WHO Technical Report Research Articles

Overall survival benefits of cancer drugs in the WHO Model List of Essential Medicines, 2015–2021

IntroductionWe examined overall survival (OS) benefits for targeted cancer drugs recommended for List of Essential Medicines (EMLs) since 2015. We assessed consistency of decisions in 2019 and 2021 with more...

Mass drug administration in neglected tropical diseases: beyond elimination

Mass drug administration in neglected tropical diseases: beyond elimination

Path Forward to Optimise Post-approval Change Management and Facilitate Continuous Supply of Medicines and Vaccines of High Quality Worldwide

Post-approval changes (PACs) to the registered information of authorised medicinal products are introduced routinely worldwide to enhance the robustness and efficiency of the manufacturing process, ensure timely supply in case of increased demand, improve quality control techniques, respond to changes in regulatory requirements and upgrade to state-of-the-art facilities. These are critical to prevent supply disruption and continuously improve existing medicines and vaccines. Due to the complexity of current PAC systems across markets, a change can take 3 to 5 years to approval globally (Hoath et al in BioProcess Int, 2016) thus hindering innovation and increasing the risk of shortages. The key messages are as follows: 1. Industry believes that global regulatory convergence of post-approval changes to Marketing Authorisations (MAs) using science- and risk-based approaches will enable a more efficient management of quality and supply improvements and will facilitate patients’ access to innovative medicines and vaccines of the highest quality. 2. National Regulatory Authorities (NRAs) should establish national or regional guidelines in line with international standards (regarding a risk-based classification of changes and standardisation of requirements) (Guidelines on procedures and data requirements for changes to approved biotherapeutic products, in WHO Technical Report Series, 2018, Guidelines on procedures and data requirements for changes to approved vaccines, in WHO Technical Report Series, 2015), have clear procedural guidance including timelines and implement reliance pathways to accelerate the approval of changes. This paper briefly outlines the challenges for PACs and provides solutions for a more flexible and aligned global system.

HTLV-1 Transmission and HIV Pre-exposure Prophylaxis: A Scoping Review.

HIV pre-exposure prophylaxis (HIV-PrEP) is effective in reducing the likelihood of HIV acquisition in HIV-negative people at high risk of exposure. Guidelines recommend testing for sexually transmitted infections (STIs) before starting, and periodically on PrEP, including bacterial infections, HIV, hepatitis C virus, and, for those who are non-immune, hepatitis B virus. Diagnosed infections can be promptly treated to reduce onward transmission. HTLV-1 is not mentioned; however, it is predominantly sexually transmitted, causes adult T-cell leukaemia/lymphoma (ATL) or myelopathy in 10% of those infected, and is associated with an increased risk of death in those without any classically HTLV-associated condition. The 2021 WHO Technical Report on HTLV-1 called for the strengthening of global public health measures against its spread. In this scoping review, we, therefore, (1) discuss the epidemiological context of HIV-PrEP and HTLV-1 transmission; (2) present current knowledge of antiretrovirals in relation to HTLV-1 transmission prevention, including nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and integrase strand transfer inhibitors (INSTIs); and (3) identify knowledge gaps where data are urgently required to inform global public health measures to protect HIV-PrEP users from HTLV-1 acquisition. We suggest that systematic seroprevalence studies among PrEP-using groups, including men who have sex with men (MSM), people who inject drugs (PWIDs), and female sex workers (FSWs), are needed. Further data are required to evaluate antiretroviral efficacy in preventing HTLV-1 transmission from in vitro studies, animal models, and clinical cohorts. PrEP delivery programmes should consider prioritizing the long-acting injectable INSTI, cabotegravir, in HTLV-1 endemic settings.

The long and winding road: transport pathways for amino acids in Arabidopsis seeds.

Pathways for assimilates. During their life cycle, plants alternate between a haploid stage, the gametophyte, and a diploid stage, the sporophyte. In higher plants, meiosis generates the gametophyte deeply embedded in the maternal tissue of the flower. The megaspore mother cell undergoes meiosis, and then, the surviving megaspore of the four megaspores produced undergoes mitotic divisions and finally gives rise to the female gametophyte, consisting of the egg cell, two synergids, the central cell, which due to the fusion of two nuclei is diploid (double haploid) in Arabidopsis and most angiosperms and the antipods, whose number is not fixed and varies significantly between species (Yadegari and Drews in Plant Cell 16(Suppl):S133-S141, 2004). The maternal tissues that harbor the female gametophyte and the female gametophyte are referred to as the ovule (Fig.1). Double fertilization of the egg cell and the central cell by the two generative nuclei of the pollen leads to the diploid embryo and the endosperm, respectively (Hamamura et al. in Curr Opin Plant Biol 15:70-77, 2012). Upon fertilization, the ovule is referred to as the seed. Seeds combine two purposes: to harbor storage compounds for use by the embryo upon germination and to protect the embryo until the correct conditions for germination are encountered. As a consequence, seeds are the plant tissue that is of highest nutritional value and the human diet, by a considerable amount, consists of seeds or seed-derived products. Amino acids are of special interest, because plants serve as the main source for the so-called essential amino acids, that animals cannot synthesize de novo and are therefore often a limiting factor for human growth and development (WHO in Protein and amino acid requirements in human nutrition. WHO technical report series, WHO, Geneva, 2007). The plant embryo needs amino acids for general protein synthesis, and additionally they are used to synthesize storage proteins in the seeds of certain plants, e.g., legumes as a resource to support the growth of the seedling after germination. The support of the embryo depends on transport processes that occur between the mother plant and the seed tissues including the embryo. In this review, we will focus on the processes of unloading amino acids from the phloem and their post-phloem transport. We will further highlight similarities between amino acid transport and the transport of the main assimilate and osmolyte, sucrose. Finally, we will discuss similarities and differences between different plant species in terms of structural aspects but for the molecular aspects we are almost exclusively focusing on Arabidopsis. Fig.1 Vascularization of the Arabidopsis ovule and seed. Plants expressing ER-localized mCherry under control of the companion cell-specific SUC2 promoter and ER-localized GFP under control of the sieve element marker PD1 as described (Müller et al. 2015) are shown to visualize the phloem in the funiculus and the chalazal regions. a Overview over an ovule. FG: female gametophyte. b A magnification of the region marked by a square in panel a. c Overview over a seed. ES: endosperm; E: embryo. d A magnification of the region marked by a square in panel c. The arrows in b and d point to the terminal companion cell and arrowheads to terminal sieve elements.

Treatment of preschool children for schistosomiasis.

Treatment of preschool children for schistosomiasis.

The Characteristics of an Ovine Lymphoid Cell-Line sensitive to Vaccinal Infectious Bursal Disease Virus Strain.

Infectious bursal disease (IBD), also known as Gumboro disease, is a globally well-known disease with a significant socio-economic effect. For control of IBD, several commercial egg- and cell-based vaccines are prepared. The cell-based IBD vaccines are significantly cost-effective; however, it is essential to confirm their safety and efficacy. The main cell line used to product the cell-based IBD vaccines, is a primary chicken embryo fibroblast (CEF). Nevertheless, manipulation of CEF is extremely challenging and time-consuming. This study aimed to characterize a sensitive suspension cell culture from ovine lymphoid, according to WHO technical report series; No. 978, Annex III. This authentication covered the growth curves, sensitivity, stability, karyotyping and identifying the adventitious agents. This cell line passed all defined tests and was considered as a suitable one for IBD vaccine preparation in a large scale.

Integration of BCTs in a Companion App to Support and Motivate Teenagers in the Adoption of Healthy Lifestyle Behaviours

Integration of BCTs in a Companion App to Support and Motivate Teenagers in the Adoption of Healthy Lifestyle Behaviours

Interchangeability Study of Multisource Paracetamol 500mg Tablets, Produced in Mongolia.

To define interchangeability of locally produced Paracetamol (Acetaminophen INN), 500mg tablets. For this purpose Paracetamol 500mg tablets produced by 7 local manufacturers were tested. As a comparator product was used Panadol 500mg, produced by GlaxoSmithKline. Bioequivalence testing was done according to the WHO guideline, Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability, WHO Technical Report Series, №.937, 2006. Based on Biopharmaceutics Classification System Paracetamol tablets bioequilvalency testing was done in vitro through determination of dissolution. In each media of pH 1.2, 4.5 and 6.8 were tested 12 unit samples. All samples were dissolved in three media in not less than 85% of the labelled amount of the paracetamol in 15 minutes. According to the questionnaire, all manufacturers producing Paracetamol tablets answered that the formulation of dosage form was considered the attribute of active pharmaceutical ingredient and excipients and used machinery’s specification. As criteria for choosing the formulation, manufacturers were used pharmacopoeial monograph, stability study data and dissolution results. Mongolian manufacturer’s Paracetamol formulations not contain excipients such as sodium bicarbonate, which is fastening the drug absorption. Three manufacturers use Povidone as a binder, same like comparator product. Most formulations contain Talc and Magnesium stearate as a lubricant mix, when comparator contains Stearic acid and Talc. All formulations contain starch and cellulose, their derivates. Paracetamol 500mg tablets produced by all 7 local manufacturers: LM1, LM2, LM3, LM4, LM5, LM6 and LM7 have dissolution more than 85% in 15 minutes in each of three media. Therefore the dissolution profile comparison with an f2 test is unnecessary [4]. Samples: LM1, LM2, LM3, LM4, LM5, LM6 and LM7 are bioequivalent and could be interchangeable with comparator pharmaceutical product.

BCSH guideline for the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn.

BCSH guideline for the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn.

Senior Labor Study: A New Definition Of Normal Hemoglobin Values In Older Healthy Individuals

▪With increasing mean age of the world population it becomes clear that biological and chronological ages might diverge on individual levels. In contrast to working age adults, older people have a higher incidence of anemia mostly in association with medical comorbidities (Artz, Fergusson et al. 2004, Merchant and Roy 2012). Incidence of anemia in the elderly has so far been investigated in large studies mostly performed on hospitalized patients, nursing homes subjects or mobile examination centers subjects seeking medical care with a variety of complaints (Kikuchi, Inagaki et al. 2001, Guralnik, Eisenstaedt et al. 2004). In the USA, the 3rd NHANES study focused on racial groups of elderly revealing a prevalence of anemia in men and women >65 yrs of ∼10% (Izaks, Westendorp et al. 1999, Guralnik, Ershler et al. 2005). In patients over 85 yrs, this number exceeded 20%.Current reference intervals for clinical laboratory assays are based on younger adult's samples. Physiologic concentrations of hemoglobin (Hb) in human blood range from 120 g/l (female) and 130 g/l (male) to 168 g/l (both genders) under which anemia and above which polycythemia get diagnosed. We are currently in need for reference ranges suited for normal older subject and unbiased by already debilitated individuals. The defining cut-offs provided by the WHO are 120 g/l for women and 130 g/l for men (WHO Technical Report Series 1968); although older age is generally associated with lower Hb levels, these cut-offs do not account for age.We have performed a large recruitment as part of our Senior Labor study (Risch, Medina et al. 2012). In contrast to previous studies, we have prospectively recruited healthy Caucasian subjects over 60, implementing strong exclusion criteria for participating subjects. For those healthy individuals, a complete blood count (CBC) as well as frequently performed clinical laboratory tests were prospectively performed.A total of 1255 subjects consented to enroll for the study after having passed the primary clinical exclusion criteria which comprised one or more of the following questions affirmatively answered (primary exclusion criteria): drugs: do you take drugs containing steroids, are you under ill-adjusted antihypertensive therapy, do you suffer from thyroid diseases/are you substituted with thyroid hormones, do you have diabetes mellitus, have you suffered from cancer during the last 5 years, were you hospitalized during the month prior to enrolment and do you abuse alcohol.Complete blood count assays were done using an XE-5000 hematology analyzer and clinical chemistry assays followed routine workflow on modular platforms.We evaluated 696 women and 559 with ages ranging from 60 to 99 years old. Mean Hb and 95% confidence intervals were calculated using logarithmic transformation in order to correct of skewness of the data. Overall, women had a mean Hb of 136 (95%CI 120-155) and men had a mean Hb of 148 (95%CI 128-172). Detailed results by age groups are presented in figure 1. [Display omitted] Hb level was steady over age groups until 74 yo for men and 79 for women. Interestingly, only a few subjects fell outside the WHO limits with 20 women having a Hb less than 120 (2.9%) and 20 men a Hb less than 130 (3.6%).We looked for frequent causes for anemia such as low ferritin and vitamin deficiencies (folic acid and B12). In the cohort, 37 subjects had a ferritin lower than 20 µg/l (2.9%). Among these, 9/37 (24.3%) had a low Hb (WHO definition) and only one in 37 (2.7%) had a MCHC below 310.The micronutrients folic acid and vitamin B12 were also assessed; 98 subjects (7.8%) had folic acid < 10 nmol/l. Among these individuals, 6/98 (6.1%) were anemic. The definition of vitamin B12 deficiency varies but is usually accepted as lower than 200 pmol/l in older persons: in the whole population, 398/1255 (31.7%) subjects had vitamin B12 levels < 200 pmol/L, and 105/1255 (8.4%) had vitamin B12 concentrations less than 150 pmol/L. Using these two limits, these subjects were anemic in 11/398 (2.8%) and 4/105 (3.8%) respectively. This indicates a limited impact of folic acid and B12 deficiency on anemia of the elderly.In this study, we were able to define new Hb reference range in older subjects reporting healthy by strict clinical criteria in a large cohort of subjects. Our results show a very limited proportion of subject with WHO defined anemia, thus indicating that even in older subjects, the discovery of a low Hb is likely to be associated to an underlying pathology. Disclosures:No relevant conflicts of interest to declare.

Progressive Applications of Dissolution, Its Impact, and Implications in the Pharmaceutical World

Progressive Applications of Dissolution, Its Impact, and Implications in the Pharmaceutical World

Dietary protein quality and malnutrition in Africa

The WHO (2007) Technical Report on protein and amino acid requirements in human nutrition states that the best estimate for a population average requirement is 105 mg nitrogen/kg body weight per day, or 0·66 g protein/kg body weight per day. In many developing countries protein intake falls significantly short of these values. Apart from protein quantity, protein quality including bioavailability and digestibility, from different food sources, are currently on the global agenda. The 1st International Symposium on Dietary Protein for Human Health held in Auckland, in March 2011, and the consecutive Food and Agricultural Organization of the United Nations (FAO) Expert Consultation on Dietary Protein Quality, both highlighted the importance of assessing the quality of protein from different food sources through determination of amino acid content. Throughout the developed world, animal products and cereals are the two most important sources of protein; in developing countries this order is reversed. In low income countries only 3 % of total dietary energy, as an indicator of diet composition, is derived from meat and offal, 11 % from roots and tubers and 6 % from pulses, nuts and oilseeds. The remainder of the dietary energy is mainly derived from cereal-based staple food. Although the production of livestock has increased in developing countries, the consumption of protein in these countries with people consuming the most limited amounts of protein are continually decreasing. Undernutrition, including insufficient consumption of protein, remains a persistent problem in the developing world, and although many diets within these developing countries are deficient in the quantity of protein compared to recommendations, the quality of the protein also strongly comes into focus.

The effectiveness and acceptability of a traffic light labelled menu with energy information to signpost customers towards healthier alternatives in a table service restaurant

Background: An increase in energy dense meals eaten outside the home has been identified as a contributing factor in the rise in obesity over the last 25 years (WHO, 2003). Initiatives that clearly signpost healthier restaurant meal choices that are lower in energy and fat may offer a valuable customer service with potentially important public health, as well as commercial, benefits. The aim of this study was to investigate whether a traffic light labelled menu with healthier choices for two main courses was an acceptable and effective means of encouraging healthier food choices in a table service restaurant. Methods: A menu was developed for an independent table service restaurant to offer ‘standard’ and ‘healthier’ (lower in fat and energy) alternatives for two main courses: one meat and one fish dish. Both sets of dishes were nutritionally analysed and colour coded on the menu in accordance with Food Standard's Agency traffic light signposting guidelines and energy information (FSA, 2009). Over a 2-week period, the choice of dishes made by customers using the menu and their views about whether they liked the initiative, found it useful and whether they would use it in future were surveyed using a questionnaire given after the meal. Practical and commercial issues around preparation, analysis and cost of implementing the menu were assessed in a qualitative interview with the head chef (also the restaurant owner). Results: Seventy surveys were returned from customers [66% female, mean age 42 years (age range 16–65+ years)] over the 2-week period. Of those ordering from the separate menu, almost half (46%) chose the healthy alternative. The concept of a healthy alternatives menu was popular, with 90% (n = 60) of customers who returned a survey stating they either did order or would consider ordering a healthy alternative when eating out. Of 24 customer comments, 25% stated they considered eating out a time to indulge. Women were more strongly in favour than men of the concept of healthy alternatives and of having nutritional information on a menu. Customers who ate out frequently were more likely to order a healthy alternative (rho = 0.249, P = 0.044). Interestingly, choosing a healthy main course increased the likelihood of ordering dessert (rho = 0.459, P = 0.000), thus potentially negating any energy and fat savings. Seventy percent (n = 39) of customers returning the survey said they would like to see healthy alternatives provided in other restaurants. Feedback from the restaurant staff suggested they were broadly in favour of the initiative as a valuable customer service but felt that analysing recipes for a rotating menu in an independent restaurant was both time consuming and costly. Discussion: A traffic light labelled menu with energy information appears to be popular and effective in signposting some customers towards healthier alternatives in a table service restaurant. The finding that the provision of this information on menus was particularly popular with women is supported by other studies (Mackison et al., 2009) and suggests a value of finding ways to increase the appeal to men. The finding that choosing a healthy main course option increased the likelihood of ordering dessert also mirrors previous research. Although exposure to nutritional information on menus may cause customers to eat less at one time point, they may over-compensate for this in subsequent eating occasions (Roberto et al., 2010). This suggests a potential value of information on overall energy balance alongside nutritional signposting information. Such initiatives may be feasible and even commercially beneficial for independent restaurants over the long term, although motivators may be needed to incentivise them alongside tools to support the development and traffic light coding of healthy recipes. Conclusions: A menu signposting healthy alternatives in an independent table service restaurant appears to be popular with customers, effective at encouraging healthier food choices and acceptable to a commercial restaurant especially if there is practical support for implementation.

Scientific Opinion on Flavouring Group Evaluation 86, Revision 1 (FGE.86Rev1): Consideration of aliphatic and aromatic amines and amides evaluated by JECFA (65th meeting)

Scientific Opinion on Flavouring Group Evaluation 86, Revision 1 (FGE.86Rev1): Consideration of aliphatic and aromatic amines and amides evaluated by JECFA (65th meeting)

Interchangeability evaluation of multisource Ibuprofen drug products using biowaiver procedure.

The WHO biowaiver procedure for BCS Class II weak acids was evaluated by running two multisource IR ibuprofen drug products (Ibuprofen, 200 mg tablets, Tatchempharmpreparaty, Russia and Ibuprofen, 200 mg tablets, Biosintez, Russia) with current Marketing Authorizations (i.e. in vivo bioequivalent) through that procedure. Risks associated with excipients interaction and therapeutic index were considered to be not critical. In vitro dissolution kinetic studies were carried out according WHO Guidance (WHO Technical Report Series, No. 937, Annexes 7 and 8) using USP Apparatus II (paddle method) at 75 rpm. Dissolution profiles of test and reference ibuprofen tablets were considered equivalent in pH 4.5 using factors f1 (13) and f2 (72) and not equivalent in pH 6.8 (factor f1 was 26 and f2 was 24). Drug release of ibuprofen at pH 1.2 was negligible due to its weak acid properties. Therefore, two in vivo bioequivalent tablets were declared bioinequivalent by this procedure, indicating that procedure seems to be over-discriminatory.

Evaluation of In Vitro Equivalence for Drugs Containing BCS Class II Compound Ketoprofen

This paper describes the evaluation of the in vitro equivalence of capsules containing a BCS Class II compound, k etoprofen, marketed in Russia under biowaiver conditions and the innovator product. The in vitro equivalence test was carried out according to WHO Technical Report Series, No. 937, Annex 8. Dissolution profiles of test and reference (innovator) ketoprofen capsules are considered equivalent at pH 6.8 without statistical treatment, equivalent at pH 4.5 (f1 = 3 and f2 = 80), and not equivalent at pH 1.2 (f1 = 22 and f2 = 41). Generally, the evaluated capsules did not meet biowaiver criteria for drugs containing BCS Class II API, possibly due to the effect of surfactant (sodium lauryl sulfate) contained in the test preparation on the solubility.

Body mass index and obstetric outcomes in Saudi Arabia: a prospective cohort study

BACKGROUND AND OBJECTIVES:We examined the effect of body mass index in early pregnancy on pregnancy outcome since no study in Saudi Arabia has addressed this question.METHODS:This prospective cohort study involved women registered for antenatal care during the first month of pregnancy at primary health care centers in Al-Hassa, Saudi Arabia. Data was collected from records and by direct interview.RESULTS:The study included 787 women. Compared to normal weight women (n=307), overweight (n=187) and obese (n=226) women were at increased risk for pregnancy-induced hypertension (RR=4.9 [95% CI 1.6-11.1] and 6.1 [95% CI 2.1-17.8], respectively), gestational diabetes (RR=4.4 [95% CI 1.2-16.3] and 8.6 [95% CI 2.6-28.8]), preeclamptic toxemia (RR=3.8 [95% CI 1.1-14.6] and 5.9 [95% CI 1.7-20.4]), urinary tract infections (RR=1.4 [95% CI 0.5-3.9] and 3.7 [95% CI 1.7-6.2]), and cesarean delivery (RR=2.0 [95% CI 1.3-3.0] in obese women). Neonates born to obese women had an increased risk for postdate pregnancy (RR=3.7 [95% CI 1.2-11.6]), macrosomia (RR=6.8 [95% CI 1.5-30.7]), low 1-minute Apgar score (RR=1.9 [95% CI 1.1-3.6]), and admission to neonatal care units (RR=2.1 [95% CI 1.2-2.7]). On the other hand, low birth weight was less frequent among obese women (RR=0.5 [95% CI 0.3-0.9]) while the risk was high among underweight women (RR=2.3 [95% CI 1.4-3.8])CONCLUSION:Even with adequate prenatal care, overweight and obesity can adversely affect pregnancy outcomes.

Evaluation of certain food additives. Sixty-ninth report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Technical Report Series No. 952. 2009. World Health Organization. Geneva, pages 208

Evaluation of certain food additives. Sixty-ninth report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Technical Report Series No. 952. 2009. World Health Organization. Geneva, pages 208

Pediatric Nonalcoholic Fatty Liver Disease in 2009

Within the so-called “globesity” epidemic, the International Obesity Task Force estimated that there at least 155 million persons are overweight/obese, including 30 to 45 million obese children worldwide. 1 Wang Y. Lobstein T. Worldwide trends in childhood overweight and obesity. Int J Pediatr Obes. 2006; 1: 11-25 Crossref PubMed Scopus (2025) Google Scholar , 2 World Health OrganisationPhysical status: the use and interpretation of anthropometry. WHO, Geneva1995 Google Scholar , 3 World Health OrganisationObesity, preventing and managing the global epidemic: report of a WHO consultation. WHO Technical Report Series, No. 894, Geneva2000 Google Scholar , 4 Cole T.J. Bellizzi M.C. Flegal K.M. Dietz W.H. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000; 320: 1240-1246 Crossref PubMed Google Scholar In parallel with epidemic obesity, nonalcoholic fatty liver disease (NAFLD) has also been increasingly recognized worldwide in the last decade. At present, NAFLD is identified as an important liver disease in children, occurring even in the very young. 5 Barshop N.J. Sirlin C.B. Schwimmer J.B. Lavine J.E. Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008; 28: 13-24 Crossref PubMed Scopus (114) Google Scholar The incidence in the general population is 2.6% but increases to 53% in obese children; thus, NAFLD is expected to become the most common cause of pediatric chronic liver disease in the near future. 6 Patton H.M. Sirlin C. Behling C. Middleton M. Schwimmer J.B. Lavine J.E. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr. 2006; 43: 413-427 Crossref PubMed Scopus (214) Google Scholar