Research in the USA on COVID-19's long-term effects: measures needed to ensure black, indigenous and Latinx communities are not left behind.

The SARS-CoV-2 (COVID-19) pandemic continues to expose underlying inequities in healthcare for black, indigenous and Latinx communities in the USA. The gaps in equitable care for communities of colour transcend the diagnosis, treatment and vaccinations related to COVID-19. We are experiencing a continued gap across racial and socioeconomic lines for those who suffer prolonged effects of COVID-19, also known as 'Long COVID-19'. What we know about the treatment for Long COVID-19 so far is that it is complex, requires a multidisciplinary approach and there is still much research needed to fully understand the effects. In this paper, we discuss pragmatic considerations for including affected communities, relevant stakeholders, and leaders from communities of colour in the planning and implementation of Long COVID-19 research.

Nucleophilic Neutralization of Organophosphates: Lack of Selectivity or Plenty of Versatility?

Neutralization of organophosphates is an issue of public health and safety, involving agrochemicals and chemical warfare. A promising approach is the nucleophilic neutralization, scope of this review, which focuses on the molecular nucleophiles: hydroxide, imidazole derivatives, alpha nucleophiles, amines and other nucleophiles. A reactivity mapping is given correlating the pathways and reaction efficiency with structural dependence of the nucleophile (basicity) and the organophosphate (electrophilic centers, P=O/P=S shift, leaving and non-leaving group). Reactions extremely unfavorable (>20 years) can be reduced to seconds with various nucleophiles, some which are catalytic. Although there is no universal nucleophile, a lack of selectivity in some cases accounts for plenty of versatility in other reactions. The ideal neutralization requires a solid mechanistic understanding, together with balancing factors such as milder conditions, fast process, selectivity and less toxic products.

Pragmatic patient engagement in designing pragmatic oncology clinical trials.

Oncology trials are the cornerstone of effective and safe therapeutic discoveries. However, there is increasing demand for pragmatism and patient engagement in the design, implementation and dissemination of oncology trials. Many researchers are uncertain about making trials more practical and even less knowledgeable about how to meaningfully engage patients without compromising scientific rigor to meet regulatory requirements. The present work provides practical guidance for addressing both pragmaticism and meaningful patient engagement. Applying evidence-based approaches like PRECIS-2-tool and the 10-Step Engagement Framework offer practical guidance to make future trials in oncology truly pragmatic and patient-centered. Consequently, such patient-centered trials have improved participation, faster recruitment and greater retention, and uptake of innovative technologies in community-based care.

Patient and Provider Acceptability of a Patient Preauthorized Concealed Opioid Reduction.

OBJECTIVE: Limited research of how to best taper opioids brings about an ethical and clinical dilemma. Experiments using overt and concealed administration of opioids have demonstrated the benefits of a concealed reduction to eliminate negative expectations and prolong analgesic benefits. This may allow for opioid tapering without significant increases in pain. Based on this, we investigated patient and provider acceptance of a concealed opioid reduction for chronic pain. METHODS: We conducted a cross-sectional survey via REDcap with 74 patients, who are currently taking or have taken high dose opioids, and 49 providers using a validated questionnaire based on two hypothetical clinical trials comparing a patient preauthorized concealed opioid reduction vs standard tapering. RESULTS: We found that patients and providers have positive attitudes toward a concealed reduction of opioid dosages. More than 60% of providers and patients surveyed viewed the hypothetical clinical trial as helpful to reduce pain, side effects, and withdrawal symptoms. Sixty-one percent of patients and 77.6% of providers recognized that there would be differences in pain relief depending upon which group the hypothetical participants would be enrolled in. CONCLUSIONS: Patients and providers appear to understand the benefits of a concealed opioid reduction. Our findings support future randomized controlled trials that compare concealed and overt opioid tapering in patients with chronic pain. More research is needed to understand the difference in attitudes between research and clinical practice and to test the acceptability of a concealed reduction following a participation in an active clinical trial.

Patient-reported outcomes in women with breast cancer enrolled in a dual-center, double-blind, randomized controlled trial assessing the effect of acupuncture in reducing aromatase inhibitor-induced musculoskeletal symptoms.

BACKGROUND: Aromatase inhibitors (AIs) have been associated with decrements in patient-reported outcomes (PROs). The objective of this study was to assess whether real acupuncture (RA), compared with sham acupuncture (SA), improves PROs in patients with breast cancer who are receiving an adjuvant AI. METHODS: Postmenopausal women with a stage 0 through III breast cancer who received an AI and had treatment-associated musculoskeletal symptoms were randomized to receive 8 weekly RA versus SA in a dual-center, randomized controlled trial. The National Surgical Adjuvant Breast and Bowel Project (NSABP) menopausal symptoms questionnaire, the Center for Epidemiological Studies Depression (CESD) scale, the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), the hot flash daily diary, the Hot Flash-Related Daily Interference Scale (HFRDI), and the European quality-of-life survey (EuroQol) were used to assess PROs at baseline and at 4weeks, 8 weeks, and 12 weeks. RESULTS: The intention-to-treat analysis included 23 patients in the RA arm and 24 patients in the SA arm. There were no significant differences in baseline characteristics between the 2 groups. Compared with baseline, scores in the RA arm improved significantly at week 8 on the CESD (P = .022), hot flash severity (P = .006), hot flash frequency (P = .011), the HFRDI (P = .014), and NSABP menopausal symptoms (P = .022); scores in the SA arm improved significantly on the EuroQol (P = .022),the HFRDI (P = .043), and NSABP menopausal symptoms (P = .005). Post-hoc analysis indicated that African American patients (n = 9) benefited more from RA than SA compared with non-African American patients (n = 38) in reducing hot flash severity (P < .001) and frequency (P < .001) scores. CONCLUSIONS: Both RA and SA were associated with improvement in PROs among patients with breast cancer who were receiving AIs, and no significant difference was detected between arms. Racial differences in response to acupuncture warrant further study.

Community-Academic Partnerships for Health Research: An Iterative and Transparent Process of Patient Engagement Before the Research Begins.

Background: The root causes of coronavirus disease 2019 (COVID-19) disparities include longstanding systemic racial bias in economic advancement and care delivery, discrimination, lack of access, and social determinants of health. To address these causes, research institutions and health care systems must shift their lens from one that focuses solely on changing behaviors among underserved and vulnerable populations to one that is inward facing. Methods: We worked with a community advisory board and an African American church that has partnered on research for more than a decade to identify community norms, needs, and key resources needed for establishing community-academic partnerships for COVID-19 testing. Participants were purposefully sampled with equal representation from 3 groups: (1) church members and leaders, (2) academic or organization researchers with experience in community-engaged research, and (3) community members with experience participating in community-engaged research. Participants engaged in a hands-on exercise in the church basement as part of a town hall-style meeting. Results: Active discussion led to the identification of business model components salient to COVID-19 testing in an underserved Baltimore community, predominantly made up of African Americans. Our discussion identified key partners, activities, resources, costs, value propositions, community relationships, community groups, communication channels, and outputs for community buy-in. Conclusion: Developing the business case for mutual trustworthiness to be better prepared for future pandemics and public health crises may foster more sustainable community-academic partnerships. Using a Business Model Canvas, we delineate the major components, activities, and value propositions that are needed to achieve authentic community-academic partnerships to advance health equity.

A dual-center randomized controlled double blind trial assessing the effect of acupuncture in reducing musculoskeletal symptoms in breast cancer patients taking aromatase inhibitors.

Up to 50 % of women receiving aromatase inhibitor (AI) complain of AI-associated musculoskeletal symptoms (AIMSS) and 15 % discontinue treatment. We conducted a randomized, sham-controlled trial to evaluate whether acupuncture improves AIMSS and to explore potential mechanisms. Postmenopausal women with early stage breast cancer, experiencing AIMSS were randomized to eight weekly real or sham acupuncture sessions. We evaluated changes in the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain visual analog scale (VAS) following the intervention compared to baseline. Serum estradiol, ß-endorphin, and proinflammatory cytokine concentrations were measured pre and post-intervention. We enrolled 51 women of whom 47 were evaluable, including 23 randomized to real and 24 to sham acupuncture. Baseline characteristics were balanced between groups with the exception of a higher HAQ-DI score in the real acupuncture group (p = 0.047). We did not observe a statistically significant difference in reduction of HAQ-DI (p = 0.30) or VAS (p = 0.31) between the two groups. Following eight weekly treatments, we observed a statistically significant reduction of IL-17 (p ≤ 0.009) in both groups. No significant modulation was seen in estradiol, ß-endorphin, or other proinflammatory cytokine concentrations in either group. We did not observe a significant difference in AIMSS changes between real and sham acupuncture. As sham acupuncture used in this study may not be equivalent to placebo, further studies with a non-acupuncture arm may be required to establish whether acupuncture is beneficial for the treatment of AIMSS.

Intramolecular general base catalysis in the hydrolysis of a phosphate diester. Calculational guidance to a choice of mechanism.

Notwithstanding its half-life of 70 years at 25 °C, the spontaneous hydrolysis of the anion of di-2-pyridyl phosphate (DPP) is thousands of times faster (ca. 3000 at 100 °C, over 10000-fold at 25 °C) than expected for a diester with leaving groups of pK(a) 9.09. The kinetic parameters do not permit a conclusive choice between five possible mechanisms considered, but the combination of kinetics and calculational evidence supports a single-step, concerted, S(N)2(P) mechanism involving the attack of solvent water on phosphorus assisted by intramolecular catalysis by a (weakly basic) pyridine nitrogen acting as a general base. Catalysis is relatively efficient for this mechanism, with an estimated effective molarity (EM) of the general base of >15 M, consistent with the absence of catalysis by typical buffers. Further new results confirm that varying the nonleaving group has minimal effect on the rate of spontaneous diester hydrolysis, in striking contrast to the major effect on the corresponding reaction of triesters: though protonation of one nitrogen of DPP(-) increases the rate of hydrolysis by 6 orders of magnitude, in line with expectation.

Major mechanistic differences between the reactions of hydroxylamine with phosphate di- and tri-esters.

Hydroxylamine reacts as an oxygen nucleophile, most likely via its ammonia oxide tautomer, towards both phosphate di- and triesters of 2-hydroxypyridine. But the reactions are very different. The product of the two-step reaction with the triester TPP is trapped by the NH2OH present in solution to generate diimide, identified from its expected disproportionation and trapping products. The reaction with H3N(+)-O(-) shows general base catalysis, which calculations show is involved in the breakdown of the phosphorane addition-intermediate of a two-step reaction. The reactivity of the diester anion DPP(-) is controlled by its more basic pyridyl N. Hydroxylamine reacts preferentially with the substrate zwitterion DPP(±) to displace first one then a second 2-pyridone, in concerted S(N)2(P) reactions, forming O-phosphorylated products which are readily hydrolysed to inorganic phosphate. The suggested mechanisms are tested and supported by extensive theoretical calculations.

Targeted Glioblastoma Treatment via Synthesis and Functionalization of Gold Nanoparticles With De Novo-Engineered Transferrin-Like Peptides: Protocol for a Novel Method.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options due to the blood-brain barrier's (BBB's) impedance and inherent resistance to chemotherapy. Gold nanoparticles (AuNPs) functionalized with transferrin-like peptides show promise in overcoming these challenges, enhancing drug delivery to the brain, and reducing chemotherapy resistance. OBJECTIVE: The primary goal of this study is to establish a detailed protocol for synthesizing and stabilizing AuNPs, functionalizing them with de novo-engineered transferrin-like peptides, and conjugating them with the chemotherapeutic agent temozolomide. This strategy aims to improve drug delivery across the BBB and circumvent chemotherapy resistance. The secondary objective includes an assessment of the safety and potential for in vivo use of the synthesized nanoparticle complex. METHODS: The proposal involves multiple steps with rigorous quality control of AuNP synthesis, stabilization with surfactants, and polyethylene glycol coating. The engineered transferrin-like peptides will be synthesized and attached to the AuNPs' surface, followed by the attachment of temozolomide and O6-methylguanine-DNA methyltransferase inhibitors. The resulting complex will undergo in vitro testing to assess BBB penetration, efficacy against GBM cells, and potential toxicity. RESULTS: Initial preliminary experiments and simulations suggest successful synthesis and stabilization of AuNPs and effective attachment of transferrin-like peptides. We propose peptide attachment verification using Fourier transform infrared spectroscopy and surface plasmon resonance. Additionally, we will conduct pH stability tests to ensure our functionalized AuNPs retain their properties in acidic brain tumor microenvironments. CONCLUSIONS: The proposed functionalization of AuNPs with de novo-engineered transferrin-like peptides represents a novel approach to GBM treatment. Our strategy opens new avenues for drug delivery across the BBB and chemotherapy resistance reduction. While we primarily focus on in vitro studies and computational modeling at this stage, successful completion will lead to further development, including in vivo studies and nanoparticle design optimization. This proposal anticipates inspiring future research and funding in neuro-oncology, presenting a potentially innovative and effective treatment option for GBM. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/49417.

Pragmatic design and inclusion of patient-partner representatives improves participant experience in clinical research.

Objectives: Patient engagement in the design and implementation of clinical trials is necessary to ensure that the research is relevant and responsive to patients. The PREP-IT trials, which include 2 pragmatic trials that evaluate different surgical preparation solutions in orthopaedic trauma patients, followed the patient-centered outcomes research (PCOR) methodology throughout the design, implementation, and conduct. We conducted a substudy within the PREP-IT trials to explore participants' experiences with trial participation. Methods: At the final follow-up visit (12 months after their fracture), patients participating in the PREP-IT trials were invited to participate in the substudy. After providing informed consent, participants completed a questionnaire that asked about their experience and satisfaction with participating in the PREP-IT trials. Descriptive statistics are used to report the findings. Results: Four hundred two participants participated in the substudy. Most participants (394 [98%]) reported a positive experience, and 376 (94%) participants felt their contributions were appreciated. The primary reasons for participation were helping future patients with fracture (279 [69%]) and to contribute to science (223 [56%]). Two hundred seventeen (46%) participants indicated that their decision to participate was influenced by the minimal time commitment. Conclusions: Most participants reported a positive experience with participating in the PREP-IT trials. Altruism was the largest motivator for participating in this research. Approximately half of the participants indicated that the pragmatic, low-participant burden design of the trial influenced their decision to participate. Meaningful patient engagement, a pragmatic, and low-burden protocol led to high levels of participant satisfaction.

Dephosphorylation reactions of mono-, di-, and triesters of 2,4-dinitrophenyl phosphate with deferoxamine and benzohydroxamic acid.

This work presents a detailed kinetic and mechanistic study of biologically interesting dephosphorylation reactions involving the exceptionally reactive nucleophilic group, hydroxamate. We compare results for hydroxamate groups anchored on the simple molecular backbone of benzohydroxamate (BHA) and on the more complex structure of the widely used drug, deferoxamine (DFO). BHA shows extraordinary reactivity toward the triester diethyl 2,4-dinitrophenyl phosphate (DEDNPP) and the diester ethyl 2,4-dinitrophenyl phosphate (EDNPP) but reacts very slowly with the monoester 2,4-dinitrophenyl phosphate (DNPP). Nucleophilic attack on phosphorus is confirmed by the detection of the phosphorylated intermediates formed. These undergo Lossen-type rearrangements, resulting in the decomposition of the nucleophile. DFO, which is used therapeutically for the treatment of acute iron intoxication, carries three hydroxamate groups and shows correspondingly high nucleophilic activity toward both triester DEDNPP and diester EDNPP. This result suggests a potential use for DFO in cases of acute poisoning with phosphorus pesticides.

Developing patient-centered outcomes research infrastructure in a rural community through patient and stakeholder engagement and education during the COVID-19 pandemic.

In addition to facing numerous healthcare disparities, rural America is chronically underrepresented in clinical research. This gap was made more evident during the COVID-19 pandemic. St Lawrence Health, located in rural Upstate New York, established its Clinical and Rural Health Research Department in 2015 to help close this gap. The research department then launched the DISRUPTS (Developing InfraStructure for Research to Utilize Patient-centered Techniques at St Lawrence Health System) program to build the infrastructure to conduct Patient-Centered Outcomes Research (PCOR). Together with a diverse committee, the team used proven methods and frameworks to develop a model for engagement, content creation, and education delivery that was successfully used to create educational programs on PCOR and COVID-19. The resulting DISRUPTS webinars had a combined total of over 450 live attendees and over 1,110 views on recordings. Furthermore, nearly one-third of those who participated in the COVID-19 vaccines webinar indicated they were more likely to receive a COVID-19 vaccine after taking part. DISRUPTS can serve as an important model for other rural communities that aim to increase access to and engagement in PCOR, and which hope to improve outreach and education efforts in their communities.

Epidemiological profile of dog attacks to patients under 14 years old assisted at the pediatric referral emergency unit of a tertiary hospital in Campinas, Brazil.

Introduction: Accidents involving dog attacks are very common, which makes this type of accident a global public health issue. The estimates point to 20% of the victims of such accidents seeking care in health units, and half of them being children. In addition to acute injuries, dog attacks might result in fractures, infections, scars, and psychological traumas. This study aimed to describe the epidemiological profile of dog attacks to children under 14 years old assisted in a pediatric emergency service in Brazil. Methods: The database of the Information and Toxicological Assistance Center of Campinas was surveyed to identify cases of children under 14 years old assisted after a dog attack in a 9-years period. Demographic data, number and type of lesions, type of exposure, part of the body affected, dog origin and condition, and the accident location and cause were analyzed. The data were presented in a descriptive way, and the age groups were classified as follows: 0-3 years old, 4-6 years old, and 7-14 years old. The different age groups were compared one to another regarding the markers evaluated using the chi-square test and the Fisher's exact test. A 0.05 alpha was adopted in all analyses. Results: The number of children assisted in the study period totaled 1,012. The 7-14-year-old group was the most affected (n = 498; 49.2%), male patients were also majority (n = 660; 65.2%). Most injuries were found on the head/neck area (n = 378; 37.4%). However, the older the patients were, the higher the frequency of lesions on upper and lower limbs was, as well as attacks occurred in external environments, thus involving animals that could not be observed. A significant increase in accidents with provoked causes was observed in younger patients. Conclusion: Accidents involving dog attacks are more likely to happen among boys. Younger children run higher risks of becoming victims of these accidents inside homes, being attacked by pets, and showing a greater incidence of head and neck lesions. Older children present more injuries on their limbs, which are caused by dogs that cannot be observed.

Storytelling training to promote stakeholder engagement in research dissemination.

Storytelling is increasingly recognized as a culturally relevant, human-centered strategy and has been linked to improvements in health knowledge, behavior, and outcomes. The Community Engagement Program of the Johns Hopkins Institute for Clinical and Translational Research designed and implemented a storytelling training program as a potentially versatile approach to promote stakeholder engagement. Data collected from multiple sources, including participant ratings, responses to open-ended questions, and field notes, consistently pointed to high-level satisfaction and acceptability of the program. As a next step, the storytelling training process and its impact need to be further investigated.

Activating water: important effects of non-leaving groups on the hydrolysis of phosphate triesters.

The high rate of spontaneous hydrolysis of tris-2-pyridyl phosphate (TPP) is explained by the activating effects of the non-leaving ("spectator") groups on P-OAr cleavage, and not by intramolecular catalysis. Previous work on phosphate-transfer reactions has concentrated on the contributions to reactivity of the nucleophile and the leaving group, but our results make clear that the effects of the non-leaving groups on phosphorus can be equally significant. Rate measurements for three series of phosphate triesters showed that sensitivities to the non-leaving groups are substantial for spontaneous hydrolysis reactions, although significantly smaller for reactions with good nucleophiles. There are clear differences between triaryl and dialkyl aryl triesters in sensitivities to leaving and non-leaving groups with the more reactive triaryl systems showing lower values for both ß(LG) and ß(NLG). Intramolecular catalysis of the hydrolysis of TPP by the neighbouring pyridine nitrogens is insignificant, primarily because of their low basicity.

Dephosphorylation reactions with deferoxamine, a potential chemical nuclease.

We report a detailed kinetic and mechanistic study of the reaction of a widely used therapeutic agent, deferoxamine (DFO), which contains three nucleophilic hydroxamate groups, with the model phosphate diester bis-2,4-dinitrophenylphosphate BDNPP. We clarify the mechanism by detecting important phosphorylated intermediates in the model reaction and show that the mechanism can be extended to the reaction with DNA. The effectiveness of DFO in cleaving DNA was examined over a range of pH in the absence and presence of a biologically available metal (Zn(2+)). The results inform and complement ongoing studies involving DFO, which can act as a powerful nucleophile toward DNA and other targets susceptible to nucleophilic attack.

Phosphorylimidazole derivatives: potentially biosignaling molecules.

The phosphorylation of imidazole by two activated phosphate diesters and a triester gives phosphorylimidazole derivatives that are stable enough in aqueous solution to be observed and identified by ESI-MS/MS and NMR. Half-lives ranging from hours to days (in the case of the monoethyl ester) show that it is possible to design molecules with variable half-lives with potential to be used for biological intervention experiments as possible inhibitors of biosignaling processes or as haptens for the generation of antibodies.

Implementing stakeholder engagement to explore alternative models of consent: An example from the PREP-IT trials.

INTRODUCTION: Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent. METHODS: The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have. RESULTS: Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation. DISCUSSION: Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal.

Efficient intramolecular general-acid catalysis of the reactions of alpha-effect nucleophiles and ammonia oxide with a phosphate triester.

The S(N)2(P) reactions with alpha-effect nucleophiles of the cationic form 1.H(+) of phosphate triester diethyl 8-(N,N-dimethylamino)-1-naphthyl phosphate are catalyzed by the neighboring dimethylammonium group, with accelerations as high as 10(6). Hydroxylamine and its N-methyl and N,N-dimethyl derivatives, which react through oxygen, we presume by way of the zwitterionic ammonia oxide tautomers, are of special interest. The alpha-effect and the efficient general-acid catalysis in this system are mutually reinforcing. The alpha-effect is greater for the reactions of the triester than for the corresponding mono- and diesters and qualitatively different for hydroxylamines RR'NOH, where the likely role of the ammonia oxide tautomer NH(3)(+)-O(-) is evaluated by ab initio calculations. The initial phosphorus-containing product NH(2)OPO(OEt)(2) reacts further with hydroxylamine to generate diethyl phosphate and diimide, identified by its disproportionation to hydrazine and N(2) and its reducing potential.