Search

Individualized genetic therapies-medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one-offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experience, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) individualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next generation of targeted individualized therapeutics.

BACKGROUND: Surgeons have come under increased scrutiny for postoperative pain management, particularly for opioid prescribing. To decrease opioid use but still provide pain control, nonopioid medications such as muscle relaxants are being used, which can be harmful in older adults. However, the prevalence of muscle relaxant prescribing, trends in use over time, and risk of prolonged use are unknown. STUDY DESIGN: Using a 20% representative Medicare sample, we conducted a retrospective analysis of muscle relaxant prescribing to patients ≥ 65 years of age. We merged patient data from Medicare Carrier, MedPAR, and Outpatient Files with Medicare Part D for the years 2013-2018. A total of 14 surgical procedures were included to represent a wide range of anatomic regions and specialties. RESULTS: The study cohort included 543,929 patients. Of the cohort, 8111 (1.5%) received a new muscle relaxant prescription at discharge. Spine procedures accounted for 12% of all procedures but 56% of postoperative prescribing. Overall, the rate of prescribing increased over the time period (1.4-2.0%, p < 0.001), with increases in prescribing primarily in the spine (7-9.6%, p < 0.0001) and orthopedic procedure groups (0.9-1.4%, p < 0.0001). Of patients discharged with a new muscle relaxant prescription, 10.7% had prolonged use. CONCLUSIONS: The use of muscle relaxants in the postoperative period for older adults is low, but increasing over time, especially in ortho and spine procedures. While pain control after surgery is crucial, surgeons should carefully consider the risks of muscle relaxant use, especially for older adults who are at higher risk for medication-related problems.

Motor vehicles are among the major sources of pollutants and greenhouse gases in urban areas and a transition to "zero emission vehicles" is underway worldwide. However, emissions associated with brake and tire wear will remain. We show here that previously unrecognized volatile and semi-volatile organic compounds, which have a similarity to biomass burning emissions are emitted during braking. These include greenhouse gases or, these classified as Hazardous Air Pollutants, as well as nitrogen-containing organics, nitrogen oxides and ammonia. The distribution and reactivity of these gaseous emissions are such that they can react in air to form ozone and other secondary pollutants with adverse health and climate consequences. Some of the compounds may prove to be unique markers of brake emissions. At higher temperatures, nucleation and growth of nanoparticles is also observed. Regions with high traffic, which are often disadvantaged communities, as well as commuters can be impacted by these emissions even after combustion-powered vehicles are phased out.

Emerging contaminants (EC) distributed on surfaces in the environment can be oxidized by gas phase species (top-down) or by oxidants generated by the underlying substrate (bottom-up). One class of EC is the neonicotinoid (NN) pesticides that are widely distributed in air, water, and on plant and soil surfaces as well as on airborne dust and building materials. This study investigates the OH oxidation of the systemic NN pesticide acetamiprid (ACM) at room temperature. ACM on particles and as thin films on solid substrates were oxidized by OH radicals either from the gas phase or from an underlying TiO2 or NaNO2 substrate, and for comparison, in the aqueous phase. The site of OH attack is both the secondary >CH2 group as well as the primary -CH3 group attached to the tertiary amine nitrogen, with the latter dominating. In the case of top-down oxidation of ACM by gas phase OH radicals, addition to the -CN group also occurs. Major products are carbonyls and alcohols, but in the presence of sufficient water, their hydrolyzed products dominate. Kinetics measurements show ACM is more reactive toward gas phase OH radicals than other NN nitroguanidines, with an atmospheric lifetime of a few days. Bottom-up oxidation of ACM on TiO2 exposed to sunlight outdoors (temperatures were above 30 °C) was also shown to occur and is likely to be competitive with top-down oxidation. These findings highlight the different potential oxidation processes for EC and provide key data for assessing their environmental fates and toxicologies.

Abstract Background Recent evidence suggests that diabetes-related lower-extremity complications (DRLECs) may be associated with cognitive changes in people with diabetes. However, existing literature has produced inconsistent findings, and no systematic reviews have been conducted to investigate whether DRLECs impact the cognition of people with diabetes. This systematic review evaluated existing studies that investigated cognition in people with diabetes with DRLECs and without DRLECs. Method Seven databases; MEDLINE, PubMed, CINAHL, EMBASE, Cochrane, PsycINFO and Web of Science were searched from inception until 22/8/2022 for studies that compared cognition in people with diabetes with and without DRLECs. Results were independently screened for eligibility and assessed for methodological quality by two authors, with key data extracted. Studies were eligible for meta-analysis if the studies reported similar cases, controls, and outcome measures. Results Thirteen studies were included in the review, with eleven of medium methodological quality, one of high quality, and one of low quality. Four studies found significant differences in cognition between those with and without DRLECs, four found significant associations between diabetes-related lower-extremity complications and cognition, and five found no differences or associations. One small meta-analysis of eligible studies found that there was no statistically significant difference in cognition in people without, compared to with, peripheral neuropathy (Mean difference = -0.49; 95%CI: -1.59–0.61; N = 3; n = 215). Leave-one-out sensitivity analyses further confirmed that there was no significant difference in cognition among people with and without peripheral neuropathy (p > 0.05). Conclusion DRLECs may be related to cognition in people with diabetes, however, existing evidence is unclear due to variability in used methodologies that may challenge concluding the findings. Future high-quality studies investigating cognition among people with and without DRLECs are needed.

Abstract Analyzing root exudates during drought poses a serious challenge; sampling root exudates in soil is destructive to roots and leads to biased molecular analysis, along with microbial decomposition and exudate sorption to soil components. Hydroponic approaches are useful to overcome these problems but lack the utility to induce drought. Nondestructive sampling techniques are thus needed to analyze root exudates from the same plants over time in combination with highly controlled variable water/nutrient stress. The proposed aeroponic approach demonstrated that cotton could be grown to maturity in the aeroponic system, then a progressive drought treatment applied while simultaneously collecting root exudates from the same plants over time. Treatments of varying irrigation rates consisted of well-watered cotton (control) that was compared to cotton given progressive water stress (drought) and subsequent drought recovery for two weeks. Plants were entering flowering as drought treatment was applied. Nondestructive morphological measurements of plant productivity were made. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was employed to analyze the molecular profile of exudates, whereas gas chromatography-mass spectroscopy (GC-MS) was used to quantify abscisic acid (ABA). Plant development was highly responsive to reduced irrigation intervals with decreased canopy height, number of green leaves, biomass, and water content. As revealed by FT-ICR MS, the complexity and connectivity of unique biochemical transformation networks in response to drought was greatest at 9 days after treatment, where severe visual symptoms were observed. Overall, the aeroponic approach is a promising technology to simulate drought while sampling root exudates nondestructively, advancing root system research and plant-stress response mechanisms.

Abstract Individualized genetic therapies—medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one—offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experience, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) individualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next generation of targeted individualized therapeutics.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic made it necessary to practice social distancing and limited in-person encounters in health care. These restrictions created alternative opportunities to enhance patient access to care in the ambulatory setting. We hypothesized that by transforming clinics into centers that prioritize procedures and transitioning ambulatory appointments to telehealth, we could establish a secure, streamlined, and productive method for providing patient care. Methods: Clinic templates were restructured to allow the use of the physical space to perform procedure-based clinics exclusively, while switching to virtual telemedicine for all nonprocedural encounters. Staff members were given specific roles to support one of the patient care modalities for a given day (Procedures vs. Telehealth). Performance and patient satisfaction metrics were collected between two periods of time defined as P1 (February-June 2019) and P2 Post-COVID (February-June 2020) and compared. These served as proxies of periods when the clinic workflow and templates were structured in the traditional versus the emerging way. Statistical analysis was performed using bivariate analyses. Results: The percentage of procedures performed among all in-person visits were higher in P2 compared to P1 (45% vs. 29%, p < 0.001). Although total charges and relative value units were lower in P2, the overall revenue generated was higher compared to P1 ($4,597,846 vs. $4,517,427$, respectively). This increase in revenue was mainly driven by the higher relative income generated by procedures. Patient experience, reflected through patient-reported outcomes, was more favorable in P2 where patients seemed more likely to "Recommend this provider office" (90% vs. 85.7%, p = 0.01), report improved "Access overall" (56% vs. 49%, p = 0.02), and felt they were "Moving through your visit overall" (59% vs. 51%, p = 0.007). Conclusions: Our data suggest that reorganizing urology clinics into a space that is centered around outpatient procedures can represent a model that improves the patient's access to care and clinical experience, while simultaneously improving operational financial strength. This efficient care model could be considered for many practice settings and drive high-value outpatient care.

BACKGROUND: For patients who may permanently or temporarily lose their ability to communicate preferences, advance care planning is a critical mechanism to guide medical decision-making but is currently underused among surgical patients. METHODS: A resident-led quality improvement project, including education and performance measurement, was conducted on an emergency general surgery service to increase the completion of inpatient advance care planning notes using a specialized template in the electronic health record. Advance care planning documentation was defined as either preadmission advance care planning documentation (eg, advance directive) or inpatient advance care planning (use of the electronic health record template). Data from patients admitted to the emergency general surgery service for 12+ hours were analyzed, and baseline data (July 2020 to June 2021) were compared with data from the intervention period (July 2021 to June 2022). The chart review evaluated the content of the inpatient advance care planning documentation from the intervention period. RESULTS: The frequency of inpatient advance care planning documentation increased (9.3%, n = 56 to 16.6%, n = 92, P < .001) with a greater contribution of inpatient advance care planning notes by the surgery team (16.7% to 55.4%) in the intervention period. Content analysis indicated that 79.0% of inpatient advance care planning notes listed preferences for life-sustaining therapy, 78.3% listed surrogacy, 57.3% listed overall health goals, and 50.3% listed treatment goals specific to the surgical encounter. CONCLUSION: Although a resident-led quality improvement project contributed to greater adoption of standardized inpatient advance care planning documentation on an emergency general surgery service, progress was slow, and integration into standard work was not achieved. Future efforts are needed to better understand the integration of essential advance care planning elements into workflows and to establish inclusive educational programming to prepare all team members for conducting and documenting advance care planning conversations.

Abstract Until recent events, the Antarctic was the only major geographical region in which high pathogenicity avian influenza virus (HPAIV) had never previously been detected. Here we report on the detection of clade 2.3.4.4b H5N1 HPAIV in the Antarctic and sub-Antarctic regions of South Georgia and the Falkland Islands, respectively. We initially detected H5N1 HPAIV in samples collected from brown skuas at Bird Island, South Georgia on 8th October 2023. Since this detection, mortalities were observed in several avian and mammalian species at multiple sites across South Georgia. Subsequent testing confirmed H5N1 HPAIV across several sampling locations in multiple avian species and two seal species. Simultaneously, we also confirmed H5N1 HPAIV in southern fulmar and black-browed albatross in the Falkland Islands. Genetic assessment of the virus indicates spread from South America, likely through movement of migratory birds. Critically, genetic assessment of sequences from mammalian species demonstrates no increased risk to human populations above that observed in other instances of mammalian infections globally. Here we describe the detection, species impact and genetic composition of the virus and propose both introductory routes and potential long-term impact on avian and mammalian species across the Antarctic region. We also speculate on the threat to specific populations following recent reports in the area.

Organic peroxides are key intermediates in the atmosphere but are challenging to detect, especially in the particle phase, due to their instability, which has led to substantial gaps in the understanding of their environmental effects. We demonstrate that matrix-assisted ionization in vacuum (MAIV) mass spectrometry (MS), which does not require an ionization source, enables in situ characterization of peroxides and other products in the surface layers of organic particles. Hydroxyl radical oxidation of glutaric acid particles yields hydroperoxides and organic peroxides, which were detected with signals of the same order of magnitude as the major, more stable products. Product identification is supported by MS/MS analysis, peroxide standards, and offline high-resolution MS. The peroxide signals relative to the stable carbonyl and alcohol products are significantly larger using MAIV compared to those in the offline bulk analysis. This is also the case for analysis using fast, online easy ambient sonic-spray ionization mass spectrometry. These studies demonstrate the advantage of MAIV for the real-time characterization of labile peroxides in the surface layers of solid particles. The presence of peroxides on the surface may be important for surface oxidation processes as well as for the toxicity of inhaled particles.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to