Influence of pH and temperature on the performance and microbial community during the production of medium-chain carboxylic acids using winery effluents as substrate.

Winery effluents containing high ethanol concentrations and diverse organic matter are ideal substrates for producing medium-chain carboxylic acids via fermentation and chain elongation. However, the process needs to be better understood. This study presents novel insights into the bioconversion mechanisms of medium-chain carboxylic acids by correlating fermentation and chain elongation kinetic profiles with the study of microbial communities at different pH (5 to 7) conditions and temperatures (30 to 40 °C). It was found that high productivities of MCCA were obtained using a native culture and winery effluents as a natural substrate. Minor pH variations significantly affected the metabolic pathway of the microorganisms for MCCA production. The maximal productivities of hexanoic (715 mg/L/d) and octanoic (350 mg/L/d) acids were found at pH 6 and 35 °C. Results evidence that the presence of Clostridium, Bacteroides, and Negativicutes promotes the high productions of MCCA. The formation of heptanoic acid was favor when Mogibacterium and Burkholderia were present.

In vitro activity of gepotidacin and comparator antimicrobials against isolates of nontuberculous mycobacteria (NTM).

Novel antimicrobials are needed to treat rising nontuberculous mycobacteria (NTM) infections. Using standard broth microdilution methods, 68 NTM isolates were tested against gepotidacin, a new, first-in-class, oral triazaacenaphthylene bacterial topoisomerase inhibitor. MICs varied (0.25 to >64 µg/mL) with the lowest being M. fortuitum complex (0.25-8 µg/mL), M. mucogenicum complex (1-2 µg/mL), M. kansasii (0.25-8 µg/mL), and M. marinum (4-16 µg/mL). Testing greater numbers of some species is suggested to better understand gepotidacin activity against NTM.

Sowing the Seeds of Recovery: A Qualitative Study of Women in Recovery From Addiction and Victimization.

The purpose of this study was to understand the lived experiences of women with histories of victimization and addiction who were recently admitted to a sober living home (SLH). From the 17 interviews conducted, five themes (i.e., experiences of violence, challenges leaving an abusive relationship, chaos, using substances to cope, and social support) and one constitutive pattern (i.e., sowing the seeds of recovery) emerged from the data. These results highlight the importance of social support in promoting recovery and that social support may foster positive relationships with safe and trustworthy individuals as well as empower and support others with similar experiences.

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells.

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in creating single-stranded DNA gaps and inducing sensitivity requires the FANCJ DNA helicase. Yet, how FANCJ relates to PARP1 inhibition or trapping, which contribute to PARPi toxicity, remains unclear. Here, we find PARPi effectiveness hinges on S-phase PARP1 activity, which is reduced in FANCJ deficient cells as G-quadruplexes sequester PARP1 and MSH2. Additionally, loss of the FANCJ-MLH1 interaction diminishes PARP1 activity; however, depleting MSH2 reinstates PARPi sensitivity and gaps. Indicating sequestered and trapped PARP1 are distinct, FANCJ loss increases PARPi resistance in cells susceptible to PARP1 trapping. However, with BRCA1 deficiency, the loss of FANCJ mirrors PARP1 loss or inhibition, with the detrimental commonality being loss of S-phase PARP1 activity. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA1 deficient cells and emphasize the importance of understanding drug mechanisms for enhancing therapeutic response.

Getting our ducks in a row: The need for data utility comparisons of healthcare systems data for clinical trials.

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS. METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status. DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells.

Single-stranded DNA gaps are postulated to be fundamental to the mechanism of anti-cancer drugs. Gaining insights into their induction could therefore be pivotal for advancing therapeutic strategies. For poly (ADP-ribose) polymerase inhibitors (PARPi) to be effective, the presence of FANCJ helicase is required. However, the relationship between FANCJ dependent gaps and PARP1 catalytic inhibition or trapping-both linked to PARPi toxicity in BRCA deficient cells-is yet to be elucidated. Here, we find that the efficacy of PARPi is contingent on S-phase PARP1 activity, which is compromised in FANCJ deficient cells because PARP1, along with MSH2, is "sequestered" by G-quadruplexes. PARP1's replication activity is also diminished in cells missing a FANCJ-MLH1 interaction, but in such cells, depleting MSH2 can release sequestered PARP1, restoring PARPi-induced gaps and sensitivity. Our observations indicate that sequestered and trapped PARP1 are different chromatin-bound forms, with FANCJ loss increasing PARPi resistance in cells susceptible to canonical PARP1 trapping. However, in BRCA1 null cells, the loss of FANCJ mirrors the effects of PARP1 loss or inhibition, with the common detrimental factor being the loss of PARP1 activity during DNA replication, not trapping. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA deficient cells and emphasize the importance of understanding drug mechanisms for enhancing precision medicine.

National survey of infectious disease fellowship program directors: A call for subspecialized training in infection prevention and control and healthcare epidemiology.

OBJECTIVE: The importance of infection prevention and control and healthcare epidemiology (IPC/HE) in healthcare facilities was highlighted during the COVID-19 pandemic. Infectious disease (ID) clinicians often hold leadership positions in IPC/HE teams; however, there is no standard for training or certification of ID physicians specializing in IPC/HE. We evaluated the current state of IPC/HE training in ID fellowship programs. DESIGN: A national survey of ID fellowship program directors was conducted to assess current IPC/HE training components in programs and plans for expanded offerings. SETTING AND PARTICIPANTS: All ID fellowship program directors in the United States and Puerto Rico. METHODS: Surveys were distributed using Research Electronic Data Capture (REDCap) to program directors in March 2023, with 2 reminder emails; the survey closed after 4 weeks. RESULTS: Of 166 program directors, 54 (32.5%) responded to the survey. Among respondent programs, 49 (90.7%) of 54 programs reported didactic training in IPC/HE averaging 4.4 hours over the course of the fellowship. Also, 18 (33.3%) of 54 reported a dedicated IPC/HE training track. Furthermore, 23 programs (42.6%) reported barriers to expanding training. There was support (n = 47, 87.0%) for formal IPC/HE certification from a professional society within the standard fellowship. CONCLUSIONS: Despite the COVID-19 pandemic highlighting the need for ID medical doctors with IPC/HE expertise, formal training in ID fellowship remains limited. Most program directors support formalization of IPC/HE training by a professional organization. Creation of standardized advanced curriculums for ID fellowship training in IPC/HE could be considered by the Society of Healthcare Epidemiology of America (SHEA) to grow, retain, and enhance the IPC/HE physician workforce.

Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage.

BACKGROUND: Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. METHODS: The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. RESULTS: Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. CONCLUSIONS: We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

Threat, Distract, and Discredit: cannabis industry rhetoric to defeat regulation of high THC cannabis products in Washington State, USA.

OBJECTIVE: Washington state legislators have attempted to regulate high THC cannabis to reduce cannabis-related harms. Historically, industry actors of other health compromising products have influenced governments' adoption of evidence-based regulation policies. A better understanding of the industry rhetoric can be used by public health advocates to develop counter arguments and disseminate alternative narratives that protect the public's health. We analyzed the arguments used by cannabis industry actors opposing regulations to de-incentivize the availability and use of high THC products in Washington State. METHOD: We analyzed 41 testimonies transcribed from 33 cannabis industry actors in 3 public bill hearings and one legislative work session that occurred between 2020 and 2023. Using a deductive thematic analysis, informed by industry actors' arguments opposing regulation of alcohol, tobacco, and high-sugar beverages, we developed a codebook to analyze and identify themes within cannabis industry rhetorical strategies. RESULTS: We identified three main rhetorical strategies used by cannabis industry actors to oppose THC content regulation: threat, distract, discredit. The most frequently used rhetorical strategy was threats to economic benefits, public health, and the will of the people. The other two most apparent strategies were distracting from the bill's focus by introducing a tangential topic and discrediting the science that supported regulation of cannabis products with high THC concentration or its advocates. CONCLUSION: Cannabis industry actors have leveraged several arguments employed by industry actors of other health compromising products to undermine initiatives to advance public health. They have also adapted rhetoric from other industries to the unique conditions of the cannabis regulatory landscape.

Identifying policy options to regulate high potency cannabis: A multiple stakeholder concept mapping study in Washington State, USA.

BACKGROUND: Cannabis legalization in some U.S.A. states has catapulted the mass production of concentrates, with tetrahydrocannabinol (THC) concentrations ranging from 50-90%. A major public health concern is that these products will increase cannabis-related harms such as use disorders, psychotic symptoms, and accidental poisonings. This paper describes and contextualizes the results of a study requested by the WA State Legislature to understand perspectives of WA stakeholders on the topic. METHODS: Concept Mapping (CM), a mixed-methods research approach that supports people-centered policy decisions was utilized. The goal of the study was to explore stakeholders' concern levels and support of policies to address the availability of high THC cannabis products. For analysis purposes, stakeholders were categorized into three groups: community, professionals, and cannabis advocates. RESULTS: CM generated an inventory of policy ideas for regulating high-potency cannabis from a variety of stakeholders. Notably, stakeholders from community and professional groups supported environmental policy changes such as such as taxation, increasing minimum age for high concentration cannabis products, and advertising prohibition. Meanwhile, cannabis advocates (mostly industry actors) opposed taxation per THC content, proposed lowering taxes, and supported policies with low population impact such as educating parents, teachers, and youth. CONCLUSION: Support for regulating high concentration THC products varied by stakeholder group. Consistent with how other health compromising industries have historically acted, cannabis industry stakeholders rejected regulation of their products. Future studies should explore non-cannabis industry stakeholders' willingness to work towards minimizing the influence of the cannabis industry in policy development processes to assure public health regulations prevail.

Monitoring metrics over time: Why clinical trialists need to systematically collect site performance metrics.

Background: Over the last decade, there has been an increasing interest in risk-based monitoring (RBM) in clinical trials, resulting in a number of guidelines from regulators and its inclusion in ICH GCP. However, there is a lack of detail on how to approach RBM from a practical perspective, and insufficient understanding of best practice. Purpose: We present a method for clinical trials units to track their metrics within clinical trials using descriptive statistics and visualisations. Research Design: We suggest descriptive statistics and visualisations within a SWAT methodology. Study Sample: We illustrate this method using the metrics from TEMPER, a monitoring study carried out in three trials at the MRC Clinical Trials Unit at UCL. Data Collection: The data collection for TEMPER is described in DOI: 10.1177/1740774518793379. Results: We show the results and discuss a protocol for a Study-Within-A-Trial (SWAT 167) for those wishing to use the method. Conclusions: The potential benefits metric tracking brings to clinical trials include enhanced assessment of sites for potential corrective action, improved evaluation and contextualisation of the influence of metrics and their thresholds, and the establishment of best practice in RBM. The standardisation of the collection of such monitoring data would benefit both individual trials and the clinical trials community.

Cashless gambling: Qualitative analysis of consumer perspectives regarding the harm minimization potential of digital payment systems for electronic gaming machines.

OBJECTIVE: Land-based gambling venues remain predominantly cash-based despite broader consumer trends toward digital payments. Little prior literature directly investigates the role of payment methods in gambling; however, digital payment systems offer a key intervention point for gambling harm minimization. This study explores the perspectives of electronic gaming machine (EGM) gamblers regarding the concept of cashless gambling-the ability to gamble without using physical currency. METHOD: Twenty-six Australian EGM gamblers (10 females, 16 males; aged 24-76 years) participated in four online focus group discussions. Using content analysis and a pragmatic approach, data were organized thematically in relation to consumer perceptions about the benefits and risks of cashless gambling, factors potentially influencing uptake of cashless gambling, and recommendations about harm reduction features that could be incorporated into the system. RESULTS: Cashless gambling was perceived to present important opportunities for more useful and meaningful harm reduction measures based on the ability to track a user's complete gambling activity. However, participants reported reluctance toward adoption of cashless gambling, tending to perceive such systems as being overly restrictive and invasive, and potentially facilitating (over)spending, depending on design and implementation. Participants commonly perceived systems as offering little value to individuals who gamble without experiencing significant harms. CONCLUSIONS: Perceived irrelevance and privacy concerns appear to be major barriers to adoption of a cashless gambling system with strong harm reduction features. Our findings provide insights for policy makers considering the optimal design, implementation, and marketing of cashless gambling from a harm reduction perspective. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Results from a Real-World Multicenter Analysis of 482 Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib: A Look at Racial Differences.

BACKGROUND: Despite recent approvals of lifesaving treatments for chronic lymphocytic leukemia (CLL), real-world data on the tolerability of the Bruton tyrosine kinase inhibitor ibrutinib for CLL treatment are lacking, especially in Black patients. OBJECTIVE: To expand upon a previously reported retrospective chart review of ibrutinib-treated patients with CLL to increase the number of sites and the enrollment period in first-line (1L) and relapsed/refractory (R/R) settings with a subanalysis based on ethnicity. PATIENTS AND METHODS: Adults with CLL who initiated ibrutinib treatment from five centers were followed for ≥ 6 months. RESULTS: We identified 482 patients with CLL [405 White (153 1L, 252 R/R), 37 Black (17 1L, 20 R/R), 40 other/unidentified]. At baseline, 58.5% of all patients (68.8% of Black patients) had hypertension. At a median follow-up of 28.2 months, 31.1% of patients overall discontinued ibrutinib, 16.2% due to adverse events (12.2% 1L, 18.8% R/R). Overall, 46.0% of patients experienced ≥ 1 dose hold (40.2% 1L, 49.8% R/R), and 28.8% of patients experienced ≥ 1 dose reduction (24.9% 1L, 31.4% R/R). Among Black patients, ibrutinib was discontinued in 24.3% of patients (17.6% 1L, 30.0% R/R), 8.1% due to disease progression and 5.4% due to adverse events; 40.5% of patients experienced ≥ 1 dose hold (35.3% 1L, 45.0% R/R), and 32.4% of patients experienced ≥ 1 dose reduction (23.5% 1L, 40.0% R/R). CONCLUSIONS: Toxicity and disease progression were the most common reasons for ibrutinib discontinuations in the overall population and among Black patients, respectively. Encouraging research participation of underrepresented patient groups will help clinicians better understand treatment outcomes.

Ibrutinib, a Bruton tyrosine kinase inhibitor, is an approved oral targeted therapy for the treatment of chronic lymphocytic leukemia (CLL). Patients treated with ibrutinib can experience side effects (referred to as adverse events) and may need to reduce the drug dose (referred to as dose reductions) or stop treatment (referred to as discontinuations) for a variety of reasons. A previous study showed that patients who were treated with ibrutinib experienced frequent dose reductions and discontinuations. This study described dose reductions and discontinuations in a larger patient population treated with ibrutinib and also described outcomes in Black patients. Patients with CLL treated with ibrutinib were identified from five medical centers and were followed for a minimum of 6 months. Patients experienced frequent dose reductions and discontinuations in routine clinical practice. The most common cause of discontinuations was adverse events in the overall patient population and disease progression in the Black patient population. Black patients treated with ibrutinib had similar rates of dose reductions and discontinuations as the overall patient population. Rates of dose reductions and discontinuations for patients with CLL treated with ibrutinib were higher in this real-world study than in clinical trials.

LVAD therapy as a catalyst to heart failure remission and myocardial recovery.

The management of chronic heart failure over the past decade has witnessed tremendous strides in medical optimization and device therapy including the use of left ventricular assist devices (LVAD). What we once thought of as irreversible damage to the myocardium is now demonstrating signs of reverse remodeling and recovery. Myocardial recovery on the structural, molecular, and hemodynamic level is necessary for sufficient recovery to withstand explant and achieve sustained recovery post-LVAD. Guideline-directed medical therapy and unloading have been shown to aid in recovery with the potential to successfully explant the LVAD. This review will summarize medical optimization, assessment for recovery, explant methodologies and outcomes post-recovery with explant of durable LVAD.

Perception of Supervisory Styles.

Supervision is a dynamic and challenging leadership process that remains an essential element within the field of speech-language pathology. This study examines a facet of the supervisory relationship and investigates whether supervision styles are similarly perceived by the supervisor and supervisee and if a mismatch in perceptions relates to satisfaction between supervisor-supervisee dyads. Data were collected through completion of a demographic questionnaire as well as the Supervisory Style Inventory, which categorizes supervisory style as being attractive, interpersonally sensitive, task-oriented, or mixed. Findings demonstrate notable variance in the self-reported supervisor style and the style supervisees perceived as being demonstrated with over half (66%) of supervisor-supervisee dyads reporting a perceived mismatch in style. There was not a significant difference in the level of supervisee satisfaction for supervisor dyads reporting a match in style compared with mismatch. Satisfaction was correlated with all three reported style characteristics; however, interpersonal and task-oriented supervisory style characteristics were more strongly correlated with supervisee satisfaction. Having a mixed style was the only style that was significantly correlated with supervisees reporting having their needs met. Discussions include practical implications, limitations of the study, as well as recommendations for future research.

Microalgal consortium tolerance to bisphenol A and triclosan in wastewater and their effects on growth, biomolecule content and nutrient removal.

Amongst the many treatments available for the removal of emerging contaminants in wastewater, microalgal cultures have been shown to be effective. However, the effectiveness of exposure of a native microalgal consortium to emerging contaminants such as bisphenol-A (BPA) and triclosan (TCS) to determine the half-maximum effective concentrations (EC50) has not yet been determined. The effect on growth and nutrient removal of such a treatment as well as on the production of biomolecules such as carbohydrates, lipids, and proteins are, at present, unknown. In this study, the EC50 of BPA and TCS (96-hour experiments) was determined using a consortium of native microalgae (Scenedesmus obliquus and Desmodesmus sp.) to define the maximum tolerance to these contaminants. The effect of BPA and TCS in synthetic wastewater (SWW) was investigated in terms of microalgal growth, chlorophyll a (Chl-a), carbohydrate, lipid, and protein content, as well as nutrient removal. Assays were performed in heterotrophic conditions (12/12 light/dark cycles). EC50-96 h values of 17 mg/L and 325 µg/L for BPA and TCS, respectively, were found at 72 h. For an initial microalgal inoculum of ≈ 300 mg TSS/L (total suspended solids per litre), growth increased by 16.1% when exposed to BPA and 17.78% for TCS. At ≈ 500 mg TSS/L, growth increased by 8.25% with BPA and 9.92% with TCS, respectively. At the EC50-96 h concentrations determined in the study, BPA and TCS did not limit the growth of microalgae in wastewater. Moreover, they were found to stimulate the content of Chl-a, carbohydrates, lipids, proteins, and enhance nutrient removal. AVAILABILITY OF DATA AND MATERIAL: Data sharing not applicable to this article as no datasets were generated or analysed during the present study.

A crystallin mutant cataract with mineral deposits.

Connexin mutant mice develop cataracts containing calcium precipitates. To test whether pathologic mineralization is a general mechanism contributing to the disease, we characterized the lenses from a nonconnexin mutant mouse cataract model. By cosegregation of the phenotype with a satellite marker and genomic sequencing, we identified the mutant as a 5-bp duplication in the γC-crystallin gene (Crygcdup). Homozygous mice developed severe cataracts early, and heterozygous animals developed small cataracts later in life. Immunoblotting studies showed that the mutant lenses contained decreased levels of crystallins, connexin46, and connexin50 but increased levels of resident proteins of the nucleus, endoplasmic reticulum, and mitochondria. The reductions in fiber cell connexins were associated with a scarcity of gap junction punctae as detected by immunofluorescence and significant reductions in gap junction-mediated coupling between fiber cells in Crygcdup lenses. Particles that stained with the calcium deposit dye, Alizarin red, were abundant in the insoluble fraction from homozygous lenses but nearly absent in wild-type and heterozygous lens preparations. Whole-mount homozygous lenses were stained with Alizarin red in the cataract region. Mineralized material with a regional distribution similar to the cataract was detected in homozygous lenses (but not wild-type lenses) by micro-computed tomography. Attenuated total internal reflection Fourier-transform infrared microspectroscopy identified the mineral as apatite. These results are consistent with previous findings that loss of lens fiber cell gap junctional coupling leads to the formation of calcium precipitates. They also support the hypothesis that pathologic mineralization contributes to the formation of cataracts of different etiologies.

Fibronectin Contributes to a BRAF Inhibitor-driven Invasive Phenotype in Thyroid Cancer through EGR1, Which Can Be Blocked by Inhibition of ERK1/2.

Mutations in BRAF are common in advanced papillary and anaplastic thyroid cancer (PTC and ATC). However, patients with BRAF-mutant PTC currently lack therapies targeting this pathway. Despite the approved combination of BRAF and MEK1/2 inhibition for patients with BRAF-mutant ATC, these patients often progress. Thus, we screened a panel of BRAF-mutant thyroid cancer cell lines to identify new therapeutic strategies. We showed that thyroid cancer cells resistant to BRAF inhibition (BRAFi) exhibit an increase in invasion and a proinvasive secretome in response to BRAFi. Using reverse-phase protein array (RPPA), we identified a nearly 2-fold increase in expression of the extracellular matrix protein, fibronectin, in response to BRAFi treatment, and a corresponding 1.8- to 3.0-fold increase in fibronectin secretion. Accordingly, the addition of exogenous fibronectin phenocopied the BRAFi-induced increase in invasion while depletion of fibronectin in resistant cells resulted in loss of increased invasion. We further showed that BRAFi-induced invasion can be blocked by inhibition of ERK1/2. In a BRAFi-resistant patient-derived xenograft model, we found that dual inhibition of BRAF and ERK1/2 slowed tumor growth and decreased circulating fibronectin. Using RNA sequencing, we identified EGR1 as a top downregulated gene in response to combined BRAF/ERK1/2 inhibition, and we further showed that EGR1 is necessary for a BRAFi-induced increase in invasion and for induction of fibronectin in response to BRAFi. IMPLICATIONS: Together, these data show that increased invasion represents a new mechanism of resistance to BRAF inhibition in thyroid cancer that can be targeted with an ERK1/2 inhibitor.