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This study aimed to determine the agreement between a rapid diagnostic test (RDT) and a dried blood spot (DBS)-based electrochemiluminescence immunoassay (ECLIA) of hepatitis B surface antigen and to compare the costs of conducting serosurveys using RDTs and DBS in a field setting.A serosurvey was conducted in the South Central Coast region of Vietnam in May 2019. Participants aged 1-39 years were recruited using a four-stage random sampling method and tested for hepatitis B surface antigen using an RDT kit (Alere Determine) and a DBS-based ECLIA. The agreement between the RDT and the DBS-based ECLIA was assessed using cross-tabulation and Cohen kappa. Cost data were categorized by input (personnel, transportation, field consumables, laboratory consumables, and capital item/overhead) and survey phase (survey preparation, data/biospecimen collection, laboratory testing, and coordination).A total of 2072 participants were analyzed. There was a 99% agreement between the RDT and the DBS-based ECLIA results, with a Cohen kappa of 0.9. The estimated cost of conducting a serosurvey by DBS was UD $75,291, whereas RDT was $53,182.RDTs and DBS-based ECLIA provide test results with high agreements. RDTs are a better option in terms of cost, whereas the DBS-based ECLIA may be useful when evaluating multiple infectious diseases.

Combination products are therapeutic and diagnostic products that include two or more of the following: drug, biologic, and device. These products are needed for enhanced clinical outcomes and have more than one Mode of Action (MOA). Therefore, they require a more complex regulatory pathway and compliance with a minimum of two (2) sets of regulatory standards. In 2013, the 21 Code of Federal Regulations (CFR) Part 4 was published to clarify the applicable GMP regulations when drugs, devices, or biological products are included. The FDA (U.S. Food and Drug Administration) released additional guidance in 2017 to streamline the regulatory framework and provide transparency about demonstrating GMP compliance when multiple regulatory standards overlap. This paper summarizes the Current Good Manufacturing Practice (CGMP) requirements for drug-device combination products (Biologic combinations are not discussed in this paper). Emphasis is placed on considerations for structuring a compliant drug-device stability program, including the use of bracketing and matrixing the test schedule to support the establishment of the product expiry date and how legacy products can be evaluated to meet current standards.

The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Controls (CMC) Community hosted two virtual panel discussions focusing on several novel regulatory review pathways for innovative oncology products: Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid (PQAAid). The panel sessions were held on August 27, 2021, for the discussion of RTOR, and January 21, 2022, for the discussion of Project Orbis and the PQAAid. Both panel sessions included representatives from the US Food and Drug Administration (FDA) and subject matter experts from the pharmaceutical and biotechnology industries, with the aim of facilitating knowledge sharing on CMC-specific advantages, challenges, eligibility criteria for participation, and operational modifications instituted through the utilization of these acceleration initiatives. Key topics included managing cross-regional regulatory CMC requirements, adapting to expedited development timelines, coordinating interactions between health authorities and industry, and potential opportunities for future improvement and expansion of these programs. As RTOR, Project Orbis, and PQAAid are relatively new initiatives, the experiences shared by the panel experts are valuable for providing deeper insight into these new regulatory pathways and processes.

Previous major infection outbreaks have shown the importance of timely information about local conditions in guiding support and health care interventions. During the COVID-19 pandemic, UNICEF deve...

Calgary-based installation artist and printmaker Kim Huynh’s projects are profoundly aware of materiality and ways in which it can encourage us to jump out of the ruts and customary ways of categorizing and thinking in late Capitalism. The media that Kim Huynh adopts can range from the extraordinary to the banal, from a vast string of pearls to orange peels. This short interview with Kim Huynh investigates matters that are material and conceptual, incorporated into two projects referencing social injustice and embodied female experiences.

Rice husk is a common agricultural waste and an abundant source in Viet Nam. In terms of composition, rice husk is a silica-rich material (SiO2) so it can be used to prepare negative electrode materials for rechargeable Li-ion batteries. Recent processes of synthesizing the silica materials for the rechargeable batteries are often complex, expensive, and energy-intensive. In this study, KOH was used to treat rice husk ash to obtain SiO2/C porous composite materials. X-ray diffraction results (XRD) showed that the diffraction peak between 22o and 23o (2q ) was characterized of SiO2 material, and the other peaks around 43-44o was featured of carbon material. Scanning electron microscope image (SEM) showed the porous structure with the pore size 3-5 mm.Besides, the amorphous structure with coverage layers was also confirmed through the Transmission Electron Microscope (TEM) images. Preliminary electrochemical results demonstratedthat Li-ion coin cell using the SiO2/C anode material exhibited a high capacity of 1200 mAh/g at a discharge current of 1.0 A/g and maintained 1000 mAh/g after 100 cycles. SiO2/C materials prepared from rice husks were highly promising for battery application thanks to their low cost, stable performance, environmental friendliness, and easy expansion for production scale.

Context Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective. Objective To investigate the safety and efficacy of Tesomet (0.5 mg tesofensine/50 mg metoprolol) in adults with hypothalamic obesity. Methods Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5 mg/50 mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite scores, quality of life, and metabolic profile. Results Eighteen patients completed 24 weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild and included sleep disturbances (Tesomet 50%, placebo 13%), dry mouth (Tesomet 43%, placebo 0%), and headache (Tesomet 36%, placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of −6.3% ((−11.3; −1.3); P = 0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, placebo 1/8; P = 0.046), and tended to augment the reduction in waist circumference by 5.7 cm ((−0.1; 11.5); P = 0.054). Conclusion Tesomet was welltolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

The Stability Community of the American Association of Pharmaceutical Scientists (AAPS) held a virtual workshop on “Vaccine Stability Considerations to Enable Rapid Development and Deployment”, on March 24-25, 2021. The workshop included distinguished speakers and panelists from across the industry, academia, regulatory agencies, as well as health care leaders. This paper presents a review of the topics covered. Specifically the challenges in accelerating vaccine development and analytical characterization techniques to establish shelf-life were covered. Additionally, vaccine stability modeling using prior knowledge stability models and advanced kinetic analysis played a key in the EUA approaches discussed during the workshop. Finally, the role of stability studies in addressing the challenges of vaccine distribution and deployment during the pandemic were a focus of presentations and panel discussions.Although the workshop did not have any presentation topics directly dedicated to the mRNA vaccines, the techniques discussed are generally applicable. The mRNA vaccine developers were represented in the panel discussions, where experts involved in the EUA approval/deployment stages for this vaccine type could discuss the challenges as applied to their vaccines.

BackgroundThe risk factors for scrub typhus in Vietnam remain unknown. Scrub typhus caused byOrientia tsutsugamushioften presents as an undifferentiated febrile illness and remains under appreciated due to the limited availability of diagnostic tests. This tropical rickettsial illness is increasingly recognized as an important cause of non-malaria acute undifferentiated fever in Asia. This study aimed to investigate behavioural and ecological related risk factors of scrub typhus to prevent this potentially life-threatening disease in Vietnam.MethodsWe conducted a clinical hospital-based active surveillance study, and a retrospective residence-enrolment date-age-matched case–control study in Khanh Hoa province, Vietnam, from August 2018 to March 2020. Clinical examinations, polymerase chain reaction and enzyme-linked immunosorbent assay IgM tests were applied to define cases and controls. All enrolled participants filled out a questionnaire including demographic socio-economic status, personal behaviors/protective equipment, habitat connections, land use, and possible exposure to the vector. Multivariable conditional logistic regression was used to define the scrub typhus associated risk factors.ResultsWe identified 44 confirmed cases and matched them with 152 controls. Among cases and controls, the largest age group was the 41–50 years old and males accounted for 61.4% and 42.8%, respectively. There were similarities in demographic characteristics between the two groups, with the exception of occupation. Several factors were significantly associated with acquisition of scrub typhus, including sitting/laying directly on household floor [adjustedOR(aOR) = 4.9, 95%CI:1.6–15.1,P = 0.006], household with poor sanitation/conditions (aOR = 7.9, 95%CI:1.9–32.9,P = 0.005), workplace environment with risk (aOR = 3.0, 95%CI:1.2–7.6,P = 0.020), always observing mice around home (aOR = 3.7, 95%CI:1.4–9.9,P = 0.008), and use of personal protective equipment in the field (aOR = 0.4, 95%CI:0.1–1.1,P = 0.076).ConclusionsEcological and household hygiene-related factors were more associated with scrub typhus infection, than individual-level exposure activities in the hyper-endemic area. These findings support local education and allow people to protect themselves from scrub typhus, especially in areas with limitations in diagnostic capacity.Graphical abstract

Summary Background The Millennium Villages Project (MVP) was a 10 year, multisector, rural development project, initiated in 2005, operating across ten sites in ten sub-Saharan African countries to achieve the Millennium Development Goals (MDGs). In this study, we aimed to estimate the project's impact, target attainment, and on-site spending. Methods In this endline evaluation of the MVP, we retrospectively selected comparison villages that best matched the project villages on possible confounding variables. Cross-sectional survey data on 40 outcomes of interest were collected from both the project and the comparison villages in 2015. Using these data, as well as on-site spending data collected during the project, we estimated project impacts as differences in outcomes between the project and comparison villages; target attainment as differences between project outcomes and prespecified targets; and on-site spending as expenditures reported by communities, donors, governments, and the project. Spending data were not collected in the comparison villages. Findings Averaged across the ten project sites, we found that impact estimates for 30 of 40 outcomes were significant (95% uncertainty intervals [UIs] for these outcomes excluded zero) and favoured the project villages. In particular, substantial effects were seen in agriculture and health, in which some outcomes were roughly one SD better in the project villages than in the comparison villages. The project was estimated to have no significant impact on the consumption-based measures of poverty, but a significant favourable impact on an index of asset ownership. Impacts on nutrition and education outcomes were often inconclusive (95% UIs included zero). Averaging across outcomes within categories, the project had significant favourable impacts on agriculture, nutrition, education, child health, maternal health, HIV and malaria, and water and sanitation. A third of the targets were met in the project sites. Total on-site spending decreased from US$132 per person in the first half of the project (of which $66 was from the MVP) to $109 per person in the second half of the project (of which $25 was from the MVP). Interpretation The MVP had favourable impacts on outcomes in all MDG areas, consistent with an integrated rural development approach. The greatest effects were in agriculture and health, suggesting support for the project's emphasis on agriculture and health systems strengthening. The project conclusively met one third of its targets. Funding The Open Society Foundations, the Islamic Development Bank, and the governments of Japan, South Korea, Mali, Senegal, and Uganda.

In this work, a single phase of P2-Na0:67Mn0:75Ni0:25O2 (NaMNO) material was successfully synthesized via a coprecipitation method with the size varying from 2 to 4 mm. According to the atomic absorption spectroscopy (AAS), all the metallic elements were uniformly distributed in the bulk material with the desired ratio Mn¸Ni = 3¸1. The electrochemical properties of P2-NaNMO were investigated in carbonate-based electrolytes using 1M NaClO4 or 1M NaPF6. Among these electrolytes, this cathode exhibited the best electrochemical performance with initial capacity up to 205.7 mAh/g and capacity retention reaches 63.2% during 60 cycles when using 1M NaClO4/PC + 2% (v/v) VC. Indeed, vinylene carbonate (VC) additive plays an important role in improving the performance of NaMNO cathode through the formation of a stable cathode electrolyte interphase layer (CEI). Electrochemical impedance spectroscopy (EIS) was performed to demonstrate CEI layer formation indicated by the elevation of the electrode surface film and double layer impedance in the initial cycle. During cycling, galvanostatic intermittent titration technique (GITT) helps to calculate the Na+ ion diffusion coefficient, which was increased clearly at the working voltages of Mn3+/Mn4+ and Ni3+/Ni4+ redox couples.

Listeriolysin O (LLO) is an important extracellular toxin of Listeria monocytogenes which degrades the phospholipid membranes of the host cells’ phagosomes at low pH during the intracellular survival. In contrast to the natural form, the mutant LLO carrying two replacements of amino acid E247M and D320K possesses stable activity at pH 7.4. In this study, we have constructed vectors that carry the mhlyA gene encoding double-mutated LLOE247M/D320K express in B. subtilis 1012. The target gene was fused to the sequence of LysRN-6xHis-TEV site to enhance the recombinant protein expression in B. subtilis and to ease the acquisition of protein by Ni2+-based affinity chromatography. As results, we have obtained the purified protein LLOE247M/D320K with high purity. The activity measurement with 3 HU hemolytic toxins in the pH range from 5.0 to 8.5 suggested that the activity of LLOE247M/D320K was much better than that of natural LLO at neutral pH and slightly alkaline. These results not only provided important scientific foundations for mutant LLO bases expression in B. subtilis but also supplied purified materials for researche and medical applications based on this protein.

Production of KPC-type carbapenemase is the most common carbapenem resistant mechanism in Klebsiella pneumoniae. The expression level of KPC in these strains is different and is mostly required other mechanisms to reach the higher resistant level such as porin lost or co-expression of extended spectrum β-lactamase (ESBL). To better understand the expression of KPC enzyme, the KPC-2 encoding genes from clinical isolated K. pneumoniae were cloned into pET28a plasmid. The recombinant plasmids containing of kpc-2 gene were subsequently transformed into E. coli OmniMax and were screened in kanamycine added LB media to select E. coli possessing of recombinant plasmid. Carbapenemase activity in the broth culture was checked in LB broth supplemented with 4 µg/mL of ertapenem and the expression induced with IPTG was checked by SDS-PAGE method. The results showed that this recombinant vector was capable of effective expression of KPC-2 protein in E. coli and this strain could be grown in LB broth supplemented with 4 µg/mL of ertapenem. A half of the target protein was soluble in the supernatant however it could be successfully collected from a HistrapHP affinity chromatography column. The result of this report is one of resources for further studies and applications of this KPC-2 protein in clinical research.

Electrolytes play an important role in the battery components it determines the electrochemical window or the working potential region of the battery according to the LUMO and HOMO energy levels and reflects its thermodynamic stability when contacting with the electrode materials. The choice of the electrolyte affects significantly the specific energy, safety, cycle life, storage performance, or operating conditions of batteries. Besides, the electrolytes could be perfectly improved its performance within the addition of some essential additives, which also help to increase the performance of the battery. In this study, the effects of NaPF6, NaClO4, NaOTf, NaFSI, and NaTFSI salts on the hard carbon anode performance were investigated in the carbonate ester solvents including EC:DMC:PC (1:1:1) of 1 M salt concentration without and with additives FEC, VC, and Py13. The compatibility hard carbon electrode-electrolyte systems were investigated for their electrochemical performance by using Galvanostatic cycling with potential limitation, Cyclic voltammetry, and electrochemical impedance spectroscopy in coin-cell type. Among the studied electrolytes, the electrolyte EC:DMC:PC (1:1:1) + 1 M NaOTf exhibited the best electrochemical performance. The specific capacity was above 246 mAh/g after 100 cycles and the Coulombic efficiency higher than 99.6%.

The liquid electrolyte transports lithium ions from anode to cathode during charging, and vice versa. The choice of electrolyte is also important since high ionic conductivity between electrodes is essential for high-performance batteries. Liquid electrolytes with lithium salt dissolved in an organic solvent have been widely used since the 1970s when lithium primary batteries were first developed. Most lithium secondary batteries available today use organic electrolytes. Ionic liquids consist of organic cations and inorganic anions, due to the absence of a combustible and flammable organic solvent, they are known to produce safer batteries. Furthermore, they have a high polarity that allows dissolution of inorganic and organic metal compounds, and they can exist in a liquid state over a wide temperature range. Another type of solvent with similar physical properties and phase behavior to ILs is deep eutectic solvents (DESs) about which the first paper was recently published in 2001. These solvents are mixtures that have a much lower melting point than that of any of their individual components, mainly due to the charge delocalization occurring through hydrogen bonds between them. DESs are generally favored over ILs because they are cheaper and easier to prepare with high purity. In this work, Deep Eutectic Solvents (DESs) were prepared by simple mixing Lithium bis[(trifluoromethane)sulfonyl] imide (LiTFSI) salt and 2,2,2-trifluoroacetamide TFA at various ratios ranging from 1:1.5 to 1:4, respectively. The formation of DESs was characterized by Infrared Spectroscopy (IR) and Thermogravimetric analysis (TGA). Their physical and electrochemical properties were also evaluated based on their viscosity, conductivity, and oxidation stability window. Amongst our systems of interest, DES with LiTFSI: FAc ratio of 1:4 is the most promising as the electrolyte for Li-ion batteries, because it exhibited the lowest viscosity (42.2 mPa.s), the highest ionic conductivity (1.53 mS.cm-1 at 30oC) and relatively good anodic stability (5.2 V vs. Li+/Li).

Brazil, the largest country in South America, has become the second largest pharmaceutical market in the emerging world. The Brazillian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA) was created in 1999 with the primary goal to protect and promote public health surveillance over products and services in Brazil. The governing body and structure of this new regulatory agency will be the aims of this paper, where the authors hope to share their understanding on the regulatory processes and its significant importance of this agency.

An American Association of Pharmaceutical Scientists (AAPS) workshop on stability challenges for clinical supplies and commercial distribution of drug product that are not addressed in the International Conference on Harmonization (ICH) Quality documents was held from April 3rd – 4th, 2017 in Rockville, MD. Seventeen subject matter experts (SME), from industry and the Food & Drug Administration (FDA) presented and facilitated the round-table discussions. A total of fifty-five participants that included experienced pharmaceutical scientists, both from small and large pharmaceutical companies and service providers, benefited from the opportunity to interact face-to-face with industry partners and regulatory agency SMEs. The two-day meeting was divided into five major sections to ensure face-to-face interactions and round-table discussions between participants and SMEs: 1) statistical approaches to stability, dissolution, and shelf life testing, 2) microbiological quality of drug products, 3) strategies to support distribution, unplanned excursions, and transportation of drug products, 4) regulatory considerations on stability testing of biologics, and 5) in-use stability during clinical and commercial phases. All in all, this interactive workshop focused on challenges and successes of addressing stability concerns that affect pharmaceutical development, manufacturing, distribution, and use of drug substances/products for which no or limited ICH guidance exists. The interactive meeting provided a unique opportunity to industrial scientists and regulatory agency liaisons to facilitate the discourse on how to address stability challenges that are not addressed in harmonized guidelines: this paper summarizes those discussions.

Microdeletion on the Y chromosome is one of the causes that makes men infertile, accounting for 2-10 % of all infertility cases, and occurs frequently at 3 regions of the Ychromosome long arm namely AZFa, AZFb and AZFc (azoospermia factor). Currently, the diagnosis of microdeletion on the Y chromosome is almost mandatory in institutes and centers for infertility diseases before selecting treatment or assisting methods. To detect microdeletion in AZF, SRY and ZFY regions, the current approach is a Multiplex – PCR assay offering by European Academy of Andrology/European Molecular Genetics Quality Network (EAA/ EMQN). However, the drawback of this method is the PCR products posess similar size and then the DNA electrophoresis bands were very close on gels causing the difficult in diagnosis. Therefore, in this study, we have redesigned primer pairs matching with genes that were recommended by EAA/EMQN but the PCR products are clearly different in sizes, making the DNA electrophoresis bands take apart further to facilitate the diagnosis. Besides, we have also created recombinant plasmids carrying the marker genes for the control sample in kits.

In the past decade, many guidance documents have been issued through collaboration of global organizations and regulatory authorities. Most of these are applicable to new products, but there is a risk that currently marketed products will not meet the new compliance standards during audits and inspections while companies continue to make changes through the product life cycle for continuous improvement or market demands. This discussion presents different strategies to bringing drug product marketing applications to meet current and emerging standards. It also discusses stability and method designs to meet process validation and global development efforts.

We report three-dimensional (3D) nanoporous graphene with preserved 2D electronic properties, tunable pore sizes, and high electron mobility for electronic applications. The complex 3D network comprised of interconnected graphene retains a 2D coherent electron system of massless Dirac fermions. The transport properties of the nanoporous graphene show a semiconducting behavior and strong pore-size dependence, together with unique angular independence. The free-standing, large-scale nanoporous graphene with 2D electronic properties and high electron mobility holds great promise for practical applications in 3D electronic devices.

Sonneratia alba J.E. Smith, Sonneratiaceae widely grows in mangrove forests. There were some studies on plants of mangrove forests, and these results showed they contained many interesting bioactive compounds. Nevertheless, Sonneratia alba has not much been studied, especially, has not yet been chemically and biologically studied in Viet Nam. From the petroleum ether extract of the leaves of Sonnertia alba, oleanolic acid (1), betulin (2), betulinic acid (3), alphitolic acid (4), methyl gallate (5) and 5-hydroxymethylfurfural (6) were isolated. Their structures were identified by comparing their NMR data as well as the physical properties with those in literatures. Among them, (1) had high yield (about 0.15% of dried leave) with numerous pharmacological activities including inhibitory activity against HIV-1 protease with IC50 of 6.3 mM, anti-inflammatory, anti-cancer. So, Sonneratia alba should be exploited to afford to a valuable source in food and pharmaceutical products. Further studies on this plant are in progress.

This article focuses attention on monitoring and evaluation approaches that will help resource managers to manage for change and uncertainty in adaptive co-management (ACM). ACM is a learning-by-doing approach that aims to build flexible community-based natural resource governance systems through collaborative or otherwise participatory means. We describe the framework for monitoring and evaluation that we developed and applied in ten African countries, which includes fixed indicators and measures for co-management performance monitoring, a process evaluation element, a platform for repeat ecological surveillance, and a longitudinal household survey. We comment on the usefulness of this framework, and its applicability to a wide range of geographic contexts. We then present a four step model to assist managers in applying the framework to specific co-management problems. The model suggests a cascade approach to defining key evaluations questions at a systems, network, individual and synthesis level. We illustrate the application of our model and framework by means of a case study of a co-managed agroforestry program in western Kenya.

Oocyte maturation and ovulation require a coordinated interaction between gonadotrophs, steroid hormones, and growth factors. The extent to which estrogen is required in this process, however, remains unclear. To better understand the role of estrogen in maintaining developmental competence of mammalian oocytes, we studied the Aromatase knockout (ArKO) mouse, which has been genetically engineered to be incapable of synthesizing endogenous estrogen. Previous studies have established that ArKO female mice are anovulatory with ovaries that progressively degenerate, developing hemorrhagic cystic follicles. In young ArKO females, however, apparently healthy follicles and oocytes have been observed. We investigated if these oocytes could be induced to ovulate, then mature, fertilize, and develop in vitro. Following a standard superovulation protocol, ArKO oocytes did not ovulate. When recovered manually from the ovary, however, ArKO oocytes successfully progressed through in vitro maturation, fertilization, and development to the blastocyst stage at the same rate as wild-type and heterozygote littermates. Therefore, it appears that estrogen is not required for the production and growth of oocytes capable of maturation and complete preimplantation development but is required for continued follicle growth and feedback regulation of ovulation.

The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on 13–14 October 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of active pharmaceutical ingredients (API) and drug products in the drug development process. These changes can affect both the safety and efficacy of drugs; therefore, the ability to rapidly predict and assess the potential for drug product performance changes for impurity formation and the associated safety concerns are important parts of speeding the development of innovative drug therapies without compromising quality. The workshop comprised four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that affect drug impurities and drug degradation products, the control of impurities, and the impact of these factors on safety and regulatory areas. Taken together, this comprehensive understanding is used to achieve a more robust development approach that enables predictability with a concomitant assurance of safety and efficacy. Innovative methodologies for development of effective stability control strategies were also presented. This article summarizes sessions 3 and 4 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues and addresses issues of safety considerations of impurities in pharmaceutical products and surveying the impurity landscape. Sessions 1 and 2 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues are summarized in Recent Trends in Product Development and Regulatory Issues on Impurities in active Pharmaceutical Ingredient (API) and Drug Products Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms published separately.

The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on October 13–14, 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of active pharmaceutical ingredients (API) and drug products in the drug development process. These changes can affect both the safety and efficacy of drugs; therefore, the ability to rapidly predict and assess the potential for drug product performance changes for impurity formation and the associated safety concerns are important parts of speeding the development of innovative drug therapies. The workshop consisted of four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that impact drug degradation, the control of impurities and the impact of these factors on safety and regulatory areas. Taken together, this comprehensive understanding is used to achieve a more robust development process that enables predictability with a concomitant assurance of safety and efficacy. Innovative methodologies for development of effective stability control strategies were also presented. This article summarizes Sessions 1 and 2 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues and addresses of predicting degradation related impurities and impurity considerations for pharmaceutical dosage forms. Sessions 3 and 4 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues are summarized in Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape published separately.

Summary Background Simultaneously addressing multiple Millennium Development Goals (MDGs) has the potential to complement essential health interventions to accelerate gains in child survival. The Millennium Villages project is an integrated multisector approach to rural development operating across diverse sub-Saharan African sites. Our aim was to assess the effects of the project on MDG-related outcomes including child mortality 3 years after implementation and compare these changes to local comparison data. Methods Village sites averaging 35 000 people were selected from rural areas across diverse agroecological zones with high baseline levels of poverty and undernutrition. Starting in 2006, simultaneous investments were made in agriculture, the environment, business development, education, infrastructure, and health in partnership with communities and local governments at an annual projected cost of US$120 per person. We assessed MDG-related progress by monitoring changes 3 years after implementation across Millenium Village sites in nine countries. The primary outcome was the mortality rate of children younger than 5 years of age. To assess plausibility and attribution, we compared changes to reference data gathered from matched randomly selected comparison sites for the mortality rate of children younger than 5 years of age. Analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT01125618. Findings Baseline levels of MDG-related spending averaged $27 per head, increasing to $116 by year 3 of which $25 was spent on health. After 3 years, reductions in poverty, food insecurity, stunting, and malaria parasitaemia were reported across nine Millennium Village sites. Access to improved water and sanitation increased, along with coverage for many maternal-child health interventions. Mortality rates in children younger than 5 years of age decreased by 22% in Millennium Village sites relative to baseline (absolute decrease 25 deaths per 1000 livebirths, p=0·015) and 32% relative to matched comparison sites (30 deaths per 1000 livebirths, p=0·033). Interpretation An integrated multisector approach for addressing the MDGs can produce rapid declines in child mortality in the first 3 years of a long-term effort in rural sub-Saharan Africa. Funding UN Human Security Trust Fund, the Lenfest Foundation, Bill & Melinda Gates Foundation, and Becton Dickinson.

Many or most genes on the mammal Y chromosome evolved a testis-specific function after diverging from an X-borne copy with a general function in both sexes. In marsupial but not eutherian mammals, a testis-specific orthologue (ATRY) of the widely expressed X-borne ATRX gene lies on the Y chromosome. Since mutations in human ATRX cause sex reversal, it is possible that one function of ATRY in marsupials is testicular differentiation. We report here the isolation and sequencing of the tammar wallaby (Macropus eugenii) ATRY cDNA, and comparison of its sequence with that of tammar ATRX. The evolution of a testis-specific function for the ATRY protein distinct from the general role of ATRX in both sexes has been accompanied by sequence changes in many protein domains that would alter protein binding partners. A large open reading frame encodes a 1771 amino acid ATRY protein that has diverged extensively from ATRX. The conservation and loss of particular motifs identify those required for testicular function (ATRY) and function in other tissues (ATRX).

The ATRX protein, associated with X-linked alpha-thalassaemia, mental retardation and developmental abnormalities including genital dysgenesis, has been proposed to function as a global transcriptional regulator within a multi-protein complex. However, an understanding of the composition and mechanics of this machinery has remained elusive. We applied inter-specific comparative analysis to identify conserved elements which may be involved in regulating the conformation of chromatin. As part of this study, we cloned and sequenced the entire translatable coding region (7.4 kb) of the ATRX gene from a model marsupial (tammar wallaby, Macropus eugenii). We identify an ATRX ancestral core, conserved between plants, fish and mammals, comprising the cysteine-rich and SWI2/SNF2 helicase-like regions and protein interaction domains. Our data are consistent with the model of the cysteine-rich region as a DNA-binding zinc finger adjacent to a protein-binding (plant homeodomain-like) domain. Alignment of vertebrate ATRX sequences highlights other conserved elements, including a negatively charged mammalian sequence which we propose to be involved in binding of positively charged histone tails.

An AAPS joint face-to-face meeting was held on April 6th, 2016 at MedImmune, Gaithersburg, MD. The meeting was organized by members of the Steering Committees of the Stability Focus Group, the Pharmaceutical Impurities Focus Group and the Chemistry, Manufacturing and Controls (CMC) Statistics Focus Group. Twenty two subject-matter-experts (SME) from the Industry and the Food & Drug Administration (FDA) participated as discussion facilitators or discussion leaders. The total participants reached 65 people representing various sizes of pharmaceutical companies. Four contemporary technical topics on analytical approaches to ensure product quality were selected to be discussed and shared information: (1) Approaches to set release limits and managing method variability; (2) Ensure product quality through lifecycle management; (3) Best practices for predictive stability programs; and (4) ICH Guideline M7 and mutagenic impurities. The purpose of the meeting was to share the best practices in the industry related to the topics; therefore, it is not intended for the participants to reach a consensus on the key issues discussed. This paper summarizes the discussions in the meeting.