Impact of an educational program and decision tool on choice of maternity hospital: the delivery decisions randomized clinical trial.

BACKGROUND: Reducing cesarean rates is a public health priority. To help pregnant people select hospitals with lower cesarean rates, numerous organizations publish publically hospital cesarean rate data. Few pregnant people use these data when deciding where to deliver. We sought to determine whether making cesarean rate data more accessible and understandable increases the likelihood of pregnant people selecting low-cesarean rate hospitals. METHODS: We conducted a 1:1 randomized controlled trial in 2019-2021 among users of a fertility and pregnancy mobile application. Eligible participants were trying to conceive for fewer than five months or were 28-104 days into their pregnancies. Of 189,456 participants approached and enrolled, 120,621 participants met entry criteria and were included in analyses. The intervention group was offered an educational program explaining the importance of hospital cesarean rates and an interactive tool presenting hospital cesarean rates as 1-to-5-star ratings. Control group users were offered an educational program about hospital choice and a hospital choice tool without cesarean rate data. The primary outcome was the star rating of the hospital selected by each patient during pregnancy. Secondary outcomes were the importance of cesarean rates in choosing a hospital and delivery method (post-hoc secondary outcome). RESULTS: Of 120,621 participants (mean [SD] age, 27.8 [7.9]), 12,284 (10.2%) reported their choice of hospital during pregnancy, with similar reporting rates in the intervention and control groups. Intervention group participants selected hospitals with higher star ratings (2.52 vs 2.16; difference, 0.37 [95% CI, 0.32 to 0.43] p < 0.001) and were more likely to believe that the hospitals they chose would impact their chances of having cesarean deliveries (38.5% vs 33.1%, p < 0.001) but did not assign higher priority to cesarean delivery rates when choosing their hospitals (76.2% vs 74.3%, p = 0.05). There was no difference in self-reported cesarean rates between the intervention and control groups (31.4% vs 31.4%, p = 0.98). CONCLUSION: People offered an educational program and interactive tool to compare hospital cesarean rates were more likely to use cesarean data in selecting a hospital and selected hospitals with lower cesarean rates but were not less likely to have a cesarean. CLINICAL TRIAL REGISTRATION: Registered December 9, 2016 at clinicaltrials.gov, First enrollment November 2019. ID NCT02987803, https://clinicaltrials.gov/ct2/show/NCT02987803.

Effect-based evaluation of ozone treatment for removal of micropollutants and their transformation products in waste water.

The aim of this interdisciplinary research project in North Rhine-Westphalia (NRW), Germany, entitled "Elimination of pharmaceuticals and organic micropollutants from waste water" involved the conception of cost-effective and innovative waste-water cleaning methods. In this project in vitro assays, in vivo assays and chemical analyses were performed on three municipal waste-water treatment plants (WWTP). This publication focuses on the study of the in vitro bioassays. Cytotoxic, estrogenic, genotoxic and mutagenic effects of the original as well as enriched water samples were monitored before and after wastewater treatment steps using MTT and PAN I, ER Calux and A-YES, micronucleus and Comet assays as well as AMES test. In most cases, the measured effects were reduced after ozonation, but in general, the biological response depended upon the water composition of the WWTP, in particular on the formed by-products and concentration of micropollutants. In order to be able to assess the genotoxic and/or mutagenic potential of waste-water samples using bioassays like Ames test, Comet assay or micronucleus test an enrichment of the water sample via solid-phase extraction is recommended. This is in agreement with previous studies such as the "ToxBox"-Project of the Environmental Agency in Germany.

Allostery Wiring Map for Kinesin Energy Transduction and Its Evolution.

How signals between the kinesin active and cytoskeletal binding sites are transmitted is an open question and an allosteric question. By extracting correlated evolutionary changes within 700+ sequences, we built a model of residues that are energetically coupled and that define molecular routes for signal transmission. Typically, these coupled residues are located at multiple distal sites and thus are predicted to form a complex, non-linear network that wires together different functional sites in the protein. Of note, our model connected the site for ATP hydrolysis with sites that ultimately utilize its free energy, such as the microtubule-binding site, drug-binding loop 5, and necklinker. To confirm the calculated energetic connectivity between non-adjacent residues, double-mutant cycle analysis was conducted with 22 kinesin mutants. There was a direct correlation between thermodynamic coupling in experiment and evolutionarily derived energetic coupling. We conclude that energy transduction is coordinated by multiple distal sites in the protein rather than only being relayed through adjacent residues. Moreover, this allosteric map forecasts how energetic orchestration gives rise to different nanomotor behaviors within the superfamily.

Small molecule screen for candidate antimalarials targeting Plasmodium Kinesin-5.

Plasmodium falciparum and vivax are responsible for the majority of malaria infections worldwide, resulting in over a million deaths annually. Malaria parasites now show measured resistance to all currently utilized drugs. Novel antimalarial drugs are urgently needed. The Plasmodium Kinesin-5 mechanoenzyme is a suitable "next generation" target. Discovered via small molecule screen experiments, the human Kinesin-5 has multiple allosteric sites that are "druggable." One site in particular, unique in its sequence divergence across all homologs in the superfamily and even within the same family, exhibits exquisite drug specificity. We propose that Plasmodium Kinesin-5 shares this allosteric site and likewise can be targeted to uncover inhibitors with high specificity. To test this idea, we performed a screen for inhibitors selective for Plasmodium Kinesin-5 ATPase activity in parallel with human Kinesin-5. Our screen of nearly 2000 compounds successfully identified compounds that selectively inhibit both P. vivax and falciparum Kinesin-5 motor domains but, as anticipated, do not impact human Kinesin-5 activity. Of note is a candidate drug that did not biochemically compete with the ATP substrate for the conserved active site or disrupt the microtubule-binding site. Together, our experiments identified MMV666693 as a selective allosteric inhibitor of Plasmodium Kinesin-5; this is the first identified protein target for the Medicines of Malaria Venture validated collection of parasite proliferation inhibitors. This work demonstrates that chemical screens against human kinesins are adaptable to homologs in disease organisms and, as such, extendable to strategies to combat infectious disease.

Benchmarking organic micropollutants in wastewater, recycled water and drinking water with in vitro bioassays.

Thousands of organic micropollutants and their transformation products occur in water. Although often present at low concentrations, individual compounds contribute to mixture effects. Cell-based bioassays that target health-relevant biological endpoints may therefore complement chemical analysis for water quality assessment. The objective of this study was to evaluate cell-based bioassays for their suitability to benchmark water quality and to assess efficacy of water treatment processes. The selected bioassays cover relevant steps in the toxicity pathways including induction of xenobiotic metabolism, specific and reactive modes of toxic action, activation of adaptive stress response pathways and system responses. Twenty laboratories applied 103 unique in vitro bioassays to a common set of 10 water samples collected in Australia, including wastewater treatment plant effluent, two types of recycled water (reverse osmosis and ozonation/activated carbon filtration), stormwater, surface water, and drinking water. Sixty-five bioassays (63%) showed positive results in at least one sample, typically in wastewater treatment plant effluent, and only five (5%) were positive in the control (ultrapure water). Each water type had a characteristic bioanalytical profile with particular groups of toxicity pathways either consistently responsive or not responsive across test systems. The most responsive health-relevant endpoints were related to xenobiotic metabolism (pregnane X and aryl hydrocarbon receptors), hormone-mediated modes of action (mainly related to the estrogen, glucocorticoid, and antiandrogen activities), reactive modes of action (genotoxicity) and adaptive stress response pathway (oxidative stress response). This study has demonstrated that selected cell-based bioassays are suitable to benchmark water quality and it is recommended to use a purpose-tailored panel of bioassays for routine monitoring.

Reaction of gadolinium chelates with ozone and hydroxyl radicals.

Gadolinium chelates are used in increasing amounts as contrast agents in magnetic resonance imaging, and their fate in wastewater treatment has recently become the focus of research. Oxidative processes, in particular the application of ozone, are currently discussed or even implemented for advanced wastewater treatment. However, reactions of the gadolinium chelates with ozone are not yet characterized. In this study, therefore, rate constants with ozone were determined for the three commonly used chelates Gd-DTPA, Gd-DTPA-BMA, and Gd-BT-DO3A, which were found to be 4.8 ± 0.88, 46 ± 2.5, and 24 ± 1.5 M(-1) s(-1), respectively. These low rate constants indicate that a direct reaction with ozone in wastewater is negligible. However, application of ozone in wastewater leads to substantial yields of (•)OH. Different methods have been applied and compared for determination of k((•)OH+Gd chelate). From rate constants determined by pulse radiolysis experiments (k((•)OH+Gd-DTPA) = 2.6 ± 0.2 × 10(9) M(-1) s(-1), k((•)OH+Gd-DTPA-BMA) = 1.9 ± 0.7 × 10(9) M(-1) s(-1), k((•)OH+Gd-BT-DO3A) = 4.3 ± 0.2 × 10(9) M(-1) s(-1)), it is concluded that a reaction in wastewater via (•)OH radicals is feasible. Toxicity has been tested for educt and product mixtures of both reactions. Cytotoxicity (MTT test) and genotoxicity (micronuclei assay) were not detectable.

Choosing Or Losing In Behavioral Health: A Study Of Patients' Experiences Selecting Telehealth Versus In-Person Care.

It is not known how the growth of telehealth has affected patients' choice of visit modalities (telehealth versus in person). In 2023 we conducted a mixed-methods study that paired a nationally representative survey of 2,071 adults (including 571 who used behavioral health services) and semistructured interviews with twenty-six people with depression or bipolar disorder. We explored patients' experiences with visit modality selection and their agency in the decision. Approximately one-third of patients receiving therapy or medication visits reported that their clinicians did not offer both modalities. Thirty-two percent reported that they did not typically receive their preferred modality, and 45 percent did not believe that their clinician considered their modality preferences. Qualitative findings revealed that some clinicians did not elicit patients' modality preferences. Perceived lack of choice affected satisfaction and rapport with clinicians and encouraged some people to seek care elsewhere. These findings highlight trade-offs in policies to preserve patient choice and approaches that clinicians can take to identify and accommodate patients' preferences.

A methodology for identifying behavioral health advanced practice registered nurses in administrative claims.

OBJECTIVE (STUDY QUESTION): Advanced practice registered nurses (APRNs) play an increased role in mental illness treatment. Health services research that uses claims to study mental health is often limited because behavioral health nurse practitioners (i.e., APRNs who specialize in mental illness, also known as psychiatric mental health APRNs) cannot be easily identified in claims data. We describe two methodologies to identify behavioral health APRNs in administrative claims. DATA SOURCES/STUDY SETTING (W/ HOSPITAL/INSTITUTION SETTING ANONYMIZED): We use 2010-2018 claims from the traditional Medicare fee-for-service program along with 2010-2019 commercial claims and Medicare Advantage data from the OptumLabs Data Warehouse (OLDW). Self-reported specialty data from the National Plan & Provider Enumeration System (NPPES) were used for validation. STUDY DESIGN: For each APRN, we calculated the percentage of visit diagnoses and of prescriptions in each database that were for mental health and classified those with ≥80% as behavioral health APRNs. We validated our definition with NPPES self-reported specialty for Medicare data. DATA COLLECTION/EXTRACTION METHODS: Not applicable. PRINCIPAL FINDINGS: Among APRNs with 10+ visits, 10,978 (8.1%) in Medicare and 9829 (11.7%) in commercial claims data met our visit-based criteria as behavioral health APRNs. Among APRNs with 10+ prescriptions, 8160 (6.2%) in Medicare and 16,538 (9.0%) in commercial claims data met our prescription-based criteria as behavioral health APRNs. Among the APRNs who self-reported they were behavioral health APRNs, 92.8% and 90.5% met our visit-based and prescription-based criteria, respectively. CONCLUSIONS: We present and validate two methods of identifying behavioral health APRNs in claims that can be used by other researchers.

Legislation Increased Medicare Telestroke Billing, But Underbilling And Erroneous Billing Remain Common.

In the Furthering Access to Stroke Telemedicine (FAST) Act, passed as part of a budget omnibus in 2018, Congress permanently expanded Medicare payment for telemedicine consultations for acute stroke ("telestroke") from delivery only in rural areas to delivery in both urban and rural areas, effective January 1, 2019. Using a controlled time-series analysis, we found that one year after FAST Act implementation, billing for Medicare telestroke increased substantially in emergency departments at both directly affected urban hospitals and indirectly affected rural hospitals. However, at that time only a minority of hospitals with known telestroke capacity had ever billed Medicare for that service, and there was substantial billing inconsistent with Medicare requirements. As Congress considers options for Medicare telemedicine payment after the COVID-19 pandemic, our findings, which are consistent with confusion among providers regarding telemedicine billing requirements, suggest that simplified payment rules would help ensure that expanded reimbursement achieves its intended impact.

Allosteric drug discrimination is coupled to mechanochemical changes in the kinesin-5 motor core.

Essential in mitosis, the human Kinesin-5 protein is a target for >80 classes of allosteric compounds that bind to a surface-exposed site formed by the L5 loop. Not established is why there are differing efficacies in drug inhibition. Here we compare the ligand-bound states of two L5-directed inhibitors against 15 Kinesin-5 mutants by ATPase assays and IR spectroscopy. Biochemical kinetics uncovers functional differences between individual residues at the N or C termini of the L5 loop. Infrared evaluation of solution structures and multivariate analysis of the vibrational spectra reveal that mutation and/or ligand binding not only can remodel the allosteric binding surface but also can transmit long range effects. Changes in L5-localized 3(10) helix and disordered content, regardless of substitution or drug potency, are experimentally detected. Principal component analysis couples these local structural events to two types of rearrangements in beta-sheet hydrogen bonding. These transformations in beta-sheet contacts are correlated with inhibitory drug response and are corroborated by wild type Kinesin-5 crystal structures. Despite considerable evolutionary divergence, our data directly support a theorized conserved element for long distance mechanochemical coupling in kinesin, myosin, and F(1)-ATPase. These findings also suggest that these relatively rapid IR approaches can provide structural biomarkers for clinical determination of drug sensitivity and drug efficacy in nucleotide triphosphatases.

Association of Hospital Telestroke Adoption With Changes in Initial Hospital Presentation and Transfers Among Patients With Stroke and Transient Ischemic Attacks.

Importance: It has been proposed that the implementation of telestroke services (a web-based approach to using video telecommunication to treat patients with stroke before hospital admission) changes where patients with stroke symptoms receive care, but this proposal has not been rigorously assessed. Objective: To assess whether the implementation of telestroke services is associated with changes in where and how patients initially present with stroke symptoms, in their decision to be transferred to another hospital, and which hospitals they are transferred to. Design, Setting, and Participants: This cross-sectional study compared changes in stroke systems of care between a sample of 593 US hospitals that adopted telestroke during the period from 2009 to 2016 but were not comprehensive stroke centers, major teaching hospitals, or thrombectomy-capable hospitals vs 593 matched control hospitals without telestroke based on rural location, critical access hospital status, bed size, primary stroke center status, presence of hospital alternatives in the community, hospital stroke volume, census region, and ownership. With the use of data on 100% of Medicare fee-for-service beneficiaries, all stroke and transient ischemic attack admissions from 2008 to 2018 were identified. Exposures: For each hospital pair (telestroke plus matched control), the telestroke hospital's implementation date and difference-in-differences approach were used to quantify the association between telestroke implementation and changes in care from 2 years before implementation to 2 years after implementation. Models also controlled for differences in observed patient characteristics. Main Outcomes and Measures: Hospital stroke volume, patients' ambulance transport distance to initial hospital, hospital case mix, interhospital transfer proportion, and size of the receiving hospital for transferred patients. Results: Of the 669 telestroke hospitals and 2143 potential control hospitals, 593 hospital pairs were matched; in each category, 261 hospitals (44.0%) were located in a rural area, 179 (30.2%) were primary stroke centers, and 130 (21.9%) were critical access hospitals. The changes in the preimplementation to postimplementation period were similar at telestroke and control hospitals in mean annual stroke volume (telestroke hospitals, decreased from 79.6 to 76.3 patients; control hospitals, decreased from 78.8 to 75.5 patients [-3.3 patients per year for both; difference-in-differences, 0.009; P ≥ .99]). Similarly, no differences were seen in ambulance transport distance, case mix, interhospital transfers, or bed size of receiving hospitals among transferred patients. Conclusions and Relevance: This study suggests that, across a national sample of hospitals implementing telestroke, no association between telestroke adoption and changes in stroke systems of care were found.

Reperfusion Treatment and Stroke Outcomes in Hospitals With Telestroke Capacity.

Importance: Telestroke is increasingly used in hospital emergency departments, but there has been limited research on its impact on treatment and outcomes. Objective: To describe differences in care patterns and outcomes among patients with acute ischemic stroke who present to hospitals with and without telestroke capacity. Design, Setting, and Participants: Patients with acute ischemic stroke who first presented to hospitals with telestroke capacity were matched with patients who presented to control hospitals without telestroke capacity. All traditional Medicare beneficiaries with a primary diagnosis of acute ischemic stroke (approximately 2.5 million) who presented to a hospital between January 2008 and June 2017 were considered. Matching was based on sociodemographic and clinical characteristics, hospital characteristics, and month and year of admission. Hospitals included short-term acute care and critical access hospitals in the US without local stroke expertise. In 643 hospitals with telestroke capacity, there were 76 636 patients with stroke who were matched 1:1 to patients at similar hospitals without telestroke capacity. Data were analyzed in July 2020. Main Outcomes and Measures: Receipt of reperfusion treatment through thrombolysis with alteplase or thrombectomy, mortality at 30 days from admission, spending through 90 days from admission, and functional status as measured by days spent living in the community after discharge. Results: In the final sample of 153 272 patients, 88 386 (57.7%) were female, and the mean (SD) age was 78.8 (10.4) years. Patients cared for at telestroke hospitals had higher rates of reperfusion treatment compared with those cared for at control hospitals (6.8% vs 6.0%; difference, 0.78 percentage points; 95% CI, 0.54-1.03; P < .001) and lower 30-day mortality (13.1% vs 13.6%; difference, 0.50 percentage points; 95% CI, 0.17-0.83, P = .003). There were no differences in days spent living in the community following discharge or in spending. Increases in reperfusion treatment were largest in the lowest-volume hospitals, among rural residents, and among patients 85 years and older. Conclusions and Relevance: Patients with ischemic stroke treated at hospitals with telestroke capacity were more likely to receive reperfusion treatment and have lower 30-day mortality.

Bioterrorism: class A agents and their potential presentations in immunocompromised patients.

A bioterrorism attack would be particularly challenging for medical professionals caring for patients with cancer who often have weakened immune systems. Knowledge of the class A agents and the potential variable presentations in immunocompromised patients is key to early recognition of an outbreak and prompt reporting. The purpose of this article is to present the class A agents: Bacillus anthracis (anthrax), botulinum toxin (botulism), variola virus (smallpox), Yersinia pestis (pneumonic plague), and Francisella tularensis (tularemia). The variable signs and symptoms that may be present in immunocompromised patients with cancer will be discussed with a focus on assessment and early recognition of an outbreak. The availability of vaccines and the implications for patients with cancer receiving these vaccines also will be discussed.

Influence of the copper-induced viable but non-culturable state on the toxicity of Pseudomonas aeruginosa towards human bronchial epithelial cells in vitro.

The viable but non-culturable (VBNC) state of the opportunistic bacterium Pseudomonas aeruginosa was previously shown to be induced by copper ions in concentrations relevant to those in drinking water plumbing systems. This decrease of bacterial culturability without loss of viability might have an influence on human health due to an underestimation of the actual contamination in drinking water systems. The aim of this study was to investigate the influence of culturable P. aeruginosa, viable but not culturable as well as culturable again after resuscitation from the VBNC state on human bronchial epithelial cells (BEAS-2B) in vitro. Cyto- and genotoxic effects of P. aeruginosa at different states were studied using trypan blue, MTT, xCELLigence as well as the micronucleus assay. While P. aeruginosa in the VBNC state did not have any cytotoxic or genotoxic effect on BEAS-2B cells, untreated (culturable) and resuscitated P. aeruginosa did show cell damage, including disruption of cell membranes, inhibition of mitochondrial activity and cell proliferation as well as DNA-damaging effects. We conclude from our study that P. aeruginosa after resuscitation from the VBNC state regains its viability and cyto-/genotoxicity and therefore might influence human health.

Toxicity of the micropollutants Bisphenol A, Ciprofloxacin, Metoprolol and Sulfamethoxazole in water samples before and after the oxidative treatment.

The amount of organic micropollutants detected in surface waters increases steadily. Common waste water treatment plants are not built to remove these substances. Thus there is a need for new technologies. A promising technology is the use of advanced oxidation processes through which organic micropollutants can be removed from waste water. However, the formation of oxidation by-products is likely and needs to be investigated since the by-products not only differ from their parent compounds in regard to their chemical and physical properties but they can also differ in toxicity. Therefore this study was designed to combine chemical and toxicological analyses of the advanced oxidation (O3 [5mg/L] or UV/H2O2 [Hg-LP lamp; 15W; 1g/L H2O2]) of waste water treatment plant effluents and pure water. Effluent samples from conventional activated sludge waste water treatment (mechanical treatment, activated sludge basin, and primary as well as secondary treatment steps) and high-purity deionized water (pure water) were spiked with Bisphenol A, Ciprofloxacin, Metoprolol or Sulfamethoxazole and treated with O3 or UV/H2O2. For the toxicological analyses mammalian cells (CHO-9, T47D) were exposed to the water samples for 24h and were tested for cytotoxicity (MTT Test), genotoxicity (Alkaline Comet Assay) and estrogenicity (ER Calux(®)). The results indicate that the oxidative treatment (O3 or UV/H2O2) of Bisphenol A, Metoprolol, Sulfamethoxazole or Ciprofloxacin in waste water did not result in toxic oxidation by-products, whereas the UV/H2O2 treatment of Bisphenol A and Ciprofloxacin in pure water resulted in by-products with cytotoxic but no estrogenic effects after 60min.

Case of vemurafenib-induced Sweet's syndrome.

Vemurafenib is a targeted therapy that has become standard treatment for patients with advanced melanoma with a V600E BRAF mutation. It has been associated with frequent skin toxicity, including photosensitivity, rash and squamous cell carcinomas. We present an 83-year-old woman with an advanced V600E BRAF-mutant melanoma who developed a severe skin rash and fatigue after taking vemurafenib. The dose was reduced from 960 to 720 to 480 mg twice a day; however, she was subsequently admitted to the hospital with fever, chills, fatigue, confusion and a diffuse skin eruption. She then developed hypoxia and acute renal failure that required hemodialysis. A biopsy of her skin lesions revealed a neutrophilic dermatitis with papillary dermal edema, consistent with Sweet's syndrome. Her symptoms resolved upon discontinuation of vemurafenib and treatment with prednisone. This constellation of symptoms and clinical course are consistent with drug-induced Sweet's syndrome caused by vemurafenib.

Kinesin-5: cross-bridging mechanism to targeted clinical therapy.

Kinesin motor proteins comprise an ATPase superfamily that works hand in hand with microtubules in every eukaryote. The mitotic kinesins, by virtue of their potential therapeutic role in cancerous cells, have been a major focus of research for the past 28 years since the discovery of the canonical Kinesin-1 heavy chain. Perhaps the simplest player in mitotic spindle assembly, Kinesin-5 (also known as Kif11, Eg5, or kinesin spindle protein, KSP) is a plus-end-directed motor localized to interpolar spindle microtubules and to the spindle poles. Comprised of a homotetramer complex, its function primarily is to slide anti-parallel microtubules apart from one another. Based on multi-faceted analyses of this motor from numerous laboratories over the years, we have learned a great deal about the function of this motor at the atomic level for catalysis and as an integrated element of the cytoskeleton. These data have, in turn, informed the function of motile kinesins on the whole, as well as spearheaded integrative models of the mitotic apparatus in particular and regulation of the microtubule cytoskeleton in general. We review what is known about how this nanomotor works, its place inside the cytoskeleton of cells, and its small-molecule inhibitors that provide a toolbox for understanding motor function and for anticancer treatment in the clinic.