, since it enables a relatively safe removal of the irritating extruded endodontic materials, proper root-end management and preservation of the natural tooth.

Epigenomic and transcriptional control of insulin resistance.

Insulin resistance is one of the defining features of type 2 diabetes and the metabolic syndrome and accompanies many other clinical conditions, ranging from obesity to lipodystrophy to glucocorticoid excess. Extraordinary efforts have gone into defining the mechanisms that underlie insulin resistance, with most attention focused on altered signalling as well as mitochondrial and endoplasmic reticulum stress. Here, nuclear mechanisms of insulin resistance, including transcriptional and epigenomic effects, will be discussed. Three levels of control involving transcription factors, transcriptional cofactors, and chromatin-modifying enzymes will be considered. Well-studied examples of the first include PPAR-γ in adipose tissue and the glucocorticoid receptor and FoxO1 in a variety of insulin-sensitive tissues. These proteins work in concert with cofactors such as PGC-1α and CRTC2, and chromatin-modifying enzymes including DNA methyltransferases and histone acetyltransferases, to regulate key genes that promote insulin-stimulated glucose uptake, gluconeogenesis or other pathways that affect systemic insulin action. Furthermore, genetic variation associated with increased risk of type 2 diabetes is often related to altered transcription factor binding, either by affecting the transcription factor itself, or more commonly by changing the binding affinity of a noncoding regulatory region. Finally, several avenues for therapeutic exploitation in the battle against metabolic disease will be discussed, including small-molecule inhibitors and activators of these factors and their related pathways.

[Use of Cone Beam Computed Tomography in endodontics: rational case selection criteria].

AIM: To present rational case selection criteria for the use of CBCT (Cone Beam Computed Tomography) in endodontics. MATERIALS AND METHODS: This article reviews the literature concerning the benefits of CBCT in endodontics, alongside its radiation risks, and present case selection criteria for referral of endodontic patients to CBCT. RESULTS: Up to date, the expected ultimate benefit of CBCT to the endodontic patient is yet uncertain, and the current literature is mainly restricted to its technical efficacy. In addition, the potential radiation risks of CBCT scan are stochastic in nature and uncertain, and are worrying especially in pediatric patients. CONCLUSIONS: Both the efficacy of CBCT in supporting the endodontic practitioner decision making and in affecting treatment outcomes, and its long term potential radiation risks are yet uncertain. Therefore, a cautious rational decision making is essential when a CBCT scan is considered in endodontics. Risk-benefit considerations are presented.

[U.S. Food and Drug Administration (FDA) strengthens warning that non-aspirin non steroidal anti-inflammatory drugs (NSAIDs) can cause myocardial infarctions or strokes: the dentist's perspective].

This short communication is aimed to update dental practitioners regarding the recently published warning of the U.S. Food and Drug Administration (FDA) regarding the risk for severe cardiovascular complications such as myocardial infarction or stroke following the use of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs).

[Medicolegal aspects of iatrogenic root perforations].

AIM: To retrospectively analyze the medico-legal aspects of iatrogenic root perforations (IRP) that occurred during endodontic treatments. METHODOLOGY: A comprehensive search in a professional liability insurance database was conducted to retrospectively identify cases of IRP following root canal treatments (RCTs). The complaints were categorized as either financial risk bearing or financial nonrisk bearing, and related demographic and endodontic variables were analyzed. RESULTS: One hundred and twenty cases of patients with IRP were identified. Twenty six cases (22%) were elective RCTs, and 94 cases (78%) were endodontic treatments performed due to pathologic processes (p < 0.05). Sixty cases (50%) were identified in mandibular molars, significantly more than other tooth locations (P < 0.05). In 102 cases (85%) the outcome was extraction, and in 18 cases (15%) the outcome was an additional treatment (p < 0.05). For both the cases with outcome of extraction and for the cases with an additional treatment, the complaints were judged as financial risk bearing in 95% of the cases. CONCLUSIONS: latrogenic root perforation is a complication of root canal treatment and may result in tooth extraction and in legal actions against the treating practitioner. Mandibular molars are more prone to medico-legal claims related to root perforations. The patient should be informed of the risks during RCT and should get information on alternative treatments and their risks and prognosis

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Medico-legal aspects of vertical root fractures in root filled teeth.

AIM: To analyse the medico-legal aspects of vertical root fracture (VRF) following root canal treatment (RCT). METHODOLOGY: A comprehensive search in a professional liability insurance database was conducted to retrospectively identify cases of VRF following RCT. The complaints were categorized as either financial risk bearing or financial nonrisk bearing, and related demographic, prosthetic and endodontic variables were analysed. RESULTS: Seventy-seven legal cases of patients with VRFs following RCT were identified. Most of the cases were either in premolars or in mandibular molar teeth (P<0.05). Poor-quality root filling was associated with an extended delay of diagnosis (P<0.05). The presence of a post significantly increased the financial risk assessment (P<0.05). CONCLUSIONS: Poor quality root fillings complicate the diagnosis of VRF, which in turn extends the time for achieving an accurate diagnosis and increasing the medico-legal risk. Premolar and mandibular molar teeth were more prone to medico-legal claims related to VRF following RCT. Post should be placed only when essential for additional core support to avoid medico-legal risk.

Modeling the functional genomics of autism using human neurons.

Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and to model some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After 4 weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASDs) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis, we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. As NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD.

[Immediate implant placement in endodontically infected sites: an alternative treatment for compromised teeth].

In certain clinical conditions when endodontic treatment is either impractical or unlikely to improve the previous results, tooth extraction and replacement with a dental implant becomes a viable alternative. Although the presence of active infection has long been considered a major contraindication to the insertion of implants immediately following tooth extraction, several articles assessing this treatment modality reported excellent and promising results. The aim of this literature review is to evaluate and discuss the clinical outcome of implants placed immediately following extraction in endodontically infected sockets. A Medline and EMBASE search was performed to identify articles published from 1966 to 2010 using the keywords "dental implants", "immediate implant", "extraction socket", "infected teeth", "infected site", "infected socket". No restrictions were placed regarding the study design. Only clinical articles with at least 6 months of follow-up were included. The available relevant literature concerning this topic was limited, and based on relatively low level of evidence study designs with limited follow-up periods. However, the data analysis of the selected articles showed that an immediate implant insertion in endodontically infected sites following tooth extraction and careful debridement of the socket, could be a predictable viable technique. Additional large scaled, well-designed studies are required in order to further assess the clinical applications of this treatment alternative.

[Preserving the natural tooth versus extraction and implant placement: making a rational clinical decision].

Modern dental practice offers a wide variety of treatment alternatives and modalities. With the wider scale of treatment options, new dilemmas emerged. A common dilemma is the decision whether to preserve the natural tooth by endodontic treatment, or to extract the tooth and replace it with a single dental implant. The clinician needs to remember that the basic goal of dental implants is to replace missing teeth, and not present teeth. Prosthodontic, periodontal, and esthetic considerations should be integrated in the treatment planning process. Long-term prognosis, the capabilities offered by the modern endodontic treatment, the alternatives in case of treatment failure, post treatment quality of life and patient's preferences should all be recognized and incorporated in the dentist decision making. An important factor is the communication between the prosthodontist and the endodontist before and during the treatment in order to avoid possible risks or treatment failure. The integration of these factors would assist the clinician to achieve a rational treatment plan for the benefit of the patient.

Magnification in modern endodontic practice.

The use of magnification devices in endodontics is becoming more and more common, with the aim of improving the quality of treatment. The common magnification systems used in modern endodontics are the surgical operation microscope, fiber-optic endoscope, and surgical loupes. The benefits of using magnification devices for conventional endodontic treatment include the increased visualization of the treatment field, enhanced possibilities in locating canals, aid in the removal of separated instruments, diagnosis of root and tooth fractures, perforation repair, and case documentation. In endodontic surgery, the use of magnification improves the ability to locate, clean, and fill the root canal system, thus achieving a predictable outcome. Further evidence-based research might better clarify the advantages and limitations of using magnification in endodontic practice.