What is going on inside of phytochrome B photobodies?

Plants exhibit an enormous phenotypic plasticity to adjust to changing environmental conditions. For this purpose, they have evolved mechanisms to detect and measure biotic and abiotic factors in their surroundings. Phytochrome B exhibits a dual function, since it serves as a photoreceptor for red and far-red light as well as a thermosensor. In 1999, it was first reported that phytochromes not only translocate into the nucleus but also form subnuclear foci upon irradiation by red light. It took more than 10 years until these phytochrome speckles received their name; these foci were coined photobodies to describe unique phytochrome-containing subnuclear domains that are regulated by light. Since their initial discovery, there has been much speculation about the significance and function of photobodies. Their presumed roles range from pure experimental artifacts to waste deposits or signaling hubs. In this review, we summarize the newest findings about the meaning of phyB photobodies for light and temperature signaling. Recent studies have established that phyB photobodies are formed by liquid-liquid phase separation via multivalent interactions and that they provide diverse functions as biochemical hotspots to regulate gene expression on multiple levels.

Optimizing Mass Casualty Triage: Using Discrete Event Simulation to Minimize Time to Resuscitation.

BACKGROUND: Urban areas in the US are increasingly focused on mass casualty incident (MCI) response. We simulated prehospital triage scenarios and hypothesized that using hospital-based blood product inventories for on-scene triage decisions would minimize time to treatment. STUDY DESIGN: Discrete event simulations modeled MCI casualty injury and patient flow after a simulated blast event in Boston, MA. Casualties were divided into moderate (Injury Severity Score 9 to 15) and severe (Injury Severity Score >15) based on injury patterns. Blood product inventories were collected from all hospitals (n = 6). The primary endpoint was the proportion of casualties managed with 1:1:1 balanced resuscitation in a target timeframe (moderate, 3.5 U red blood cells in 6 hours; severe, 10 U red blood cells in 1 hour). Three triage scenarios were compared, including unimpeded casualty movement to proximate hospitals (Nearest), equal distribution among hospitals (Equal), and blood product inventory-based triage (Supply-Guided). RESULTS: Simulated MCIs generated a mean ± SD of 302 ± 7 casualties, including 57 ± 2 moderate and 15 ± 2 severe casualties. Nearest triage resulted in significantly fewer overall casualties treated in the target time (55% vs Equal 86% vs Supply-Guided 91%, p < 0.001). These differences were principally due to fewer moderate casualties treated, but there was no difference among strategies for severe casualties. CONCLUSIONS: In this simulation study comparing different triage strategies, including one based on actual blood product inventories, nearest hospital triage was inferior to equal distribution or a Supply-Guided strategy. Disaster response leaders in US urban areas should consider modeling different MCI scenarios and casualty numbers to determine optimal triage strategies for their area given hospital numbers and blood product availability.

Third National Registry of Cardiac Rehabilitation Programs in Mexico (RENAPREC III-2022) / Tercer Registro Nacional de Programas de Rehabilitación Cardiaca en México (RENAPREC III-2022)

Abstract Introduction: In Mexico, cardiac rehabilitation (CR) as an interdisciplinary intervention with therapeutic impact in patients with heart disease is growing. There is the need to know actual conditions of CR in our country. Objectives: The objective of this National Registry is to follow-up those existing and new CR units in Mexico through the comparison between the two previous registries, RENAPREC-2009 and RENAPREC II-2015 studies. This is a descriptive study focused on diverse CR activities such as assistance training, and certification of health professionals, barriers, reference, population attended, interdisciplinarity, permanence over time, growth prospects, regulations, post-pandemic condition, integrative characteristics, and scientific research. Results: Data were collected from 45 CR centers in the 32 states, 75.5% are private practice units, 67% are new, 33% were part of RENAPREC II-2015, and 17 have continued since 2009. With a better distribution of CR units along the territory, the median reference of candidates for CR programs is 9% with a significant reduction into tiempo of enrollment to Phase II admission (19 ± 11 days). Regarding to previous registries, the coverance of Phases I, II, and III is 71%, 100%, and 93%, respectively; and a coverance increases in evaluation, risk stratification, and prescription, more comprehensive attendance and prevention strategies. Conclusions: CR in Mexico has grown in the past 7 years. Even there is still low reference and heterogeneity in specific processes, there are strengths such as interdisciplinarity, scientific professionalization of specialists, national diversification, and an official society that are consolidated over time.

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[Numerical expression of the clinical course of the disease. Data management]. / Expresión numérica del curso clínico de la enfermedad. Manejo de datos.

Data management "behind the scenes" refers to collection, cleaning, imputation, and demarcation; and despite of being indispensable processes, they are usually neglected and thus, generate erroneous information. During the collection are errors: omission of covariates, deviation from the objective, and insufficient quality. The omission of covariates distorts the result attributed to the main manoeuvre. Deviation from the primary objective commonly occurs when the outcome is rare, delayed, or subjective and promotes substitution by non-equivalent surrogate variables. Moreover, insufficient quality occurs due to inadequate instruments, omission of the measurement procedure, or measurements out of context, such as attribution at the wrong time or equivalent. Furthermore, cleaning implies identifying erroneous, extreme, and missing values, which may or may not be imputed, depending on the percentage. The values of the manoeuvre or the outcome are never imputed, nor are patients eliminated due to a lack of values. Finally, the demarcation of each variable seeks to give it a clinical meaning about the outcome, for which a hierarchical sequence of criteria is followed: 1) previous clinical study, 2) expert agreement, 3) clinical judgment of the investigator/investigators, and 4) statistics. Acting without quality controls in data management frequently causes involuntary lies and confuses instead of clarifying.

El manejo de datos "tras bambalinas" se refiere a los procesos de recopilación, limpieza, imputación y demarcación; los cuales, aun siendo indispensables, usualmente suelen ser descuidados, por lo que generan información errónea. Durante la recopilación son errores: omisión de covariables, desvío del objetivo, y calidad insuficiente. La omisión de covariables distorsiona el resultado atribuido a la maniobra principal. El desvío del objetivo primario es común cuando el desenlace es raro, tardado o subjetivo y promueve la sustitución por variables subrogadas no equivalentes. Además, la calidad insuficiente, sucede por instrumentos inadecuados, omisión del procedimiento de medición, o medición fuera de contexto -como atribución a destiempo o equivalente-. Por otro lado, la limpieza implica identificar valores erróneos, extremos y faltantes, que podrán ser o no imputados, dependiendo del porcentaje se imputará comúnmente por la medida de resumen. Nunca se imputan los valores de la maniobra ni del desenlace, ni se eliminan pacientes por falta de valores. Finalmente, la demarcación de cada variable busca un significado clínico en referencia al desenlace, para ello se sigue una secuencia jerárquica de criterios: 1) estudio clínico previo, 2) acuerdo de expertos, 3) juicio clínico del investigador/investigadores y 4) estadística. Actuar sin controles de calidad en el manejo de datos provoca frecuentemente mentiras involuntarias y confunde en lugar de esclarecer.

[Third National Registry of Cardiac Rehabilitation Programs in Mexico (RENAPREC III-2022)]. / Tercer Registro Nacional de Programas de Rehabilitación Cardiaca en México (RENAPREC III-2022).

Introduction: In Mexico, cardiac rehabilitation (CR) as an interdisciplinary intervention with therapeutic impact in patients with heart disease is growing. There is the need to know actual conditions of CR in our country. Objectives: The objective of this National Registry is to follow-up those existing and new CR units in Mexico through the comparison between the two previous registries, RENAPREC-2009 and RENAPREC II-2015 studies. This is a descriptive study focused on diverse CR activities such as assistance training, and certification of health professionals, barriers, reference, population attended, interdisciplinarity, permanence over time, growth prospects, regulations, post-pandemic condition, integrative characteristics, and scientific research. Results: Data were collected from 45 CR centers in the 32 states, 75.5% are private practice units, 67% are new, 33% were part of RENAPREC II-2015, and 17 have continued since 2009. With a better distribution of CR units along the territory, the median reference of candidates for CR programs is 9% with a significant reduction into tiempo of enrollment to Phase II admission (19 ± 11 days). Regarding to previous registries, the coverance of Phases I, II, and III is 71%, 100%, and 93%, respectively; and a coverance increases in evaluation, risk stratification, and prescription, more comprehensive attendance and prevention strategies. Conclusions: CR in Mexico has grown in the past 7 years. Even there is still low reference and heterogeneity in specific processes, there are strengths such as interdisciplinarity, scientific professionalization of specialists, national diversification, and an official society that are consolidated over time.

Introducción: En México, la Rehabilitación Cardíaca (RC) como intervención interdisciplinaria con impacto terapéutico en paciente con cardiopatía está en crecimiento. Existe la necesidad de conocer las condiciones actuales de la RC en nuestro país. Objetivo: El objetivo de este Registro es dar seguimiento comparativo de las unidades nuevas y existentes entre los registros anteriores, RENAPREC-2009 y RENAPREC II-2015. Se trata de un estudio descriptivo centrado en diversas actividades de la RC: formación asistencial y certificación de sus profesionales, barreras, referencia, población atendida, interdisciplinariedad, permanencia en el tiempo, perspectivas de crecimiento, normativa, condición pospandemia, características integradoras e investigación. Resultados: Se recolectaron datos de 45 centros en los 32 estados, 67% son nuevos 75.5% son de práctica privada, 33% fueron parte de RENAPREC II-2015 y 17 desde 2009. Con una mejor distribución de las unidades de RC a lo largo del territorio, la mediana de referencia de pacientes candidatos a RC es ahora del 9% con reducción significativa del tiempo de admisión a Fase II (19 ± 11 días). Respecto a registros anteriores las coberturas de las Fases I, II y III son del 71%, 100% y 93%, respectivamente; con un aumento de la cobertura en evaluación, estratificación de riesgo y prescripción, atención más integral y estrategias de prevención. Conclusiones: La RC en México ha crecido en los últimos 7 años. Si bien aún existe baja referencia y heterogeneidad en procesos específicos, existen fortalezas como la interdisciplinariedad, la profesionalización científica de los especialistas, la diversificación nacional y una sociedad oficial que se consolida en el tiempo.

Generation of two induced pluripotent stem cell lines from spinal muscular atrophy type 1 patients carrying no functional copies of SMN1 gene.

Spinal muscular atrophy (SMA) is a severe neurodegenerative muscular disease caused by the homozygous loss of survival of motor neuron 1 (SMN1) genes. SMA patients exhibit marked skeletal muscle (SKM) loss, eventually leading to death. Here we generated two iPSC lines from two SMA type I patients with homozygous SMN1 mutations and validated the pluripotency and the ability to differentiate into three germ layers. The iPSC lines can be applied to generate skeletal muscles to model muscle atrophy of SMA that persists after treatment of motor neurons and will serve as a complementary platform for drug screening in vitro.

Laser-Assisted Lip Repositioning Surgery: A Modification to The Conventional Technique.

Introduction: The lip repositioning surgical technique arose with the objective of correcting and harmonizing the act of smiling. Since the conventional technique was published, some modifications of the technique have been proposed in order to counteract postoperative recurrence and to achieve the best esthetic appearance of the smile. The objective of this paper was to describe the laser-assisted lip repositioning technique (laser-assisted LRS) with a 940nm diode laser and 2780nm Er,Cr: YSGG, as a modification to the conventional lip repositioning technique, for the treatment of a gummy smile. Case Report: The proposed technique consists in achieving the descent of the upper lip by removing the intraoral mucosal band through the laser peeling of oral mucosa, preserving the connective tissue intact for healing by secondary intention. The technique was implemented in two patients with a diagnosis of a gummy smile caused by a short and hyperactive upper lip; the healing process was satisfactory, and there was no bleeding or postoperative edema. Postoperative controls were performed at 3 and 10 months, and no recurrence was found. Conclusion: the 940nm Diode laser or 2780nm Er,Cr: YSGG laser-assisted lip repositioning technique described here is less invasive than that performed with a conventional scalpel, offers aesthetic results, lower risk of infection and recurrence of the gummy smile in the long term.

U.S. cities will not meet blood product resuscitation standards during major mass casualty incidents: Results of a THOR-AABB working party prospective analysis.

BACKGROUND: Mass casualty incidents (MCIs) create an immediate surge in blood product demand. We hypothesize local inventories in major U.S. cities would not meet this demand. STUDY DESIGN AND METHODS: A simulated blast in a large crowd estimated casualty numbers. Ideal resuscitation was defined as equal amounts of red blood cells (RBCs), plasma, platelets, and cryoprecipitate. Inventory was prospectively collected from six major U.S. cities at six time points between January and July 2019. City-wide blood inventories were classified as READY (>1 U/injured survivor), DEFICIENT (<10 U/severely injured survivor), or RISK (between READY and DEFICIENT), before and after resupply from local distribution centers (DC), and features of DEFICIENT cities were identified. RESULTS: The simulated blast resulted in 2218 injured survivors including 95 with severe injuries. Balanced resuscitation would require between 950 and 2218 units each RBC, plasma, platelets and cryoprecipitate. Inventories in 88 hospitals/health systems and 10 DCs were assessed. Of 36 city-wide surveys, RISK inventories included RBCs (n = 16; 44%), plasma (n = 24; 67%), platelets (n = 6; 17%), and cryoprecipitate (n = 22; 61%) while DEFICIENT inventories included platelets (n = 30; 83%) and cryoprecipitate (n = 12; 33%). Resupply shifted most RBC and plasma inventories to READY, but some platelet and cryoprecipitate inventories remained at RISK (n = 24; 67% and n = 12; 33%, respectively) or even DEFICIENT (n = 11; 31% and n = 6; 17%, respectively). Cities with DEFICIENT inventories were smaller (p <.001) with fewer blood products per trauma bed (p <.001). DISCUSSION: In this simulated blast event, blood product demand exceeded local supply in some major U.S. cities. Options for closing this gap should be explored to optimize resuscitation during MCIs.

Does Gender Matter: A Multi-Institutional Analysis of Viscoelastic Profiles for 1565 Trauma Patients With Severe Hemorrhage.

BACKGROUND: Viscoelastic tests including thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are being used in patients with severe hemorrhage at trauma centers to guide resuscitation. Several recent studies demonstrated hypercoagulability in female trauma patients that was associated with a survival advantage. The objective of our study was to elucidate the effects of gender differences in TEG/ROTEM values on survival in trauma patients with severe hemorrhage. METHODS: A retrospective review of consecutive adult patients receiving massive transfusion protocol (MTP) at 7 Level I trauma centers was performed from 2013 to 2018. Data were stratified by gender and then further examined by TEG or ROTEM parameters. Results were analyzed using univariate and multi-variate analyses. RESULTS: A total of 1565 patients were included with 70.9% male gender (n = 1110/1565). Female trauma patients were older than male patients (43.5 ± .9 vs 41.1 ± .6 years, P = .01). On TEG, females had longer reaction times (6.1 ± .9 min vs 4.8 ± .2 min, P = .03), increased alpha angle (68.6 ± .8 vs 65.7 ± .4, P < .001), and higher maximum amplitude (59.8 ± .8 vs 56.3 ± .4, P < .001). On ROTEM, females had significantly longer clot time (99.2 ± 13.7 vs 75.1 ± 2.6 sec, P = .09) and clot formation time (153.6 ± 10.6 sec vs 106.9 ± 3.8 sec, P < .001). When comparing by gender, no difference for in-hospital mortality was found for patients in the TEG or ROTEM group (P > .05). Multivariate analysis showed no survival difference for female patients (OR 1.11, 95% CI .83-1.50, P = .48). CONCLUSIONS: Although a difference between male and females was found on TEG/ROTEM for certain clotting parameters, no difference in mortality was observed. Prospective multi-institutional studies are needed.

Genome-wide association study applied to type traits related to milk yield in water buffaloes (Bubalus bubalis).

This research aimed to estimate genetic parameters for milk yield and type traits [withers height (WH), croup height (CH), body length (BL), croup length (CL), iliac width (ILW), ischial width (ISW), and thoracic circumference] in Murrah buffaloes and to identify genomic regions related to type traits by applying a single-step genome-wide association study. Data used to estimate the genetic parameters consisted of 601 records of milk yield in the first lactation and the aforementioned type traits. For the single-step genome-wide association study, 322 samples genotyped with a 90K Axiom Buffalo Genotyping array (Thermo Fisher Scientific, Santa Clara, CA) were used. Bivariate analysis revealed that heritability for milk yield (kg) at 305 d was 0.31 ± 0.11, whereas it ranged from 0.22 ± 0.07 to 0.34 ± 0.09 for the studied conformation traits. Based on the percentages of genetic variance explained by windows of 10 markers, there were 16 genomic regions explaining more than 0.5% of the variance for WH, CH, BL, CL, ILW, ISW, and thoracic circumference. Between those regions, 4 were associated with more than 1 trait, suggesting pleiotropic roles for some genes of Bos taurus autosome (BTA) 12 on CL and WH, BTA13 on ISW and ILW, BTA23 on CH and BL, and BTA28 on ISW and BL. Most of these regions coincide with known quantitative trait loci for milk traits. Thus, further studies based on sequence data will help to validate the association of this region with type traits and likely identify the causal mutations.

Cold-stored whole blood: A better method of trauma resuscitation?

BACKGROUND: Cold-stored whole blood (CWB) provides a balance of red blood cells, plasma, and platelets in less anticoagulant volume than standard blood component therapy (BCT). We hypothesize that patients receiving CWB along with BCT have improved survival compared with patients receiving only BCT. METHODS: We performed a dual-center case-match study of trauma patients who received CWB and BCT at two urban, Level-I Trauma Centers. Criteria to receive CWB included boys 16 years of older, women older than 50 years, SBP less than 90 mm Hg, and identifiable source of hemorrhage. We performed a 2:1 propensity match against any trauma patient who received 1 unit or greater of packed red cells during their initial trauma bay resuscitation. Endpoints included trauma bay mortality, 30-day mortality, laboratory values at 4 hours and 24 hours, and overall blood product utilization. Comparisons were made with Wilcoxon-ranked sum and Fisher's exact test, p less than 0.05 was significant. RESULTS: Between both institutions, a total of 107 patients received CWB during the study period with 91 being matched to 182 BCT patients for analysis. Hemodynamic parameters of the patients in both groups at the time of presentation were similar. The CWB patients had higher mean hemoglobin (10 ± 2 g/dL vs. 11 ± 2 g/dL; p < 0.001) and hematocrit (29.2 ± 6.1% vs. 32.1 ± 5.8%; p < 0.001) at 24 hours. Importantly, trauma bay mortality was less in CWB patients (8.8% vs. 2.2%;p = 0.039). Thirty-day mortality was not different in CWB patients, and there were no differences in the total amount of blood products transfused at the 4-hour and 24-hour periods. CONCLUSION: Cold-stored whole blood offers the benefit of a balanced resuscitation with improved trauma bay survival and higher mean hemoglobin at 24 hours. A larger, prospective study is needed to determine whether it has a longer-term survival benefit for severely injured patients. LEVEL OF EVIDENCE: Therapeutic, level III.

PIKfyve Deficiency in Myeloid Cells Impairs Lysosomal Homeostasis in Macrophages and Promotes Systemic Inflammation in Mice.

Macrophages are professional phagocytes that are essential for host defense and tissue homeostasis. Proper membrane trafficking and degradative functions of the endolysosomal system are known to be critical for the function of these cells. We have found that PIKfyve, the kinase that synthesizes the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate, is an essential regulator of lysosomal biogenesis and degradative functions in macrophages. Genetically engineered mice lacking PIKfyve in their myeloid cells (PIKfyvefl/fl LysM-Cre) develop diffuse tissue infiltration of foamy macrophages, hepatosplenomegaly, and systemic inflammation. PIKfyve loss in macrophages causes enlarged endolysosomal compartments and impairs the lysosomal degradative function. Moreover, PIKfyve deficiency increases the cellular levels of lysosomal proteins. Although PIKfyve deficiency reduced the activation of mTORC1 pathway and was associated with increased cleavage of TFEB proteins, this does not translate into transcriptional activation of lysosomal genes, suggesting that PIKfyve modulates the abundance of lysosomal proteins by affecting the degradation of these proteins. Our study shows that PIKfyve modulation of lysosomal degradative activity and protein expression is essential to maintain lysosomal homeostasis in macrophages.

Understanding drivers of domestic public expenditure on reproductive, maternal, neonatal and child health in Peru at district level: an ecological study.

BACKGROUND: Peru has increased substantially its domestic public expenditure in maternal and child health. Peruvian departments are heterogeneous in contextual and geographic factors, underlining the importance of disaggregated expenditure analysis up to the district level. We aimed to assess possible district level factors influencing public expenditure on reproductive, maternal, neonatal and child health (RMNCH) in Peru. METHODS: We performed an ecological study in 24 departments, with specific RMNCH expenditure indicators as outcomes, and covariates of different hierarchical dimensions as predictors. To account for the influence of variables included in the different dimensions over time and across departments, we chose a stepwise multilevel mixed-effects regression model, with department-year as the unit of analysis. RESULTS: Public expenditure increased in all departments, particularly for maternal-neonatal and child health activities, with a different pace across departments. The multilevel analysis did not reveal consistently influential factors, except for previous year expenditure on reproductive and maternal-neonatal health. Our findings may be explained by a combination of inertial expenditure, a results-based budgeting approach to increase expenditure efficiency and effectiveness, and by a mixed-effects decentralization process. Sample size, interactions and collinearity cannot be ruled out completely. CONCLUSIONS: Public district-level RMNCH expenditure has increased remarkably in Peru. Evidence on underlying factors influencing such trends warrants further research, most likely through a combination of quantitative and qualitative approaches.

Enabling reproductive, maternal, neonatal and child health interventions: Time trends and driving factors of health expenditure in the successful story of Peru.

We compared expenditure trends for reproductive, maternal, neonatal and child health (RMNCH) with trends in RMNCH service coverage in Peru. We used National Health Accounts data to report on total health expenditure by source; the Countdown database for trends in external funding to RMNCH, and Ministry of Finance data for trends in domestic funding to RMNCH. We undertook over 170 interviews and group discussions to explore factors explaining expenditure trends. We describe trends in total health expenditure and RMNCH expenditure in constant 2012 US$ between 1995 and 2012. We estimated expenditure to coverage ratios. There was a substantial increase in domestic health expenditure over the period. However, domestic health expenditure as share of total government spending and GDP remained stable. Out-of-pocket health spending (OOPS) as a share of total health expenditure remained above 35%, and increased in real terms. Expenditure on reproductive health per woman of reproductive age varied from US$ 1.0 in 2002 to US$ 6.3 in 2012. Expenditure on maternal and neonatal health per pregnant woman increased from US$ 34 in 2000 to US$ 512 in 2012, and per capita expenditure on under-five children increased from US$ 5.6 in 2000 to US$ 148.6 in 2012. Increased expenditure on RMNCH reflects a greater political support for RMNCH, along with greater emphasis on social assistance, family planning, and health reforms targeting poor areas, and a recent emphasis on antipoverty and crosscutting equitable policies and programmes focused on nutrition and maternal and neonatal mortality. Increasing domestic RMNCH expenditure likely enabled Peru to achieve substantial health gains. Peru can provide useful lessons to other countries struggling to achieve sustained gains in RMNCH by relying on their own health financing.

Transmission of Bacterial Endophytes.

Plants are hosts to complex communities of endophytic bacteria that colonize the interior of both below- and aboveground tissues. Bacteria living inside plant tissues as endophytes can be horizontally acquired from the environment with each new generation, or vertically transmitted from generation to generation via seed. A better understanding of bacterial endophyte transmission routes and modes will benefit studies of plant-endophyte interactions in both agricultural and natural ecosystems. In this review, we provide an overview of the transmission routes that bacteria can take to colonize plants, including vertically via seeds and pollen, and horizontally via soil, atmosphere, and insects. We discuss both well-documented and understudied transmission routes, and identify gaps in our knowledge on how bacteria reach the inside of plants. Where little knowledge is available on endophytes, we draw from studies on bacterial plant pathogens to discuss potential transmission routes. Colonization of roots from soil is the best studied transmission route, and probably the most important, although more studies of transmission to aerial parts and stomatal colonization are needed, as are studies that conclusively confirm vertical transfer. While vertical transfer of bacterial endophytes likely occurs, obligate and strictly vertically transferred symbioses with bacteria are probably unusual in plants. Instead, plants appear to benefit from the ability to respond to a changing environment by acquiring its endophytic microbiome anew with each generation, and over the lifetime of individuals.

Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience.

Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype-phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.

Factors behind the success story of under-five stunting in Peru: a district ecological multilevel analysis.

BACKGROUND: Stunting prevalence in children less than 5 years has remained stagnated in Peru from 1992 to 2007, with a rapid reduction thereafter. We aimed to assess the role of different predictors on stunting reduction over time and across departments, from 2000 to 2012. METHODS: We used various secondary data sources to describe time trends of stunting and of possible predictors that included distal to proximal determinants. We determined a ranking of departments by annual change of stunting and of different predictors. To account for variation over time and across departments, we used an ecological hierarchical approach based on a multilevel mixed-effects regression model, considering stunting as the outcome. Our unit of analysis was one department-year. RESULTS: Stunting followed a decreasing trend in all departments, with differing slopes. The reduction pace was higher from 2007-2008 onwards. The departments with the highest annual stunting reduction were Cusco (-2.31%), Amazonas (-1.57%), Puno (-1.54%), Huanuco (-1.52%), and Ancash (-1.44). Those with the lowest reduction were Ica (-0.67%), Ucayali (-0.64%), Tumbes (-0.45%), Lima (-0.37%), and Tacna (-0.31%). Amazon and Andean departments, with the highest baseline poverty rates and concentrating the highest rural populations, showed the highest stunting reduction. In the multilevel analysis, when accounting for confounding, social determinants seemed to be the most important factors influencing annual stunting reduction, with significant variation between departments. CONCLUSIONS: Stunting reduction may be explained by the adoption of anti-poverty policies and sustained implementation of equitable crosscutting interventions, with focus on poorest areas. Inclusion of quality indicators for reproductive, maternal, neonatal and child health interventions may enable further analyses to show the influence of these factors. After a long stagnation period, Peru reduced dramatically its national and departmental stunting prevalence, thanks to a combination of social determinants and crosscutting factors. This experience offers useful lessons to other countries trying to improve their children's nutrition.

Distributed Cognition and Process Management Enabling Individualized Translational Research: The NIH Undiagnosed Diseases Program Experience.

The National Institutes of Health Undiagnosed Diseases Program (NIH UDP) applies translational research systematically to diagnose patients with undiagnosed diseases. The challenge is to implement an information system enabling scalable translational research. The authors hypothesized that similar complex problems are resolvable through process management and the distributed cognition of communities. The team, therefore, built the NIH UDP integrated collaboration system (UDPICS) to form virtual collaborative multidisciplinary research networks or communities. UDPICS supports these communities through integrated process management, ontology-based phenotyping, biospecimen management, cloud-based genomic analysis, and an electronic laboratory notebook. UDPICS provided a mechanism for efficient, transparent, and scalable translational research and thereby addressed many of the complex and diverse research and logistical problems of the NIH UDP. Full definition of the strengths and deficiencies of UDPICS will require formal qualitative and quantitative usability and process improvement measurement.

Examining national and district-level trends in neonatal health in Peru through an equity lens: a success story driven by political will and societal advocacy.

BACKGROUND: Peru has impressively reduced its neonatal mortality rate (NMR). We aimed, for the period 2000-2013, to: (a) describe national and district NMR variations over time; (b) assess NMR trends by wealth quintile and place of residence; (c) describe evolution of mortality causes; (d) assess completeness of registered mortality; (e) assess coverage and equity of NMR-related interventions; and (f) explore underlying driving factors. METHODS: We compared national NMR time trends from different sources. To describe NMR trends by wealth quintiles, place of residence and districts, we pooled data on births and deaths by calendar year for neonates born to women interviewed in multiple surveys. We disaggregated coverage of NMR-related interventions by wealth quintiles and place of residence. To identify success factors, we ran regression analyses and combined desk reviews with qualitative interviews and group discussions. RESULTS: NMR fell by 51 % from 2000 to 2013, second only to Brazil in Latin America. Reduction was higher in rural and poorest segments (52 and 58 %). District NMR change varied by source. Regarding cause-specific NMRs, prematurity decreased from 7.0 to 3.2 per 1,000 live births, intra-partum related events from 2.9 to 1.2, congenital abnormalities from 2.4 to 1.8, sepsis from 1.9 to 0.8, pneumonia from 0.9 to 0.4, and other conditions from 1.2 to 0.7. Under-registration of neonatal deaths decreased recently, more in districts with higher development index and lower rural population. Coverage of family planning, antenatal care and skilled birth attendance increased more in rural areas and in the poorest quintile. Regressions did not show consistent associations between mortality and predictors. During the study period social determinants improved substantially, and dramatic out-of-health-sector and health-sector changes occurred. Rural areas and the poorest quintile experienced greater NMR reduction. This progress was driven, within a context of economic growth and poverty reduction, by a combination of strong societal advocacy and political will, which translated into pro-poor implementation of evidence-based interventions with a rights-based approach. CONCLUSIONS: Although progress in Peru for reducing NMR has been remarkable, future challenges include closing remaining gaps for urban and rural populations and improving newborn health with qualified staff and intermediate- and intensive-level health facilities.

Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience.

PURPOSE: Using single-nucleotide polymorphism (SNP) chip and exome sequence data from individuals participating in the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP), we evaluated the number and therapeutic informativeness of incidental pharmacogenetic variants. METHODS: Pharmacogenomics Knowledgebase (PharmGKB) annotated sequence variants were identified in 1,101 individuals. Medication records of participants were used to identify individuals prescribed medications with a genetic variant that might alter efficacy. RESULTS: A total of 395 sequence variants, including 19 PharmGKB 1A and 1B variants, were identified in SNP chip sequence data, and 388 variants, including 21 PharmGKB 1A and 1B variants, were identified in the exome sequence data. Nine participants had incidental pharmacogenetic variants associated with altered efficacy of a prescribed medication. CONCLUSIONS: Despite the small size of the NIH UDP patient cohort, we identified pharmacogenetic incidental findings potentially useful for guiding therapy. Consequently, groups conducting clinical genomic studies might consider reporting of pharmacogenetic incidental findings.Genet Med 18 12, 1303-1307.