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IntroductionIn March 2016, the Centers for Disease Control and Prevention released the Guideline for Prescribing Opioids for Chronic Pain, intended for primary care clinicians. One recommendation advised against concurrent prescription of opioids and benzodiazepines. Although existing research suggests a reduction in co-prescribing of these drug classes by clinicians after guideline release, there are limited data assessing its possible effect on patient medical outcomes, such as overdoses.MethodsThis retrospective observational study analyzed opioid and benzodiazepine exposures, alone or in combination, reported to the California Poison Control System from January 2012 to June 2021. Interrupted time series analyses identified the difference in monthly call volume between pre- and post-guideline release. For exposures resulting in serious medical outcomes, additional analyses assessed trends and identified associated variables.ResultsThere was no significant change in concomitant opioid and benzodiazepine exposures reported to California Poison Control System between pre- and post-guideline release. Compared to pre-guideline release, exposures to a single opioid or to a single benzodiazepine significantly decreased by 1.07 (95% CI: -1.62, -0.51) and 1.82 (95% CI: -2.33, -1.31) calls per month, respectively, after the guideline release. For exposure calls associated with serious medical outcomes, there was a significant increase of 0.11 (95% CI: 0.04, 0.18) and 0.2 (95% CI: 0.05, 0.34) calls per month for concomitant opioid and benzodiazepine and single opioid exposures, respectively, following guideline release.DiscussionThe guideline release appeared to have a variable association with exposures to single opioid, single benzodiazepines, and concomitant opioid and benzodiazepine cases reported to California Poison Control System. Although exposures to opioids or benzodiazepines alone significantly decreased after guideline release, there was no significant change in

In response to the rapidly rising number of asylum applications, student-run asylum clinics (SRACs) designed to provide pro bono forensic medical evaluations have emerged at medical schools across the United States. Distinct from traditional student-run clinics in the services they provide and in their operational models, SRACs face a unique set of challenges. This study aims to identify the common challenges in building SRACs and to collect insights to inform a structured approach to collaborative problem-solving. This study gathered data from online surveys and semi-structured phone interviews with representative medical student SRAC leaders. 14 clinics participated in the 2017 online survey, 15 clinics in the 2018 online survey, and eight clinics in the 2018-2019 phone interviews. We identified common challenges in five areas: volunteer recruitment, clinic operations, case demand, institutional support, and leadership. SRACs stand to benefit from ongoing extramural collaborations to overcome shared challenges.

ImportanceUse of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.ObjectiveTo develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies.Evidence reviewThe MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.FindingsThe MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

The development of ectodermal organs, such as teeth, requires epithelial–mesenchymal interactions. Basic helix–loop–helix (bHLH) transcription factors regulate various aspects of tissue development, and we have previously identified a bHLH transcription factor, AmeloD, from a tooth germ cDNA library. Here, we provide both in vitro and in vivo evidence that AmeloD is important in tooth development. We created AmeloD-knockout (KO) mice to identify the in vivo functions of AmeloD that are critical for tooth morphogenesis. We found that AmeloD-KO mice developed enamel hypoplasia and small teeth because of increased expression of E-cadherin in inner enamel epithelial (IEE) cells, and it may cause inhibition of the cell migration. We used the CLDE dental epithelial cell line to conduct further mechanistic analyses to determine whether AmeloD overexpression in CLDE cells suppresses E-cadherin expression and promotes cell migration. Knockout of epiprofin (Epfn), another transcription factor required for tooth morphogenesis and development, and analysis of AmeloD expression and deletion revealed that AmeloD also contributed to multiple tooth formation in Epfn-KO mice by promoting the invasion of dental epithelial cells into the mesenchymal region. Thus, AmeloD appears to play an important role in tooth morphogenesis by modulating E-cadherin and dental epithelial–mesenchymal interactions. These findings provide detailed insights into the mechanism of ectodermal organ development.

Aerosols in planetary atmospheres play a critical role in radiative transfer and thus also in determining the penetration depth of UV radiation and atmospheric temperatures. For early Mars and an anoxic early Earth, aerosols may have significantly influenced the stability of liquid water at the surface, as well as climate and habitability, yet the study of aerosol formation remains poorly constrained by models and experiments, making conclusions difficult. Significant progress can be made in reducing these uncertainties by providing additional laboratory constraints and tests for the photochemical and microphysical models used to generate the greatly varying predictions about aerosol formation in terrestrial-like atmospheres. Photochemistry experiments measuring gas- and condensed-phase species were conducted to determine (1) the extent to which a photochemical haze could have formed in Mars' and Earth's early atmospheres and (2) whether such aerosols might be depleted in carbon-13, providing a potentially false biosignature in organic matter in the Martian and terrestrial rock and meteorite records.To gain a greater understanding of the fundamentals of aerosol formation in the CO2-rich atmospheres of early Earth and Mars, methane (CH4) and mixtures of CH4 and carbon dioxide (CO2) were irradiated with UV light in a static stainless steel reaction chamber, leading to the formation of aerosols. HeNe laser scattering was used to detect in situ the presence and relative amounts of aerosol produced, as well as the induction time required to form aerosols from the irradiation of the gases. Online mass spectrometry measurements were used to monitor the time evolution of gas phase species and, by difference, the relative amounts of carbon in the aerosol formed during an experiment. For comparison, particle samples were also collected during the irradiation experiments for "offline" analysis by elemental analyzer-isotope ratio mass spectrometry (EA-IRMS); the IRMS peak areas

Aerosols in planetary atmospheres play a critical role in radiative transfer and thus also in determining the penetration depth of UV radiation and atmospheric temperatures. For early Mars and an anoxic early Earth, aerosols may have significantly influenced the stability of liquid water at the surface, as well as climate and habitability, yet the study of aerosol formation remains poorly constrained by models and experiments, making conclusions difficult. Significant progress can be made in reducing these uncertainties by providing additional laboratory constraints and tests for the photochemical and microphysical models used to generate the greatly varying predictions about aerosol formation in terrestrial-like atmospheres. Photochemistry experiments measuring gas- and condensed-phase species were conducted to determine (1) the extent to which a photochemical haze could have formed in Mars' and Earth's early atmospheres and (2) whether such aerosols might be depleted in carbon-13, providing a potentially false biosignature in organic matter in the Martian and terrestrial rock and meteorite records.To gain a greater understanding of the fundamentals of aerosol formation in the CO2-rich atmospheres of early Earth and Mars, methane (CH4) and mixtures of CH4 and carbon dioxide (CO2) were irradiated with UV light in a static stainless steel reaction chamber, leading to the formation of aerosols. HeNe laser scattering was used to detect in situ the presence and relative amounts of aerosol produced, as well as the induction time required to form aerosols from the irradiation of the gases. Online mass spectrometry measurements were used to monitor the time evolution of gas phase species and, by difference, the relative amounts of carbon in the aerosol formed during an experiment. For comparison, particle samples were also collected during the irradiation experiments for "offline" analysis by elemental analyzer-isotope ratio mass spectrometry (EA-IRMS); the IRMS peak areas

Hollow cathode discharge studies have shown the existence of energetic ions at high discharge currents that are likely responsible for the high erosion rates and erosion patterns observed on the keeper electrode of the hollow cathode. This thesis uses experimental methods to study the effects of neutral gas injection in the xenon hollow cathode discharge plume on the production of energetic ions to determine the injection conditions that yield optimum hollow cathode operation and life. Parameters considered include the flow split between the cathode internal flow and the external gas injectors, the number of external gas injection sites, the locations of these injection sites, and the orifice size of the injectors, all as a function of the discharge current level. Two lanthanum hexaboride hollow cathodes of diameters 1.5 cm and 2 cm are studied for discharge currents of up to 100 A and 250 A, respectively. Internal measurements of the 1.5-cm-dia. cathode with a Langmuir probe reveal plasma potential and electron temperature profiles that are characteristic of hollow cathodes and relative insensitivity to the discharge and flow conditions. Plasma density measurements inside the cathode show that the density is sufficiently high and in contact with the entire 2.5-cm insert length only at relatively low internal cathode flow rates so that space-charge limitations on the emitted electron current density are not an issue. At high internal cathode flows, the density peak is pushed toward the orifice plate and the plasma contact with the insert is reduced. A retarding-potential analyzer is used to make ion energy measurements in the discharge plume of the 2-cm-dia. cathode at discharge currents of 25 to 250 A and at various gas-flow conditions. In general, increasing discharge current increases the energetic ion production at any given flow rate or injection location. External gas injection reduces energetic ion production with fewer energetic ions at higher external injec

Hollow cathode discharge studies have shown the existence of energetic ions at high discharge currents that are likely responsible for the high erosion rates and erosion patterns observed on the keeper electrode of the hollow cathode. This thesis uses experimental methods to study the effects of neutral gas injection in the xenon hollow cathode discharge plume on the production of energetic ions to determine the injection conditions that yield optimum hollow cathode operation and life. Parameters considered include the flow split between the cathode internal flow and the external gas injectors, the number of external gas injection sites, the locations of these injection sites, and the orifice size of the injectors, all as a function of the discharge current level. Two lanthanum hexaboride hollow cathodes of diameters 1.5 cm and 2 cm are studied for discharge currents of up to 100 A and 250 A, respectively. Internal measurements of the 1.5-cm-dia. cathode with a Langmuir probe reveal plasma potential and electron temperature profiles that are characteristic of hollow cathodes and relative insensitivity to the discharge and flow conditions. Plasma density measurements inside the cathode show that the density is sufficiently high and in contact with the entire 2.5-cm insert length only at relatively low internal cathode flow rates so that space-charge limitations on the emitted electron current density are not an issue. At high internal cathode flows, the density peak is pushed toward the orifice plate and the plasma contact with the insert is reduced. A retarding-potential analyzer is used to make ion energy measurements in the discharge plume of the 2-cm-dia. cathode at discharge currents of 25 to 250 A and at various gas-flow conditions. In general, increasing discharge current increases the energetic ion production at any given flow rate or injection location. External gas injection reduces energetic ion production with fewer energetic ions at higher external injec

A healthy 66 year-old man presented with a complaint of changes within a nodule on the scalp, which had first appeared over 10 years prior. He had no previous history of skin cancer. On physical examination a solitary, asymmetric, purple-black nodule with irregular borders was identified on the right vertex of his scalp. The remainder of his examination did not reveal any additional lesions.

A healthy 66 year-old man presented with a complaint of changes within a nodule on the scalp, which had first appeared over 10 years prior. He had no previous history of skin cancer. On physical examination a solitary, asymmetric, purple-black nodule with irregular borders was identified on the right vertex of his scalp. The remainder of his examination did not reveal any additional lesions.

A healthy 66 year-old man presented with a complaint of changes within a nodule on the scalp, which had first appeared over 10 years prior. He had no previous history of skin cancer. On physical examination a solitary, asymmetric, purple-black nodule with irregular borders was identified on the right vertex of his scalp. The remainder of his examination did not reveal any additional lesions.