Regional Medical Research Centre

Five aromatic constituents of essential oils (cineole, citral, geraniol, linalool and menthol) were tested for antimicrobial activity against eighteen bacteria (including Gram-positive cocci and rods, and Gram-negative rods) and twelve fungi (three yeast-like and nine filamentous). In terms of antibacterial activity linalool was the most effective and inhibited seventeen bacteria, followed by cineole, geraniol (each of which inhibited sixteen bacteria), menthol and citral aromatic compounds, which inhibited fifteen and fourteen bacteria, respectively. Against fungi the citral and geraniol oils were the most effective (inhibiting all twelve fungi), followed by linalool (inhibiting ten fungi), cineole and menthol (each of which inhibited seven fungi) compounds.

BACKGROUND: Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and statistical evidence. However, in the past 20 years, considerable variability has existed in the study design and quality of evidence supporting reported gene-disease associations, raising concerns of the validity of many published disease-causing genes. Brugada syndrome (BrS) is an arrhythmia syndrome with a risk of sudden death. More than 20 genes have been reported to cause BrS and are assessed routinely on genetic testing panels in the absence of a systematic, evidence-based evaluation of the evidence supporting the causality of these genes. METHODS: We evaluated the clinical validity of genes tested by diagnostic laboratories for BrS by assembling 3 gene curation teams. Using an evidence-based semiquantitative scoring system of genetic and experimental evidence for gene-disease associations, curation teams independently classified genes as demonstrating limited, moderate, strong, or definitive evidence for disease causation in BrS. The classification of curator teams was reviewed by a clinical domain expert panel that could modify the classifications based on their independent review and consensus. RESULTS: Of 21 genes curated for clinical validity, biocurators classified only 1 gene ( SCN5A) as definitive evidence, whereas all other genes were classified as limited evidence. After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS. CONCLUSIONS: Our results contest the clinical validity of all but 1 gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations before use in patient care.

SUMMARY Eighty‐seven per cent of a cohort of 299 low‐birthweight (LBW) infants (2000g) were examined at age 6 years 8 months, together with 111 control children. All the controls and 248 of the LBW children were individually assessed in school. Information about another 13 LBW children was obtained by questionnaire. Problems in primary school were related to social grade, evidence of early intra‐uterine insult, sex, postnatal complications and neurological and developmental status in the first year of life. Multiple birth, gestation and intra‐uterine growth were not clearly related to problems in school. The incidence of major handicap, as compared with LBW infants born between 1953 and 1955, showed little change when earlier‐born infants who had been subjected to severe restriction of fluid and calorie intake were excluded. Ninety‐two per cent of LBW children traced were attending normal schools. Those who showed no evidence of early intra‐uterine insult and who were neurologically normal in the first year of life were largely indistinguishable from control children reared in similar homes. RÉSUMÉ Enfants de faible poids de naissance au début de 'âge scolaire: étude longitudinale Sur un groupe de 299 nourrissons de faible poids de naissance (2000g ou moins), 87 pour cent ont été examinés à 'âge de six ans huit mois et compareés à un groupe contrôle de 111 enfants. Les deux groupes 'enfants ont été examinés individuellement à 'école, à 'exception de 13 enfants pour lesquels les informations ont été obtenues par questionnaire. Pour le groupe de faible poids de naissance, les problèmes à 'école primaire étaient reliés à la classe sociale, à 'existence 'une agression intra‐utérine précoce, au sexe, aux complications post‐natales et à 'état neurologique et dévelopmental durant la première année de vie. La naissance multiple, la durée de gestation et la croissance intra‐utérine ne sont pas apparues clairement liées à 'existence de problèmes à 'école. La fréquence de handicaps majeurs compareée avec celle 'enfants de faible poids de naissance nés entre 1953 et 1955, montrait peu de modifications une fois exclus les nourrissons de groupe le plus ancien ayant été soumis à une restriction sévère de 'absorption liquidienne et calorique. 92 pour cent des enfants de faible poids de naissance examinés, fréquentaient les écoles normales. Ceux qui ne montraient pas de signes 'agression intra‐utérine précoce et qui étaient neurologiquement normaux dans la première année, étaient globalement identiques aux enfants du groupe contrôle élevés dans des foyers équivalents. ZUSAMMENFASSUNG Kinder mit niedrigem Geburtsgewicht, die jet zt im frühen Schulalter sind: eine Langzeitstudie Aus einer Gruppe von 299 Kindern mit niedrigem Geburtsgewicht (2000g oder weniger) wurden 87 Prozent im Alter von sechs Jahren und acht Monaten zusammen mit 111 Kontrollkindern untersucht. Jede Gruppe wurde in der Schule individuell beurteilt mit Ausnahme von 13 Kindern, für die man die Informationen über einen Fragebogen einholte. Für die Kinder mit niedrigem Geburtsgewicht bestand eine Relation zwischen Problemen in der Schule und sozialer Schicht, dem Anhalt für eine frühe intra‐uterine Schädigung, dem Geschlecht, postnatalen Komplikationen und dem neurologischen Status und Entwicklungsstand im ersten Lebensjahr. Geburtenzahl, Gestation und intra‐uterines Wachstum zeigten keine deutliche Relation zu Problemen in der Schule. Die Häufigkeit schwerer Störungen war im Vergleich zu Kindern mit niedrigem Geburtsgewicht, die in den Jahren von 1953 bis 1955 geboren worden waren, kaum verändert, wenn man die Kinder ausschließt, bei denen die Flüssigkeits‐ und Kalorienzufuhr eingeschränkt war. 92 Prozent der erfaßten Kinder mit niedrigem Geburtsgewicht besuchten eine normale Schule. Die Kinder ohne einen Hinweis auf eine frühe intra‐uterine Schädigung und mit normalem neurologischen Befund im ersten Lebensjahr unterschieden sich kaum von den Kontrollkindern, die in entsprechenden Verhältnissen aufwuchsen. RESUMEN Lactantes eon bajo peso al naeer al llegar a la edad escolar precoz: estudio longitudinal De uno grupo de 299 lactantes con bajo peso al nacer (2000g o menos) 87 por ciento fueron examinados a la edad de seis años ocho meses, junto con 111 niños control. Ambos grupos de niños fueron evaluados individualmente en la escuela, a exceptión de 13 niños en los cuales la informatión se obtuvo a partir de un cuestionario. Para el grupo de bajo peso al nacer, los problemas de la escuela primaria estaban en relatión con la clase social, la evidencia de un insulto intrauterine precoz, el sexo, las complicaciones postnatales y el estado neurológico y de desarrollo durante el primer año de vida. Los partos múltiples, la gestación y el crecimiento intrauterine no estaba en relatión clara con problemas escolares. La incidencia de una minusvalía mayor, en comparación con lactantes bajo peso al nacer nacidos entre 1953 y 1955 mostró pocos cambios cuando se excluyeron los niños nacidos precozmente que habían sido sometidos a una grave restricción de ingreso de fluidos o de calorías. 92 por ciento de los niños con bajo peso al nacer que fueron seguidos, iban a escuelas normales. Aquéllos que no mostraban evidencia de un insulto intrauterino precoz y que eran neurológicamente normales en al primer año de vida apenas eran distinguibles de los grupos control que habían crecido en hogares semejantes.

This longitudinal follow-up study of 203 patients with serologically confirmed chikungunya (CHIK) virus infection describes the clinical features of CHIK fever during the first and tenth months of illness. During the acute stage CHIK fever presents with a wide array of symptoms. The foremost chronic symptoms at the end of a month were rheumatism (75%) and fatigue (30%). During the tenth month of follow-up the symptoms/signs observed were joint pain/swelling (46%), fatigue (13%) and neuritis (6%). The cure rate at the end of 9 months was 51%. Among the patients who had joint pain, 36% (34/94) met the American College of Rheumatology criteria to classify them as having rheumatoid arthritis. A subpopulation of the patients with joint pain (20/94) was tested for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody, and the joints were imaged by X-ray and magnetic resonance imaging (MRI). All tested negative for RF and one tested positive for anti-CCP. A radiolucent lesion in the X-ray was seen in the bones of five patients. The MRI findings were joint effusion, bony erosion, marrow oedema, synovial thickening, tendinitis and tenosynovitis. The study proves with relative certainty that CHIK arthritis is chronic inflammatory erosive arthritis, which has implications for management of the infection.

Background: Internet-videos, though popular sources of public health information, are often unverified and anecdotal. We critically evaluated YouTube videos about Zika virus available during the recent Zika pandemic.Methods: Hundred-and-one videos were retrieved from YouTube (search term: zika virus). Based upon content, they were classified as: informative, misleading or personal experience videos. Quality and reliability of these videos were evaluated using standardized tools. The viewer interaction metrics (e.g. no. of views, shares, etc.), video characteristics (video length, etc.) and the sources of upload were also assessed; and their relationship with the type, quality and reliability of the videos analyzed.Results: Overall, 70.3% videos were informative, while 23.8% and 5.9% videos were misleading and related to personal experiences, respectively. Although with shorter lengths (P < 0.01) and superior quality (P < 0.01), yet informative videos were viewed (P = 0.054), liked (P < 0.01) and shared (P < 0.05) less often than their misleading counterparts. Videos from independent users were more likely to be misleading (adjusted OR = 6.48, 95% CI: 1.69 – 24.83), of poorer (P < 0.05) quality and reliability than government/news agency videos.Conclusion: A considerable chunk of the videos were misleading. They were more popular (than informative videos) and could potentially spread misinformation. Videos from trustworthy sources like university/health organizations were scarce. Curation/authentication of health information in online video platforms (like YouTube) is necessary. We discuss means to harness them as useful source of information and highlight measures to curb dissemination of misinformation during public health emergencies.

BACKGROUND & OBJECTIVES: Population-based seroepidemiological studies measure the extent of SARS-CoV-2 infection in a country. We report the findings of the first round of a national serosurvey, conducted to estimate the seroprevalence of SARS-CoV-2 infection among adult population of India. METHODS: From May 11 to June 4, 2020, a randomly sampled, community-based survey was conducted in 700 villages/wards, selected from the 70 districts of the 21 States of India, categorized into four strata based on the incidence of reported COVID-19 cases. Four hundred adults per district were enrolled from 10 clusters with one adult per household. Serum samples were tested for IgG antibodies using COVID Kavach ELISA kit. All positive serum samples were re-tested using Euroimmun SARS-CoV-2 ELISA. Adjusting for survey design and serial test performance, weighted seroprevalence, number of infections, infection to case ratio (ICR) and infection fatality ratio (IFR) were calculated. Logistic regression was used to determine the factors associated with IgG positivity. RESULTS: Total of 30,283 households were visited and 28,000 individuals were enrolled. Population-weighted seroprevalence after adjusting for test performance was 0.73 per cent [95% confidence interval (CI): 0.34-1.13]. Males, living in urban slums and occupation with high risk of exposure to potentially infected persons were associated with seropositivity. A cumulative 6,468,388 adult infections (95% CI: 3,829,029-11,199,423) were estimated in India by the early May. The overall ICR was between 81.6 (95% CI: 48.3-141.4) and 130.1 (95% CI: 77.0-225.2) with May 11 and May 3, 2020 as plausible reference points for reported cases. The IFR in the surveyed districts from high stratum, where death reporting was more robust, was 11.72 (95% CI: 7.21-19.19) to 15.04 (9.26-24.62) per 10,000 adults, using May 24 and June 1, 2020 as plausible reference points for reported deaths. INTERPRETATION & CONCLUSIONS: Seroprevalence of SARS-CoV-2 was low among the adult population in India around the beginning of May 2020. Further national and local serosurveys are recommended to better inform the public health strategy for containment and mitigation of the epidemic in various parts of the country.

CAKUT, a Family of Diseases with a Diverse Anatomical Spectrum Congenital anomalies of the kidney and urinary tract (CAKUT) account for more than 50% of abdominal masses found in neonates and involve some 0.5% of all pregnancies (1,2). Despite recent advancements in prenatal diagnosis and early surgical intervention, these anomalies still remain the primary cause of kidney failure in infants. Notably, the therapeutic interventions that are available to adults and older children, such as kidney transplantation, are often not feasible in infants. Ureteropelvic junction (UPJ) obstruction (e.g., stenosis or atresia) is the most common cause of a palpable abdominal mass in the newborn (3). Other forms of CAKUT include multicystic dysplastic kidneys (MCDK); hypoplastic kidneys (HK); vesicoureteral reflux (VUR); nonobstructed, nonrefluxing primary megaureter (MU); and bladder outlet obstruction (e.g., posterior urethral valves) (3,4). There are a number of well-recognized but puzzling features associated with CAKUT. For example, anomalies such as UPJ stenosis/atresia and MCDK are most often unilateral or highly asymmetrical. In the newborn, many of the abnormalities, such as UPJ stenosis/atresia MCDK, prenatal hydronephrosis associated with VUR, and primary MU are overwhelmingly found in males (5,6,7,8,9,10). By contrast, in older children and adults there is a female preponderance of several of these entities (11). Some such anomalies are often concurrent (8,9,10,12). For instance, renal hypoplasia and dysplasia are often accompanied by VUR or UPJ stenosis/atresia involving the ipsilateral or contralateral kidney. The true incidence of this “dysmorphosis” is undoubtedly higher than that currently recognized since most involved kidneys are affected subclinically or escape detection by ultrasonography or other imaging modalities and do not usually receive a pathologic diagnosis (i.e., biopsy or autopsy). It is also noteworthy that these abnormalities often take a familial pattern, showing incomplete and variable genetic penetrance (13). It is therefore believed that these assorted anatomical anomalies share a common genetic cause (14,15). Genetic analyses on a number of families identified several different chromosomal loci that are associated with CAKUT. Indeed, a number of syndromes that involve multiple organ anomalies, including that of the kidney and urinary tract system, have been reported to take specific inheritance patterns, some autosomal dominant or recessive (16) and others X-linked dominant or recessive (17). Moreover, recent genetic analyses on several families identified several different chromosomal loci that are associated with CAKUT (18,19,20), although no specific gene involved has been identified from these studies. Most recently, the PAX2 gene was identified as the first specific gene whose mutation is associated with CAKUT (21). In view of the extremely high penetrance rate (autosomal dominant) of this anomaly within the same family and the uniform involvement of other organs, the PAX2 gene mutation appears to represent a special subgroup of CAKUT. Other forms of inherited VUR have also been reported in that 40 to 50% of siblings of affected children may also have demonstrable VUR early in life (22). Others have reported that VUR is possibly inherited in a dominant manner with a single familial gene acting with incomplete dominance (23). It is likely, however, that the remaining majority of VUR and other forms of CAKUT (which present with isolated involvement of the kidney and urinary tract and low penetrance within a given family) are examples of complex hereditary traits resulting from a minor mutation of multiple specific genes that are involved in normal embryogenesis. Several theories have been proposed regarding the ontogeny of various forms of CAKUT. Many have been derived from human embryo dissection and others from animal experiments. In the absence of congenital animal models closely mimicking the human CAKUT, human CAKUT have often been equated with the structural changes that occur after surgical ligation of the ureter in young animals ex utero. Limited relevance of such animal models to humans has been noted for some time. For instance, human CAKUT are often identified in utero when nephronogenesis has not yet begun for many nephron units, whereas in postnatal animal ureteral ligation studies, nephronogenesis is already near completion. This discrepancy appears to underlie the numerous observations that histologic changes described in these animal studies vastly differ from those characteristically seen with CAKUT in human embryos or newborns. Is the Obstructive Mechanism Intrinsic or Extrinsic to the Ureter? Ruano-Gil and Tejedo-Mateu (24) studied normal human embryos of 5 to 55 mm. They found that the main ureteric duct (future ureter) undergoes a process of temporary obliteration followed by recanalization of the lumen as the embryos grow from the 14- to 22-mm stage. These processes begin in the middle zone of the ureters and progress proximally and distally until they cover its entire length. In embryos of approximately 17 mm in length the primitive ureter forms a solid cord, but in 23-mm embryos it is totally patent. The obliteration phase was found in conjunction with atrophy and loss of urine-producing function of the mesonephros, whereas that of recanalization follows generation of urine by the metanephros (the kidney precursor) and the intense longitudinal growth of the ureters. These observations in normal embryonic development are the basis of the theory that strictures of the ureteropelvic and ureterovesical junctions in CAKUT may arise from incomplete recanalization of the ureter at the most proximal and distal locations. This notion of “obliteration,” however, has not been substantiated by other studies. This phenomenon is widely viewed, instead, to represent the status of a collapsed, although patent, lumen after mesonephric urine production has ceased but before the metanephros (i.e., kidney precursor) has started producing urine, and hence this hypothetical intraluminal obstructive mechanism has not gained wide acceptance from the community. Allen (25) examined stenotic ureteral segments from patients undergoing surgery because of congenital ureteral strictures. These segments were microdissected and compared to normal urinary tracts. The obstructed segment of the ureter had a diminished ureteral caliber with reduced muscle bulk. In addition, it appeared that the obstruction had been aggravated by external compression from transient overlying vessels and by dilation of the urinary tract proximally with resultant kinking of the ureter. These observations appeared to indicate that the obstruction is fundamentally extrinsic in nature and not the result of a primary abnormality in neuromuscular development intrinsic to the urinary tract. Etiologically, the areas of obstruction appeared to represent areas of localized developmental arrest. Allen further explained that the three areas in the urinary tract where congenital strictures commonly develop—the UPJ, the mid-ureter at the level of the pelvic brim, and the ureterovesical junction (UVJ)—correspond to the three sites of major branches of the fetal arterial tree. He therefore postulated that the areas of ureteral stricture represent the sites of external compression by contiguous fetal vessels, resulting in incomplete muscularization of the ureter. Since most of the fetal vessels in this area become atrophied and vanish as a part of the normal ontogenic process, Allen speculated that this event of ureteral compression by vessels leaves the stricture behind as the sole evidence that the vessel ever existed. Of interest, Barnett and Stephens (26) described a common extrinsic form of UPJ obstruction caused by an anatomically normal lower pole hilar vessel that acutely angulated and held the upper ureter against the renal pelvis, thus providing supporting evidence that extrinsic vessels can indeed cause partial obstruction and hydronephrosis. In addition to normal structural development of the ureter and pelvis, there needs to be normal peristalsis or propulsion of urine from the kidney downstream to the bladder. The normal flow of urine proceeds from the glomerulus through tubules to calyces and then into the pelvis, which is responsible for propelling urine down the ureter. Successful conduction of urine out of the renal pelvis requires both normal anatomic patency as well as intact and ordered transmission of peristaltic contractions down the ureter. Thus, an abnormality in not only the former but also the latter may result in a UPJ “obstruction.” A narrowing or an amuscular segment of the UPJ are sometimes associated with pressure-dependent resistance to urinary outflow. Murnaghan (27) noted muscle bundles with abnormal configuration at the site of the UPJ “obstruction,” while a decreased quantity of musculature was noted by Foote et al. (28). Electron microscopy has revealed disruption of the intercellular relationship between muscle bundles of the UPJ (29). These observations echo the notion that an intrinsic aperistaltic segment of the ureter may be found in association with the replacement of normal circular muscle by muscle having a predominant longitudinal orientation. Is the Hypo- or Dysplastic Kidney a Fetal Form of Obstructive Nephropathy? It has long been thought that renal dysgenesis, often seen in combination with other phenotypes of CAKUT, is caused by embryonic urinary tract obstruction. Although it is recognized that renal hypoplasia or dysplasia or both (hypodysplasia) present with a spectrum of severity, it is commonly accompanied by poor function in the involved kidney. The most severe form is the multicystic dysplastic kidney, which has no demonstrable function and is accompanied by complete obstruction in some part of the outflow tract. Experimentally, complete unilateral ureteral obstruction in the fetal sheep can, but not always, result in dysplastic development of the ipsilateral kidney (14). Peters et al. created complete obstuction at various anatomic levels along the urinary tract of fetal sheep at 55 to 60 d gestation (comparable to 14 to 16 wk gestation in humans) and found a variety of responses by the renal parenchyma (14). of the to obstruction the anatomic level of obstruction (i.e., where along the urinary and the of of the (i.e., of the renal to the high by the They noted that the most of fetal obstructive was its on the renal with unilateral ureteral obstruction kidneys were and more than because these kidneys had a system, and thus had no to the resulting from obstruction. These observations some to that some of and the resultant abnormal in the upper urinary tract are the for the development of renal Although complete urinary obstruction in fetal sheep can dysplastic kidneys other the that in the development of renal associated with human CAKUT Many have noted a of in human between the of renal anomalies and the of obstruction Moreover, studies have that an abnormality in the early embryonic process before nephron can renal in several Thus, of the ureteric (i.e., of a for the of the kidney and can both renal as well as urinary tract It may therefore be that the renal changes are to an abnormal ureteric and that the is a have that of to in the absence of obstruction while abnormal also when are not to against and normal with the ureteric The ureteric the and of to which into and possibly other only is the between the ureteric and but the other various to and development of the It has been that there are at from the ureteric which that the from undergoing yet have no on and that with the It has been proposed that (i.e., or of are the that the ureteric to of the and thus to the number of available nephron others have proposed that from the of the ureteric in complete renal to a of of the ureteric levels of have been noted in but not in the ureteric Thus, from these may for ureteric of the gene of the specific for have in kidney development Thus, it appears that of of these ureteric and processes can to of the kidney and urinary tract. It to be in the specific and described underlie human CAKUT. The A but theory was derived from a different studies of from human embryos and or is often accompanied by anomalies of the distal urinary tract. It was found that both of renal and of closely with the of the ureteral within the the of from the normal site The latter and Stephens to the of kidney and urinary tract abnormalities The theory from of between the of the ureteral the of kidney or and between the of the ureteral the abnormalities of the ureter (i.e., VUR, primary The theory that these abnormalities in both the kidney and the ureter are derived from a single common mechanism and are at a early of at the first of ureteral from the duct that the ureteral is from its site on the duct into the bladder. This is by of the part of the duct with the ureter and its into the of the bladder as the the more on the the of the ureteral an of the The of the that the length of the is the mechanism is and vesicoureteral reflux the is bladder and ureter become in of kidney and ureteral development and the ureteral The of the ureter in the bladder and that of the in normal animals are at the and of the and in the These sites result from the and of the segment of the duct into the the of the bladder. The the normal ureteric on the of the and the on an The ureterovesical junction from the ureteral is in a that in a ureterovesical and vesicoureteral The is well when with a at the normal site but and The between and is thus for the ontogeny of both ureter and and abnormal can result in various forms of congenital anomalies of the kidney and urinary tract (CAKUT) of distal from the duct is the on the metanephros the distal of the duct the which is the to development of the normal kidney. the distal or proximal to the normal it into or to and of is of the distal of the duct and the ureteral to of the of the ureteral of the and of the ureter. In this different abnormalities (i.e., VUR and renal are derived from abnormal event (i.e., abnormal ureteral A The of animal models has been a major in the of CAKUT. In this a by genetic has a to this The in which the gene is by gene this phenotypes for all features common human CAKUT, including the anatomical high and a further that an abnormality in the same gene is involved in CAKUT. Thus, a on the human gene revealed that a minor a mutation within the of which in a in the and quantity of the to abnormal Moreover, a of studies on and of patients with CAKUT revealed a between the incidence of CAKUT and this specific mutation in the of the is an embryonic and in humans and in of in and association with the of the the embryonic urinary tract These are the that not in the of the or in the of the distal urinary tract (i.e., renal pelvis and ureter) In studies have also that in of the Most recent in and in studies that of the within these to of It that embryonic of the of the that not in the of the or by in these It has also been that until the first ureteral the duct is with that In this as the ureteric requires from the metanephros involving both (e.g., from the (i.e., and specific to the on the (i.e., therefore that a failure in the of these the first between the ureteric and the This result in (e.g., of the which an abnormal of the ureteral to The in with of the resulting in a hypoplastic dysplastic kidney. Of the from the ureteric to the metanephros is not and hence of where an is to the between the ureteric and the further with the growth of both embryonic development of the kidney and urinary tract several of the ureteral lumen at the of first urine and growth of the ureter These take in with the of which the metanephros and the ureter and bladder. further that the of the urinary tract the growth of the ureter and its vessels in producing a or are present and the embryonic kidney and urinary tract. are present in the of the metanephros and the ureter the of embryonic in the ureteral and metanephros are and by the metanephros and its ureter while from vessels that more levels of the the vessels, and metanephros are by the of kidney the between ureteral segments are to the These are of of the renal parenchyma into normal form requires of the which are the between and This is the which before its is with and It is that a in the of these the the histologic of dysplastic which are by of that the and These most recent hypothetical for the ontogeny of CAKUT are in with in ontogeny of a wide variety of is recognized to involve or This process is not only for or but also for that are for a or only at of as well as for into while has long been as a its involvement in kidney is widely on a spectrum of although the majority of the latter are in nature Of a recent on revealed that acting this the muscle development of the renal pelvis and ureter the The latter is the when urine as the kidney the function of the of the ontogenic of CAKUT is in and the that the of CAKUT, while possibly a common genetic is involved in the of CAKUT. A primary in the ureter or the can cause both ureter and kidney. since from both ureter and metanephros an abnormality in can cause anomalies of the and the resulting high on the parenchyma may development of or dysplastic A primary in development can also to renal of to of these is believed to the event in the ureteral theory (i.e., ureteric are thought to other including and growth of the and of the from the there are numerous regarding the of CAKUT, no single all the CAKUT is not a single but a to include all congenital anomalies in the kidney urinary tract. a single is to be responsible for all of the various forms of CAKUT. It be to however, a common to a variety of that account for the abnormal the studies described identified a specific gene (i.e., and a specific event (i.e., that were involved in a of CAKUT, the studies also revealed involvement of other genes and since the relationship is not uniform in and the penetrance of abnormal phenotypes in was Thus, it is that minor in other genes are involved in the majority of CAKUT in Indeed, the of the urinary tract be the of a number of and of which may to the of CAKUT. Many CAKUT to The by is often not the anatomic associated with CAKUT, but the associated incidence of renal and that are to This loss of renal function is not a of kidney growth to growth as widely but also appears to some form of intrinsic developmental of the kidney, which is time. Several studies have been that the of surgical of various forms of CAKUT. It had been that surgical further renal and the of the several studies have that this is not the The that patients with surgical of reflux no with to renal renal of renal or the development of These in a that a of patients was at of renal failure surgical In the in also found that a of patients have renal surgical that there is a of patients in there is of to the renal parenchyma to abnormalities within the urinary tract. In the of congenital urinary tract it has also been that surgical often not of renal to the of patients in renal failure is and this is to be in the of kidneys CAKUT. in CAKUT in a spectrum of structural CAKUT appears in the kidney in the form of or CAKUT with severe kidney involvement may result in or after those that the first from of renal function surgical of example, until recently, it had been thought that reflux for In patients with normal bladder function and no (i.e., renal was thought to be and studies have commonly areas of that occur in the absence of and found that of reflux kidneys in were abnormal by also that of kidneys in with reflux had Moreover, of children with and with reflux had abnormal that in low of were common and reported three major of abnormal seen on in children with and patients those with and a of a with to these of in and dysplasia in and in and and in and These studies that be explained by the of the reflux or the of the to intrinsic (i.e., that The of UPJ obstruction and its in renal to be as in some there is and that is often there is available the number of patients with such This is to the that the of UPJ obstruction is highly variable and the is usually unilateral with the contralateral kidney for the affected kidney. Some studies, however, in function in children whose obstruction was in the first of life flow studies, although not are currently the for ureteral obstruction. These studies involve of through a and the between the renal pelvis and the bladder is then to the of ureteral obstruction. These studies, however, have not been the relationship between and the of obstruction In some kidneys do well obstruction while others do of or of obstruction. The are that from the of UPJ the kidney may be or already intrinsic that its The of such intrinsic abnormalities can be in studies on normal animals in which complete ureteral obstruction is created after to obstructive in the renal including of and a in renal resistance These however, were early of the obstruction. This with many CAKUT, as surgical of the anatomic abnormality often to of renal CAKUT in a to Other Kidney Diseases A number of studies have that in a in renal mass (i.e., congenital renal surgical of renal renal to structural and of the In humans as severe is to the development of renal of this is a by a of that is accompanied by a of the remaining and by the basis of these it is believed that a common mechanism for the of many common renal Although specific theories on this common mechanism in they share the congenital or in cause a of through The latter to of the kidney as an which to abnormal of in the The of such although yet to be has been in the of Thus, to of normal whereas of with or of the The indicate the of that are by or and an in the of renal the of such in the to There are a number of that may be involved in these changes of nephron function and including and most growth The of this is the kidney of and structural by many renal congenital or to or loss of The latter the to reduced function of the kidney and the (e.g., of and growth further to of the renal The of this is complete of the renal which are other examples of in which there may be a congenital in nephron mass resulting from the intrinsic abnormal development of the kidney. It has been that CAKUT are often accompanied by on the contralateral kidney, when accompanied by VUR The in ipsilateral and contralateral kidneys are by which in of and renal mass the of CAKUT other features of renal For example, a recent as in and the of to renal failure in CAKUT is affected by a specific These are all in with the evidence by Stephens et al. more than showing that the renal parenchyma in VUR is to abnormal development of the kidney of on the normal kidney. CAKUT are that often surgical in the to renal failure and the for renal It is believed that these anomalies share a common genetic cause and to there has been no animal with which to these Although the abnormal between the ureteral and to renal vesicoureteral and ureters to a the genetic and of urinary tract development is not the for have given into this The animals of in the area the kidney and urinary tract. This abnormal may well with the normal between the ureteral and resulting in CAKUT. This abnormal to intrinsic abnormalities of the kidney, which are and take early in embryonic In the the renal abnormalities to of renal there are more genes and involved in this process other than the and animal and with which to development of the kidney and urinary tract and of an often

BACKGROUND: The first national severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurvey in India, done in May-June, 2020, among adults aged 18 years or older from 21 states, found a SARS-CoV-2 IgG antibody seroprevalence of 0·73% (95% CI 0·34-1·13). We aimed to assess the more recent nationwide seroprevalence in the general population in India. METHODS: We did a second household serosurvey among individuals aged 10 years or older in the same 700 villages or wards within 70 districts in India that were included in the first serosurvey. Individuals aged younger than 10 years and households that did not respond at the time of survey were excluded. Participants were interviewed to collect information on sociodemographics, symptoms suggestive of COVID-19, exposure history to laboratory-confirmed COVID-19 cases, and history of COVID-19 illness. 3-5 mL of venous blood was collected from each participant and blood samples were tested using the Abbott SARS-CoV-2 IgG assay. Seroprevalence was estimated after applying the sampling weights and adjusting for clustering and assay characteristics. We randomly selected one adult serum sample from each household to compare the seroprevalence among adults between the two serosurveys. FINDINGS: Between Aug 18 and Sept 20, 2020, we enrolled and collected serum samples from 29 082 individuals from 15 613 households. The weighted and adjusted seroprevalence of SARS-CoV-2 IgG antibodies in individuals aged 10 years or older was 6·6% (95% CI 5·8-7·4). Among 15 084 randomly selected adults (one per household), the weighted and adjusted seroprevalence was 7·1% (6·2-8·2). Seroprevalence was similar across age groups, sexes, and occupations. Seroprevalence was highest in urban slum areas followed by urban non-slum and rural areas. We estimated a cumulative 74·3 million infections in the country by Aug 18, 2020, with 26-32 infections for every reported COVID-19 case. INTERPRETATION: Approximately one in 15 individuals aged 10 years or older in India had SARS-CoV-2 infection by Aug 18, 2020. The adult seroprevalence increased approximately tenfold between May and August, 2020. Lower infection-to-case ratio in August than in May reflects a substantial increase in testing across the country. FUNDING: Indian Council of Medical Research.

BACKGROUND: The burden of dengue virus (DENV) infection across geographical regions of India is poorly quantified. We estimated the age-specific seroprevalence, force of infection, and number of infections in India. METHODS: We did a community-based survey in 240 clusters (118 rural, 122 urban), selected from 60 districts of 15 Indian states from five geographical regions. We enumerated each cluster, randomly selected (with an Andriod application developed specifically for the survey) 25 individuals from age groups of 5-8 years, 9-17 years, and 18-45 years, and sampled a minimum of 11 individuals from each age group (all the 25 randomly selected individuals in each age group were visited in their houses and individuals who consented for the survey were included in the study). Age was the only inclusion criterion; for the purpose of enumeration, individuals residing in the household for more than 6 months were included. Sera were tested centrally by a laboratory team of scientific and technical staff for IgG antibodies against the DENV with the use of indirect ELISA. We calculated age group specific seroprevalence and constructed catalytic models to estimate force of infection. FINDINGS: From June 19, 2017, to April 12, 2018, we randomly selected 17 930 individuals from three age groups. Of these, blood samples were collected and tested for 12 300 individuals (5-8 years, n=4059; 9-17 years, n=4265; 18-45 years, n=3976). The overall seroprevalence of DENV infection in India was 48·7% (95% CI 43·5-54·0), increasing from 28·3% (21·5-36·2) among children aged 5-8 years to 41·0% (32·4-50·1) among children aged 9-17 years and 56·2% (49·0-63·1) among individuals aged between 18-45 years. The seroprevalence was high in the southern (76·9% [69·1-83·2]), western (62·3% [55·3-68·8]), and northern (60·3% [49·3-70·5]) regions. The estimated number of primary DENV infections with the constant force of infection model was 12 991 357 (12 825 128-13 130 258) and for the age-dependent force of infection model was 8 655 425 (7 243 630-9 545 052) among individuals aged 5-45 years from 30 Indian states in 2017. INTERPRETATION: The burden of dengue infection in India was heterogeneous, with evidence of high transmission in northern, western, and southern regions. The survey findings will be useful in making informed decisions about introduction of upcoming dengue vaccines in India. FUNDING: Indian Council of Medical Research.

BACKGROUND: Earlier serosurveys in India revealed seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) of 0.73% in May-June 2020 and 7.1% in August-September 2020. A third serosurvey was conducted between December 2020 and January 2021 to estimate the seroprevalence of SARS-CoV-2 infection among the general population and healthcare workers (HCWs) in India. METHODS: The third serosurvey was conducted in the same 70 districts as the first and second serosurveys. For each district, at least 400 individuals aged ≥10 years from the general population and 100 HCWs from subdistrict-level health facilities were enrolled. Serum samples from the general population were tested for the presence of immunoglobulin G (IgG) antibodies against the nucleocapsid (N) and spike (S1-RBD) proteins of SARS-CoV-2, whereas serum samples from HCWs were tested for anti-S1-RBD. Weighted seroprevalence adjusted for assay characteristics was estimated. RESULTS: Of the 28,598 serum samples from the general population, 4585 (16%) had IgG antibodies against the N protein, 6647 (23.2%) had IgG antibodies against the S1-RBD protein, and 7436 (26%) had IgG antibodies against either the N protein or the S1-RBD protein. Weighted and assay-characteristic-adjusted seroprevalence against either of the antibodies was 24.1% [95% confidence interval (CI) 23.0-25.3%]. Among 7385 HCWs, the seroprevalence of anti-S1-RBD IgG antibodies was 25.6% (95% CI 23.5-27.8%). CONCLUSIONS: Nearly one in four individuals aged ≥10 years from the general population as well as HCWs in India had been exposed to SARS-CoV-2 by December 2020.

BACKGROUND: Influenza surveillance is an important tool to identify emerging/reemerging strains, and defining seasonality. We describe the distinct patterns of circulating strains of the virus in different areas in India from 2009 to 2013. METHODS: Patients in ten cities presenting with influenza like illness in out-patient departments of dispensaries/hospitals and hospitalized patients with severe acute respiratory infections were enrolled. Nasopharangeal swabs were tested for influenza viruses by real-time RT-PCR, and subtyping; antigenic and genetic analysis were carried out using standard assays. RESULTS: Of the 44,127 ILI/SARI cases, 6,193 (14.0%) were positive for influenza virus. Peaks of influenza were observed during July-September coinciding with monsoon in cities Delhi and Lucknow (north), Pune (west), Allaphuza (southwest), Nagpur (central), Kolkata (east) and Dibrugarh (northeast), whereas Chennai and Vellore (southeast) revealed peaks in October-November, coinciding with the monsoon months in these cities. In Srinagar (Northern most city at 34°N latitude) influenza circulation peaked in January-March in winter months. The patterns of circulating strains varied over the years: whereas A/H1N1pdm09 and type B co-circulated in 2009 and 2010, H3N2 was the predominant circulating strain in 2011, followed by circulation of A/H1N1pdm09 and influenza B in 2012 and return of A/H3N2 in 2013. Antigenic analysis revealed that most circulating viruses were close to vaccine selected viral strains. CONCLUSIONS: Our data shows that India, though physically located in northern hemisphere, has distinct seasonality that might be related to latitude and environmental factors. While cities with temperate seasonality will benefit from vaccination in September-October, cities with peaks in the monsoon season in July-September will benefit from vaccination in April-May. Continued surveillance is critical to understand regional differences in influenza seasonality at regional and sub-regional level, especially in countries with large latitude span.

Chikungunya virus (CHIKV) has caused large outbreaks worldwide in recent years. Acute-phase CHIKV infection has been reported to cause mild to severe febrile illness, and in some patients, this may be followed by long-lasting polyarthritis. The mainstay of treatment includes nonsteroidal anti-inflammatory drugs and other disease-modifying agents, the use of which is based on the assumption of an immunological interference mechanism in the pathogenesis. The present study has been designed to generate preliminary evidence to test this hypothesis. The levels of 30 cytokines were estimated in serum samples of acute CHIKV-infected patients, fully-recovered patients, patients with chronic CHIKV arthritis, and controls, using a quantitative multiplex bead ELISA. The levels of the proinflammatory cytokines IL-1 and IL-6 were elevated in acute patients, but IFN-γ/β and TNF-α levels remained stable. IL-10, which might have an anti-inflammatory effect, was also elevated, indicating a predominantly anti-inflammatory response in the acute phase of infection. Elevation of MCP-1, IL-6, IL-8, MIP-1α, and MIP-1β was most prominent in the chronic phase. These cytokines and chemokines have been shown to play important roles in other arthritides, including epidemic polyarthritis (EPA) caused by Ross River virus (RRV) and rheumatoid arthritis (RA).The immunopathogenesis of chronic CHIKV arthritis might have similarities to these arthritides. The novel intervention strategies being developed for EPA and RA, such as IL-6 and IL-8 signaling blockade, may also be considered for chronic CHIKV arthritis.

An outbreak of acute febrile illness with haemorrhagic manifestations and pulmonary involvement occurred in Diglipur of North Andaman during October-November 1993. Investigations were carried out to see whether leptospires were responsible for this outbreak. Serum samples were collected from suspected cases and tested for presence of antibodies to leptospires by microscopic agglutination test (MAT) using a battery of 19 antigens representing 16 serogroups. 66.7 per cent of the specimens showed significant titres of antibodies against leptospires, 18 of 23 paired sera (78.3%) showed sero-conversion or four-fold rise in antibody titres. The commonest serovar involved was Leptospira grippotyphosa followed by L. canicola and L. JEZ bratislava. In 7 patients L. grippotyphosa was the sole serovar against which antibodies were detected. Clinical and epidemiological observations of this outbreak were similar with that of earlier seasonal outbreaks of acute febrile illness with haemorrhagic manifestations occurring in the same area, indicating that the past outbreaks may also have been due to leptospires. This is the first report of pulmonary leptospirosis from India.

Emissions of ozone precursors are expected to multiply the next 20 years in China, and the levels of photo-oxidants may increase substantially. Increased surface ozone gives cause for concern regarding the prospects for Chinese agricultural production. We show that crop production may be substantially reduced in the future due to elevated ozone concentrations, and that productivity may already be affected for some crops. However, crop-yield loss estimates obtained by using alternative exposure-response functions vary substantially. Spring wheat, soybean, and corn may be especially vulnerable to future ozone increases, due to a likely concurrence of peak levels of ozone and the growth season of these crops.

Human Papillomavirus is the major etiological agent in the development of cervical cancer but not a sufficient cause. Despite significant research, the underlying mechanisms of progression from a low-grade squamous intraepithelial lesion to high grade squamous intraepithelial lesion are yet to be understood. Deregulation of viral gene expression and host genomic instability play a central role in virus-mediated carcinogenesis. Key events such as viral integration and epigenetic modifications may lead to the deregulation of viral and host gene expression. This review has summarized the available literature to describe the possible mechanism and role of viral integration in mediating carcinogenesis. HPV integration begins with DNA damage or double strand break induced either by oxidative stress or HPV proteins and the subsequent steps are driven by the DNA damage responses. Inflammation and oxidative stress could be considered as cofactors in stimulating viral integration and deregulation of cellular and viral oncogenes during the progression of cervical carcinoma. All these events together with the host and viral genetic and epigenetic modifications in neoplastic progression have also been reviewed which may be relevant in identifying a new preventive therapeutic strategy. In the absence of therapeutic intervention for HPV-infected individuals, future research focus should be directed towards preventing and reversing of HPV integration. DNA damage response, knocking out integrated HPV sequences, siRNA approach, modulating the selection mechanism of cells harboring integrated genomes and epigenetic modifiers are the possible therapeutic targets.

Hemoglobinopathies in India are Important public health problems. Of the several abnormal of hemoglobin molecules, there are three variants, viz. Sickle cell, hemoglobin E and hemoglobin D which are predominantly prevalent in India. The cumulative gene frequencies of these hemoglobins have been found to be 5.35% in India. The average gene frequency of sickle cell and hemoglobin D in India has been observed to be 4.3% and 0.86%, respectively. In the North Eastern region of India, the gene frequency of hemoglobin E is 10.9%. Gene frequencies and spatial distribution of the predominant abnormal hemoglobins in India have been discussed in variance with the previous generalisations.

Recent advances in sequencing allow population-genomic data to be generated for virtually any species. However, approaches to analyse such data lag behind the ability to generate it, particularly in nonmodel species. Linkage disequilibrium (LD, the nonrandom association of alleles from different loci) is a highly sensitive indicator of many evolutionary phenomena including chromosomal inversions, local adaptation and geographical structure. Here, we present linkage disequilibrium network analysis (LDna), which accesses information on LD shared between multiple loci genomewide. In LD networks, vertices represent loci, and connections between vertices represent the LD between them. We analysed such networks in two test cases: a new restriction-site-associated DNA sequence (RAD-seq) data set for Anopheles baimaii, a Southeast Asian malaria vector; and a well-characterized single nucleotide polymorphism (SNP) data set from 21 three-spined stickleback individuals. In each case, we readily identified five distinct LD network clusters (single-outlier clusters, SOCs), each comprising many loci connected by high LD. In A. baimaii, further population-genetic analyses supported the inference that each SOC corresponds to a large inversion, consistent with previous cytological studies. For sticklebacks, we inferred that each SOC was associated with a distinct evolutionary phenomenon: two chromosomal inversions, local adaptation, population-demographic history and geographic structure. LDna is thus a useful exploratory tool, able to give a global overview of LD associated with diverse evolutionary phenomena and identify loci potentially involved. LDna does not require a linkage map or reference genome, so it is applicable to any population-genomic data set, making it especially valuable for nonmodel species.

Emissions of ozone precursors are expected to multiply the next 20 years in China, and the levels of photo-oxidants may increase substantially. Increased surface ozone gives cause for concern regarding the prospects for Chinese agricultural production. We show that crop production may be substantially reduced in the future due to elevated ozone concentrations, and that productivity may already be affected for some crops. However, crop-yield loss estimates obtained by using alternative exposure-response functions vary substantially. Spring wheat, soybean, and corn may be especially vulnerable to future ozone increases, due to a likely concurrence of peak levels of ozone and the growth season of these crops.

Three rare human G12 strains were detected from diarrheic clinical samples of children (<8 months of age) in Calcutta during a routine surveillance study of rotaviral diarrhea in India. The VP7 genes of G12 strains and their products showed maximum homology (97 to 99% at the nucleotide level and 98% at the amino acid level, respectively) with those of two recently reported G12 strains (from the United States and Thailand) but lesser homology with those of prototype G12 strain L26.

Abstract Oxidative stress is implicated in both hypo- and hyper-thyroid conditions. In the present study an attempt has been made to elucidate possible interaction between vitamin E or/and curcumin (two established antioxidants) with active portion (redox signaling intervening region) of nuclear factor erythroid 2-related factor 2 (NRF2) as a mechanism to alleviate oxidative stress in rat heart under altered thyroid states. Fifty Wistar strain rats were divided into two clusters (Cluster A: hypothyroidism; Cluster B: hyperthyroidism). The hypo- (0.05% (w/v) propylthiouracil in drinking water) and hyper- (0.0012% (w/v) T4 in drinking water) thyroid rats in both clusters were supplemented orally with antioxidants (vitamin E or/and curcumin) for 30 days. Interactive least count difference and principal component analyses indicated increase in lipid peroxidation, reduced glutathione level, alteration in the activities and protein expression of antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase under altered thyroid states. However, the expression of stress survival molecules; nuclear factor κB (NFκB) and the serine-threonine kinase B (Akt), in hyper-thyroidism only points towards different mechanisms responsible for either condition. Co-administration of vitamin E and curcumin showed better result in attenuating expression of mammalian target for rapamycin (mTOR), restoration of total protein content and biological activity of Ca 2+ ATPase in hyperthyroid rats, whereas, their individual treatment showed partial restoration. Since NRF2 is responsible for activation of antioxidant response element and subsequent expression of antioxidant enzymes, possible interactions of both vitamin E or/and curcumin with the antioxidant enzymes, NRF2 and its regulator Kelch ECH associating protein (KEAP1) were studied in silico . For the first time, a modeled active portion of the zipped protein NRF2 indicated its interaction with both vitamin E and curcumin. Further, curcumin and vitamin E complex showed in silico interaction with KEAP1. Reduction of oxidative stress by curcumin and/or vitamin E may be due to modulation of NRF2 and KEAP1 function in rat heart under altered thyroid states.