Results From La Vida Buena (The Good Life): A Quasi-Experimental Intervention of a Community Health Worker-Led Family-Based Childhood Obesity Program for Latino Children 5-8 Years of Age on the U.S.-Mexico Border.

OBJECTIVE: To evaluate the effectiveness of the 8-week, community health worker (CHW)-led La Vida Buena childhood obesity program among Latino children 5 to 8 years old in a rural county along the U.S.-Mexico border. METHODS: This quasi-experimental study used a community-based participatory research approach to compare the effectiveness of the La Vida Buena (The Good Life) curriculum as compared with a single educational session. We took anthropomorphic measures and administered parent-reported nutrition and physical activity surveys at baseline, 3 months, and 6 months. The study took place between 2017 and 2020 in Santa Cruz County, Arizona. RESULTS: Change in body mass index (BMI) z-score was negligible for both groups. The parent-reported behavior indicated a shift toward healthier family behaviors and environment in the intervention group. IMPLICATIONS FOR PRACTICE: This study adds to the growing literature of CHW-led childhood obesity interventions. The engagement of the CHWs in all aspects of the intervention helped to facilitate important behavior changes. Future interventions should emphasize health and wellness rather than BMI z-score and include community, socioeconomic, and systems-level interventions to promote healthy environments.

Synthesis and Anti-Hepatitis B Activities of 3'-Fluoro-2'-Substituted Apionucleosides.

Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2'-hydroxy- and 2'-hydroxymethyl-apionucleosides, 4 and 5, corresponding triphosphates and phosphoramidate prodrugs. Triphosphate 38 of 2'-hydroxymethyl-apionucleoside 5 exhibited potent inhibition of HBV polymerase with an IC50 value of 120 nM. In an HBV cell-based assay, the phosphoramidate prodrug 39 demonstrated potent activity with an EC50 value of 7.8 nM.

La Vida Buena (The Good Life) evaluation: a quasi experimental intervention of a community health worker-led family-based childhood obesity program for Latino children 5-8 years of age on the US-Mexico border.

BACKGROUND: Due to multiple and interacting factors, Latino children are disproportionately at risk for overweight and obesity in the United States. Childhood obesity increases the risk for adverse physical and psychosocial outcomes throughout the lifespan. Intensive behavioral interventions recommended in primary care settings may not conform to current practices, and the most vulnerable populations are often unable to access these services. Community Health Workers (CHWs) offer a promising approach to bridging the gap between vulnerable communities and culturally competent services. La Vida Buena (The Good Life) is an 8-week family-focused intervention for Latino children 5-8 years old and their parents or caregivers who are patients at a Federally-Qualified Community Health Center (FQHC). It is a culturally and linguistically appropriate curriculum, facilitated by CHWs, that targets family behaviors to foster a healthy lifestyle in order to prevent and mitigate childhood overweight and obesity. METHODS: The primary objective is to test the effectiveness of the La Vida Buena (LVB) childhood obesity program among Latino children 5-8 years old and their families as compared with a single educational session. This study uses a parallel two-arm quasi-experimental design. The intervention group receives the 8-week La Vida Buena intervention and the comparison group receives a single educational session. The primary outcome is the change in the child's BMI z-score from baseline to 6 months. DISCUSSION: The implementation and evaluation of La Vida Buena may inform research and practice for linking Latino patients in FQHCs to culturally responsive community-based childhood obesity interventions. It will also contribute to the literature about CHWs as facilitators of behavior change for families underserved by health services and preventive programs. La Vida Buena can serve as a culturally and linguistically appropriate early intervention curriculum that will foster a healthy home environment for childhood obesity mitigation and prevention. TRIAL REGISTRATION: The trial was retrospectively registered on December 18, 2018. The ClinicalTrials.gov Identifier is NCT03781856.

Media reporting of health interventions in New Zealand: a retrospective analysis.

AIM: To evaluate New Zealand media articles on their coverage of key issues regarding health interventions and whether it is consistent with available evidence. METHODS: A retrospective analysis was carried out of all articles published in five New Zealand media sources over a 6-week period between 15 October and 26 November 2014. Articles were included if their primary focus was on health interventions involving medications, devices or in-hospital procedures. Articles were assessed for coverage of key issues using previously validated 10-point criteria. A literature review was performed to compare content with scientific evidence. RESULTS: We identified 30 articles for review. Only 4 of 30 articles covered indications, benefits and risks, and of these, two were consistent with available evidence (7%, 95% CI 1%-22%). For articles that discussed at least one of indications, benefits or risks, and there was corresponding evidence available, there was a high level of consistency with the evidence (89%, 95% CI 77%-95%). The overall mean value of coverage from the 10-point criteria was 51% (95% CI 45%-58%). Single questions regarding the potential harm, costs associated with the intervention and the availability of alternative options were particularly poorly covered. They were rated as 'satisfactory' in 13%, 23% and 33% of the 30 articles respectively. CONCLUSION: New Zealand news articles covering medical treatments and interventions are largely consistent with available evidence but are incomplete. Vital information is being consistently missed, especially around the potential harms and costs of medical interventions.

Structure-activity relationship analysis of mitochondrial toxicity caused by antiviral ribonucleoside analogs.

Recent cases of severe toxicity during clinical trials have been associated with antiviral ribonucleoside analogs (e.g. INX-08189 and balapiravir). Some have hypothesized that the active metabolites of toxic ribonucleoside analogs, the triphosphate forms, inadvertently target human mitochondrial RNA polymerase (POLRMT), thus inhibiting mitochondrial RNA transcription and protein synthesis. Others have proposed that the prodrug moiety released from the ribonucleoside analogs might instead cause toxicity. Here, we report the mitochondrial effects of several clinically relevant and structurally diverse ribonucleoside analogs including NITD-008, T-705 (favipiravir), R1479 (parent nucleoside of balapiravir), PSI-7851 (sofosbuvir), and INX-08189 (BMS-986094). We found that efficient substrates and chain terminators of POLRMT, such as the nucleoside triphosphate forms of R1479, NITD-008, and INX-08189, are likely to cause mitochondrial toxicity in cells, while weaker chain terminators and inhibitors of POLRMT such as T-705 ribonucleoside triphosphate do not elicit strong in vitro mitochondrial effects. Within a fixed 3'-deoxy or 2'-C-methyl ribose scaffold, changing the base moiety of nucleotides did not strongly affect their inhibition constant (Ki) against POLRMT. By swapping the nucleoside and prodrug moieties of PSI-7851 and INX-08189, we demonstrated that the cell-based toxicity of INX-08189 is mainly caused by the nucleoside component of the molecule. Taken together, these results show that diverse 2' or 4' mono-substituted ribonucleoside scaffolds cause mitochondrial toxicity. Given the unpredictable structure-activity relationship of this ribonucleoside liability, we propose a rapid and systematic in vitro screen combining cell-based and biochemical assays to identify the early potential for mitochondrial toxicity.

Engineering Styrene Monooxygenase for Biocatalysis: Reductase-Epoxidase Fusion Proteins.

The enantioselective epoxidation of styrene and related compounds by two-component styrene monooxygenases (SMOs) has targeted these enzymes for development as biocatalysts. In the present work, we prepare genetically engineered fusion proteins that join the C-terminus of the epoxidase (StyA) to the N-terminus of the reductase (StyB) through a linker peptide and demonstrate their utility as biocatalysts in the synthesis of Tyrain purple and other indigoid dyes. A single-vector expression system offers a simplified platform for transformation and expansion of the catalytic function of styrene monooxygenases, and the resulting fusion proteins are self-regulated and couple efficiently NADH oxidation to styrene epoxidation. We find that the reductase domain proceeds through a sequential ternary-complex mechanism at low FAD concentration and a double-displacement mechanism at higher concentrations of FAD. Single-turnover studies indicate an observed rate constant for FAD-to-FAD hydride transfer of ~8 s-1. This step is rate limiting in the styrene epoxidation reaction and helps to ensure that flavin reduction and styrene epoxidation reactions proceed without wasteful side reactions. Comparison of the reductase activity of the fusion proteins with the naturally occurring reductase, SMOB, and N-terminally histidine-tagged reductase, NSMOB, suggests that the observed changes in catalytic mechanism are due in part to an increase in flavin-binding affinity associated with the N-terminal extension of the reductase.

Genetic inhibition of autophagy promotes p53 loss-of-heterozygosity and tumorigenesis.

Autophagy is an evolutionarily conserved lysosomal degradation pathway that plays an essential role in enabling eukaryotic organisms to adapt to nutrient deprivation and other forms of environmental stress. In metazoan organisms, autophagy is essential for differentiation and normal development; however, whether the autophagy pathway promotes or inhibits tumorigenesis is controversial, and the possible mechanisms linking defective autophagy to cancer remain unclear. To determine if autophagy is important for tumor suppression, we inhibited autophagy in transgenic zebrafish via stable, tissue-specific expression of a dominant-negative autophagy protein Atg5K130R. In heterozygous tp53 mutants, expression of dominant-negative atg5K130R increased tumor incidence and decreased tumor latency compared to non-transgenic heterozygous tp53 mutant controls. In a tp53-deficient background, Tg(mitfa:atg5K130R) mutantsdeveloped malignant peripheral nerve sheath tumors (MPNSTs), neuroendocrine tumors and small-cell tumors. Expression of a Sox10-dependent GFP transgene in the tumors demonstrated their origin from neural crest cells, lending support to a model in which mitfa-expressing cells can arise from sox10+ Schwann cell precursors. Tumors from the transgenic animals exhibited increased DNA damage and loss-of-heterozygosity of tp53. Taken together, our data indicate that genetic inhibition of autophagy promotes tumorigenesis in tp53 mutant zebrafish, and suggest a possible role for autophagy in the regulation of genome stability during oncogenesis.

Biochemical Evaluation of the Inhibition Properties of Favipiravir and 2'-C-Methyl-Cytidine Triphosphates against Human and Mouse Norovirus RNA Polymerases.

Norovirus (NoV) is a positive-sense single-stranded RNA virus that causes acute gastroenteritis and is responsible for 200,000 deaths per year worldwide. No effective vaccine or treatment is available. Recent studies have shown that the nucleoside analogs favipiravir (T-705) and 2'-C-methyl-cytidine (2CM-C) inhibit NoV replication in vitro and in animal models, but their precise mechanism of action is unknown. We evaluated the molecular interactions between nucleoside triphosphates and NoV RNA-dependent RNA polymerase (NoVpol), the enzyme responsible for replication and transcription of NoV genomic RNA. We found that T-705 ribonucleoside triphosphate (RTP) and 2CM-C triphosphate (2CM-CTP) equally inhibited human and mouse NoVpol activities at concentrations resulting in 50% of maximum inhibition (IC50s) in the low micromolar range. 2CM-CTP inhibited the viral polymerases by competing directly with natural CTP during primer elongation, whereas T-705 RTP competed mostly with ATP and GTP at the initiation and elongation steps. Incorporation of 2CM-CTP into viral RNA blocked subsequent RNA synthesis, whereas T-705 RTP did not cause immediate chain termination of NoVpol. 2CM-CTP and T-705 RTP displayed low levels of enzyme selectivity, as they were both recognized as substrates by human mitochondrial RNA polymerase. The level of discrimination by the human enzyme was increased with a novel analog of T-705 RTP containing a 2'-C-methyl substitution. Collectively, our data suggest that 2CM-C inhibits replication of NoV by acting as a classic chain terminator, while T-705 may inhibit the virus by multiple mechanisms of action. Understanding the precise mechanism of action of anti-NoV compounds could provide a rational basis for optimizing their inhibition potencies and selectivities.

The acceptability and feasibility of an intercultural birth center in the highlands of Chiapas, Mexico.

BACKGROUND: An intercultural birthing house was established in the Highlands of Chiapas, Mexico, as an intervention to reduce maternal mortality among indigenous women. This birth center, known locally as the Casa Materna, is a place where women can come to give birth with their traditional birth attendant. However, three months after opening, no woman had used the birthing house. METHODS: This study reports on the knowledge, attitudes and practices related to childbirth and use of the Casa Materna from the perspective of the health workers, traditional birth attendants and the program's target population. Structured interviews, in-depth interviews and focus group discussions were conducted with participants from each of these groups. Data was searched for emerging themes and coded. RESULTS AND CONCLUSIONS: Findings show that the potential success of this program is jeopardized by lack of transport and a strong cultural preference for home births. The paper highlights the importance of community participation in planning and implementing such an intervention and of establishing trust and mutual respect among key actors. Recommendations are provided for moving forward the maternal health agenda of indigenous women in Chiapas.

Aid in dying: guidance for an emerging end-of-life practice.

Patients approaching death because of terminal illness may find themselves trapped in a dying process they find unbearable, even with excellent pain and symptom management. Some will want the option of aid in dying. Aid in dying is the practice of a physician writing a prescription for medication for a mentally competent, terminally ill patient that the patient may ingest to bring about a peaceful death. The practice is increasingly accepted by physicians, and it is likely that a growing population of patients will inquire about it. Data from states that give terminally ill patients a statutory right to aid in dying demonstrate that the practice improves end-of-life care. Therefore, it is timely for clinical practice guidelines to emerge to offer guidance to physicians willing to provide aid in dying.

Automated external defibrillator availability and CPR training among state police agencies in the United States.

STUDY OBJECTIVE: Access to automated external defibrillators and cardiopulmonary resuscitation (CPR) training are key determinants of cardiac arrest survival. State police officers represent an important class of cardiac arrest first responders responsible for the large network of highways in the United States. We seek to determine accessibility of automated external defibrillators and CPR training among state police agencies. METHODS: Contact was attempted with all 50 state police agencies by telephone and electronic mail. Officers at each agency were guided to complete a 15-question Internet-based survey. Descriptive statistics of the responses were performed. RESULTS: Attempts were made to contact all 50 states, and 46 surveys were completed (92% response rate). Most surveys were filled out by police leadership or individuals responsible for medical programs. The median agency size was 725 (interquartile range 482 to 1,485) state police officers, with 695 (interquartile range 450 to 1,100) patrol vehicles ("squad cars"). Thirty-three percent of responding agencies (15/46) reported equipping police vehicles with automated external defibrillators. Of these, 53% (8/15) equipped less than half of their fleet with the devices. Regarding emergency medical training, 78% (35/45) of state police agencies reported training their officers in automated external defibrillator usage, and 98% (44/45) reported training them in CPR. CONCLUSION: One third of state police agencies surveyed equipped their vehicles with automated external defibrillators, and among those that did, most equipped only a minority of their fleet. Most state police agencies reported training their officers in automated external defibrillator usage and CPR. Increasing automated external defibrillator deployment among state police represents an important opportunity to improve first responder preparedness for cardiac arrest care.

A kinetic and isotope effect investigation of the urease-catalyzed hydrolysis of hydroxyurea.

The urease-catalyzed hydrolysis of hydroxyurea is known to exhibit biphasic kinetics, showing a rapid burst phase followed by a slow plateau phase. Kinetic isotope effects for both phases of this reaction were measured at pH 6.0 and 25 °C. The observed nitrogen isotope effects for the ammonia leaving group [(15)(V/K)(NH(3))] were 1.0016 ± 0.0005 during the burst phase and 1.0019 ± 0.0007 during the plateau phase, while those for the hydroxylamine leaving group [(15)(V/K)(NH(2)OH)] were 1.0013 ± 0.0005 for the burst phase and 1.0022 ± 0.0003 for the plateau phase. These isotope effects are consistent with a rate-determining step that occurs prior to breaking either of the two possible C-N bonds. The observed carbonyl carbon isotope effects [(13)(V/K)] were 1.0135 ± 0.0003 during the burst phase and 1.0178 ± 0.0003 during the plateau phase. The similarity of the magnitude of the carbon isotope effects argues for formation of a common intermediate during both phases.

Oxygen breathing accelerates decompression from saturation at 40 msw in 70-kg swine.

INTRODUCTION: Submarine disaster survivors can be transferred from a disabled submarine at a pressure of 40 meters of seawater (msw) to a new rescue vehicle; however, they face an inherently risky surface interval before recompression and an enormous decompression obligation due to a high likelihood of saturation. The goal was to design a safe decompression protocol using oxygen breathing and a trial-and-error methodology. We hypothesized that depth, timing, and duration of oxygen breathing during decompression from saturation play a role to mitigate decompression outcomes. METHODS: Yorkshire swine (67-75 kg), compressed to 40 msw for 22 h, underwent one of three accelerated decompression profiles: (1) 13.3 h staged air decompression to 18 msw, followed by 1 h oxygen breathing, then dropout; (2) direct decompression to 18 msw followed by 1 h oxygen breathing then dropout; and (3) 1 h oxygen prebreathe at 40 msw followed by 1 h mixed gas breathing at 26 msw, 1 h oxygen breathing at 18 msw, and 1 h ascent breathing oxygen. Animals underwent 2-h observation for signs of DCS. RESULTS: Profile 1 (14.3 h total) resulted in no deaths, no Type II DCS, and 20% Type I DCS. Profile 2 (2.1 h total) resulted in 13% death, 50% Type II DCS, and 75% Type I DCS. Profile 3 (4.5 h total) resulted in 14% death, 21% Type II DCS, and 57% Type I DCS. No oxygen associated seizures occurred. DISCUSSION: Profile 1 performed best, shortening decompression with no death or severe DCS, yet it may still exceed emergency operational utility in an actual submarine rescue.

Some practical problems in implementing randomization.

BACKGROUND: While often theoretically simple, implementing randomization to treatment in a masked, but confirmable, fashion can prove difficult in practice. PURPOSE: At least three categories of problems occur in randomization: (1) bad judgment in the choice of method, (2) design and programming errors in implementing the method, and (3) human error during the conduct of the trial. This article focuses on these latter two types of errors, dealing operationally with what can go wrong after trial designers have selected the allocation method. RESULTS: We offer several case studies and corresponding recommendations for lessening the frequency of problems in allocating treatment or for mitigating the consequences of errors. Recommendations include: (1) reviewing the randomization schedule before starting a trial, (2) being especially cautious of systems that use on-demand random number generators, (3) drafting unambiguous randomization specifications, (4) performing thorough testing before entering a randomization system into production, (5) maintaining a dataset that captures the values investigators used to randomize participants, thereby allowing the process of treatment allocation to be reproduced and verified, (6) resisting the urge to correct errors that occur in individual treatment assignments, (7) preventing inadvertent unmasking to treatment assignments in kit allocations, and (8) checking a sample of study drug kits to allow detection of errors in drug packaging and labeling. LIMITATIONS: Although we performed a literature search of documented randomization errors, the examples that we provide and the resultant recommendations are based largely on our own experience in industry-sponsored clinical trials. We do not know how representative our experience is or how common errors of the type we have seen occur. CONCLUSIONS: Our experience underscores the importance of verifying the integrity of the treatment allocation process before and during a trial. Clinical Trials 2010; 7: 235-245. http://ctj.sagepub.com.

Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-gamma/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection.

Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed "LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10microg LSA-NRC/0.5ml AS01 (n=5), high dose (HD) LSA-NRC/AS01: 50microg LSA-NRC/0.5ml AS01 (n=13); LD LSA-NRC/AS02: 10microg LSA-NRC/0.5ml AS02 (n=5) and HD LSA-NRC/AS02: 50microg LSA-NRC/0.5ml AS02 (n=13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-gamma) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-gamma responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p=0.95). LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.