Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is ...unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin,
N
-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.
The recent development of a system for long-term in vitro culture of the syphilis spirochete, Treponema pallidum subsp. pallidum, has introduced the possibility of detailed genetic analysis of this ...bacterium. In this study, the in vitro culture system was used to isolate and characterize clonal populations of T. pallidum subsp. pallidum Nichols, the most widely studied strain. In limiting dilutions experiments, it was possible to establish cultures with inocula as low as 0.5 T. pallidum per well despite the long generation time (~35 to 40 hours) of this organism. Six Nichols strain clones isolated by limiting dilution were characterized in detail. All clones exhibited indistinguishable morphology and motility, highly similar in vitro multiplication rates, and comparable infectivity in the rabbit model (ID50 ≤ 100 bacteria). Genomic sequencing revealed sequence heterogeneity in the form of insertions or deletions at 5 sites, single nucleotide variations at 20 sites, and polynucleotide (polyG/C) tract length differences at 22 locations. Genomic sequences of the uncloned Nichols strain preparations propagated in rabbits or in vitro cultures exhibited substantial heterogeneity at these locations, indicating coexistence of many varied 'clonotypes' within these populations. Nearly all genetic variations were specific for the Nichols strain and were not detected in the >280 T. pallidum genomic sequences that are currently available. We hypothesize that these Nichols strain-specific sequence variations arose independently either during human infection or within the 110 years since the strain's initial isolation, and thus represent examples of microevolution and divergence.
It has been hypothesized that the composition of particulate matter (PM) may be a better predictor of health effects than PM mass alone. The regional differences in PM composition and the ...heterogeneity in PM risk estimates in large multi-city epidemiologic studies are consistent with this hypothesis. Since 2005, efforts have been made to relate apportioned components and sources of PM with human health outcomes in epidemiology, controlled human exposure and toxicology studies. We reviewed published studies that: 1) focused on short-term exposure to PM; 2) included at least five components of PM; 3) grouped them into factors or sources; and 4) used quantitative methods to examine the relationship between the factors or sources and health effects. We then examined whether specific groups of PM components or sources of PM are consistently linked to specific health effects across studies. Collectively, these studies suggest that cardiovascular effects may be associated with PM2.5 from crustal or combustion sources, including traffic, but at this time, no consistent relationships have emerged. Fewer studies evaluated respiratory health effects, and the evidence for associations was limited. Apportionment methods have linked a variety of health effects to multiple groups of PM components and sources of PM, but the collective evidence has not yet isolated factors or sources that would be closely and unequivocally related to specific health outcomes.
► PM chemical composition may better predict health effects than PM mass or size. ► We reviewed 29 studies that attempted this by using apportionment methods. ► Were specific sources or factors consistently linked to specific health effects? ► Apportionment methods have identified links, but we found little if any consistency.
VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants ...including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089–1095
Purpose To establish the performance of screening with serum cancer antigen 125 (CA-125), interpreted using the risk of ovarian cancer algorithm (ROCA), and transvaginal sonography (TVS) for women at ...high risk of ovarian cancer (OC) or fallopian tube cancer (FTC). Patients and Methods Women whose estimated lifetime risk of OC/FTC was ≥ 10% were recruited at 42 centers in the United Kingdom and underwent ROCA screening every 4 months. TVS occurred annually if ROCA results were normal or within 2 months of an abnormal ROCA result. Risk-reducing salpingo-oophorectomy (RRSO) was encouraged throughout the study. Participants were observed via cancer registries, questionnaires, and notification by centers. Performance was calculated after censoring 365 days after prior screen, with modeling of occult cancers detected at RRSO. Results Between June 14, 2007, and May 15, 2012, 4,348 women underwent 13,728 women-years of screening. The median follow-up time was 4.8 years. Nineteen patients were diagnosed with invasive OC/FTC within 1 year of prior screening (13 diagnoses were screen-detected and six were occult at RRSO). No symptomatic interval cancers occurred. Ten (52.6%) of the total 19 diagnoses were stage I to II OC/FTC (CI, 28.9% to 75.6%). Of the 13 screen-detected cancers, five (38.5%) were stage I to II (CI, 13.9% to 68.4%). Of the six occult cancers, five (83.3%) were stage I to II (CI, 35.9% to 99.6%). Modeled sensitivity, positive predictive value, and negative predictive value for OC/FTC detection within 1 year were 94.7% (CI, 74.0% to 99.9%), 10.8% (6.5% to 16.5%), and 100% (CI, 100% to 100%), respectively. Seven (36.8%) of the 19 cancers diagnosed < 1 year after prior screen were stage IIIb to IV (CI, 16.3% to 61.6%) compared with 17 (94.4%) of 18 cancers diagnosed > 1 year after screening ended (CI, 72.7% to 99.9%; P < .001). Eighteen (94.8%) of 19 cancers diagnosed < 1 year after prior screen had zero residual disease (with lower surgical complexity, P = .16) (CI, 74.0% to 99.9%) compared with 13 (72.2%) of 18 cancers subsequently diagnosed (CI, 46.5% to 90.3%; P = .09). Conclusion ROCA-based screening is an option for women at high risk of OC/FTC who defer or decline RRSO, given its high sensitivity and significant stage shift. However, it remains unknown whether this strategy would improve survival in screened high-risk women.
(See the commentary by Moro, on pages 978-980 .) Infection surveillance definitions for long-term care facilities (ie, the McGeer Criteria) have not been updated since 1991. An expert consensus panel ...modified these definitions on the basis of a structured review of the literature. Significant changes were made to the criteria defining urinary tract and respiratory tract infections. New definitions were added for norovirus gastroenteritis and Clostridum difficile infections.
The Administrative Procedure Act (APA) permits judicial review of "final agency action." Agency action is "final" when it is both the "consummation of the agency's decision making process" and a ...decision by which "rights or obligations have been determined," or from which "legal consequences will flow." Some forms of agency action uncontroversially satisfy both of these conditions for finality. For example, "legislative rules" promulgated by agencies pursuant to congressional delegations of policy-making authority after a period of public notice and comment are certainly "final agency action" that can be challenged before their application. Other forms of agency action pose challenges for the finality doctrine. In particular, agencies sometimes issue nonlegislative "interpretative rules" construing arguably ambiguous statutory provisions. While these interpretative rules are often the consummation of an agency's decision-making process, do they determine rights or obligations? Do legal consequences flow from their issuance? The Supreme Court has only given this topic cursory treatment, and its precedents on the subject probably confuse more than they clarify. Given this lack of guidance, the courts of appeals have struggled to coalesce around a single approach to understanding the finality of interpretative rules. That said, some courts, including the D.C. Circuit, have demonstrated increasing interest in a bright-line rule deeming interpretative rules as nonfinal prior to enforcement. On this view, interpretative rules never determine rights or obligations, or produce legal consequences until they are applied to a regulated party. At the same time, however, several commentators have also argued that the legalconsequence condition for finality should be eliminated altogether. This Note argues that the categorical exclusion of interpretative rules from the ambit of "final agency action" is presently unwarranted. It begins by canvassing the present doctrine and finding it wanting. The Note then turns to the contemporaneous history surrounding the APA's enactment for answers. Examining that history, it demonstrates that there existed a broad consensus shortly before and after the APA's adoption that legal consequence was the central determinant for whether a given agency action was judicially reviewable. Therefore, the academic critics of the finality doctrine's legal-consequence condition appear to have missed the mark. Moreover, the history demonstrates that while courts sometimes deferred to an agency's interpretative rules, those rules lacked the force of law because, at the end of the day, the courts always remained free to substitute their preferred statutory interpretation for the agency's. At first blush, therefore, it might appear that the categorical exclusion of interpretative rules from "final agency action" has a sound historic pedigree. However, the historical unreviewability of interpretative rules hinged on the premise that the rules could never bind the courts. But the current regime of Chevron deference undermines that premise and should change the calculus for whether interpretative rules produce the legal consequences sufficient for finality. All told, any interpretative rule that is eligible for Chevron deference should also be "final agency action" under the APA. The Note concludes by explaining how a unified deference-finality doctrine might operate in practice.
One of the current methods for cycle optimization in primary drying to is develop a graphical design space based on quality by design (QbD). In order to construct the design space, the vial heat ...transfer coefficient (
K
v
) is needed. This paper investigated experimental factors that can affect the
K
v
result, examined the relationship between the batch average
K
v
and
K
v
values for individual vials, and recommended best practices for measuring
K
v
. Factors investigated included the technique for measuring ice temperature, shelf temperature, the use of a radiation shield on the door of the freeze-dry chamber, and shelf spacing. All experiments reported here used a chamber pressure of 100 mTorr. The most important factor was the technique for ice temperature measurement, where it is important to assure that any restrictions to vapor flow at the top of the vial are the same between monitored and non-monitored vials. Another factor that was found to play a role was the shelf temperature whereby the lower the shelf temperature, the larger the “edge effect,” and the larger the average
K
v
. Factors that were found to not have a significant effect were the use of a radiation shield inside the chamber door and the shelf spacing. Being aware of these factors and knowing best practices when determining the vial heat coefficient will lead to more accurate design spaces and better cycle optimization.
Despite growing interest in edible seaweeds, there is limited information on seaweed chemical contaminant levels in the Salish Sea. Without this knowledge, health-based consumption advisories can not ...be determined for consumers that include Tribes and First Nations, Asian and Pacific Islander community members, and recreational harvesters. We measured contaminant concentrations in edible seaweeds (Fucus distichus, F. spiralis, and Nereocystis luetkeana) from 43 locations in the Salish Sea. Metals were analyzed in all samples, and 94 persistent organic pollutants (POPs) (i.e. 40 PCBs, 15 PBDEs, 17 PCDD/Fs, and 22 organochlorine pesticides) and 51 PAHs were analyzed in Fucus spp. We compared concentrations of contaminants to human health-based screening levels calculated from the USEPA and to international limits. We then worked with six focal contaminants that either exceeded screening levels or international limits (Cd, total Hg, Pb, benzoapyrene BaP, and PCBs) or are of regional interest (total As). USEPA cancer-based screening levels were exceeded in 30 samples for the PCBs and two samples for BaP. Cadmium concentrations did not exceed the USEPA noncancer-based screening level but did exceed international limits at all sites. Lead exceeded international limits at three sites. Because there are no screening levels for total Hg and total As, and to be conservative, we made comparisons to methyl Hg and inorganic As screening levels. All samples were below the methyl Hg and above the inorganic As screening levels. Without knowledge of the As speciation, we cannot assess the health risk associated with the As. While seaweed was the focus, we did not consider contaminant exposure from consuming other foods. Other chemicals, such as contaminants of emerging concern (e.g., PFAS, pharmaceuticals and personal care products), should also be considered. Additionally, although we focused on toxicological aspects, there are cultural and health benefits of seaweed use that may affect consumer choice.
The purpose of this study was to determine patient compliance and effectiveness of antiarrhythmic treatment by the wearable cardioverter-defibrillator (WCD).
Effectiveness of the WCD for prevention ...of sudden death is dependent on event type, patient compliance, and appropriate management of ventricular tachycardia/ventricular fibrillation (VT/VF).
Compliance and events were recorded in a nationwide registry of post-market release WCDs. Survival, using the Social Security Death Index, was compared with survival in implantable cardioverter-defibrillator (ICD) patients.
Of 3,569 patients wearing the WCD (age 59.3+/-14.7 years, duration 52.6+/-69.9 days), daily use was 19.9+/-4.7 h (>90% of the day) in 52% of patients. More days of use correlated with higher daily use (p<0.001). Eighty sustained VT/VF events occurred in 59 patients (1.7%). First-shock success was 76 of 76 (100%) for unconscious VT/VF and 79 of 80 (99%) for all VT/VF. Eight patients died after successful conversion of unconscious VT/VF (89.5% survival of VT/VF events). Asystole occurred in 23 (17 died), pulseless electrical activity in 2, and respiratory arrest in 1 (3 died), representing 24.5% of sudden cardiac arrests. During WCD use, 3,541 of 3,569 patients (99.2%) survived overall. Survival occurred in 72 of 80 (90%) VT/VF events and 78 of 106 (73.6%) for all events. Long-term mortality was not significantly different from first ICD implant patients but highest among patients with traditional ICD indications.
Compliance was satisfactory with 90% wear time in >50% of patients and low sudden death mortality during use. Survival was comparable to that of ICD patients. However, asystole was an important cause of mortality in sudden cardiac arrest events.
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