Rapid Progression of Native Renal Artery Fibromuscular Dysplasia Following Kidney Donation

Fibromuscular dysplasia is the second commonest anatomical abnormality apart from multiple renal arteries in the potential live donors. Pretransplant evaluation of the donors may include an angiography to evaluate the renal arteries, and failure to recognize renal arterial stenosis, particularly fibromuscular dysplasia, by noninvasive methods may eventually lead to hypertension and ischemic renal failure. We report a case of fibromuscular dysplasia that was undetected by computed tomographic angiography prior to donation. One year after kidney donation, it rapidly progressed to severe symptomatic stenosis with hypertension and acute renal failure. Following renal artery angioplasty, her blood pressure normalized over a period of 2 weeks without any need for antihypertensive medications and the serum creatinine returned to her baseline. The acceptability of renal donors with fibromuscular dysplasia depends on the age, race and the availability of the other suitable donors. Mild fibromuscular dysplasia in a normotensive potential renal donor cannot be considered a benign condition. Such donors need regular follow-up postdonation for timely detection and treatment.     

Two Sri Lankan cases of identified sea snake bites, without envenoming.

Sea snakes are among the most venomous creatures encountered around coasts and reefs, in estuaries, rivers and at sea. Their venoms are more toxic than those of land snakes. However, they are rarely aggressive or menacing. Bites have become unusual with the advent of modern fishing methods but the two encounters we report, in the Indian Ocean off the shores of Sri Lanka, emphasise that sea snake bites may not result in envenoming.     

Frequency of bystander exposure to antibiotics for enteropathogenic bacteria among young children in low-resource settings

Children in low-resource settings carry enteric pathogens asymptomatically and are frequently treated with antibiotics, resulting in opportunities for pathogens to be exposed to antibiotics when not the target of treatment (i.e., bystander exposure). We quantified the frequency of bystander antibiotic exposures for enteric pathogens and estimated associations with resistance among children in eight low-resource settings. We analyzed 15,697 antibiotic courses from 1,715 children aged 0 to 2 y from the MAL-ED birth cohort. We calculated the incidence of bystander exposures and attributed exposures to respiratory and diarrheal illnesses. We associated bystander exposure with phenotypic susceptibility of E. coli isolates in the 30 d following exposure and at the level of the study site. There were 744.1 subclinical pathogen exposures to antibiotics per 100 child-years. Enteroaggregative Escherichia coli was the most frequently exposed pathogen, with 229.6 exposures per 100 child-years. Almost all antibiotic exposures for Campylobacter (98.8%), enterotoxigenic E. coli (95.6%), and typical enteropathogenic E. coli (99.4%), and the majority for Shigella (77.6%), occurred when the pathogens were not the target of treatment. Respiratory infections accounted for half (49.9%) and diarrheal illnesses accounted for one-fourth (24.6%) of subclinical enteric bacteria exposures to antibiotics. Bystander exposure of E. coli to class-specific antibiotics was associated with the prevalence of phenotypic resistance at the community level. Antimicrobial stewardship and illness-prevention interventions among children in low-resource settings would have a large ancillary benefit of reducing bystander selection that may contribute to antimicrobial resistance.

Antibiotic use causes selection pressure for antimicrobial resistance (AMR), a growing global public health crisis that threatens to render antibiotics ineffective against many high-burden infections (1). Most of the concern is placed on the development of resistance in the target pathogen of treatment (i.e., the pathogen causing the treated illness). However, systemic treatment also results in antibiotic exposure for commensal bacteria and pathogens carried asymptomatically at the time of treatment (2). Selective pressure for resistance among organisms that are not the target pathogen has been called “bystander selection” (3, 4). While the public health relevance of resistance in nonpathogenic commensal organisms is less clear, bystander selection among pathogens carried asymptomatically at the time of treatment has direct consequences for the development of resistance in those pathogens (4). This type of selection has the potential to promote antibiotic-resistant disease in settings where subclinical carriage of pathogens is common.Children in low-resource settings frequently carry enteric pathogens in the absence of diarrheal symptoms (5). Enteroaggregative Escherichia coli (EAEC), for example, was detected in nearly half (49%) of nondiarrheal stools collected in the first 2 y of life in the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) birth cohort study conducted in South America, South Asia, and sub-Saharan Africa (6). Campylobacter and Shigella, which are on the World Health Organization priority pathogen list for concern for AMR (7), were detected in 28% (5) and 10% (8) of nondiarrheal stools, respectively. Antibiotic treatment is also highly common in these populations, with approximately five treatment courses per child-year observed in MAL-ED (9). Children were treated with more than one antibiotic course per child year for diarrhea alone (10), despite treatment guidelines that only recommend treatment for dysentery (11), which comprised less than 5% of diarrheal episodes (10). For these reasons, children in low-resource settings represent a unique population in which the burden of bystander selection on enteric pathogens could be particularly high.Antimicrobial stewardship interventions to prevent antibiotic overuse and interventions to prevent illnesses that prompt antibiotic treatment, such as vaccines, could have the ancillary benefit of reducing bystander selection (12). However, the magnitude of this potential impact is unknown. A prior study quantified the proportion of antibiotic exposures for specific pathogens that were not related to the treatment of that pathogen based on modeled data from unrelated sources (3). The observational birth cohort study, MAL-ED, provides a unique opportunity to characterize bystander antibiotic exposure directly since testing for enteric pathogen carriage was conducted monthly in nondiarrheal stools from birth to 2 y of age, and antibiotic use was comprehensively documented during twice-weekly surveillance visits. Here, we aimed to quantify the absolute frequency of bystander antibiotic exposures for enteric bacterial pathogens carried asymptomatically at the time of treatment among children in MAL-ED. We compared the frequency of antibiotic exposures that occurred when the bacteria were the target pathogen to when they were bystanders and attributed bystander exposure to specific indications for treatment. We also identified child characteristics that were associated with bystander antibiotic exposures. Finally, we assessed the association between bystander antibiotic exposure and resistance both at the individual and the community level using E. coli as a model organism.     

Interspecies Recombination-Led Speciation of a Novel Geminivirus in Pakistan

Recombination between isolates of different virus species has been known to be one of the sources of speciation. Weeds serve as mixing vessels for begomoviruses, infecting a wide range of economically important plants, thereby facilitating recombination. Chenopodium album is an economically important weed spread worldwide. Here, we present the molecular characterization of a novel recombinant begomovirus identified from C. album in Lahore, Pakistan. The complete DNA- A genome of the virus associated with the leaf distortion occurred in the infected C. album plants was cloned and sequenced. DNA sequence analysis showed that the nucleotide sequence of the virus shared 93% identity with those of the rose leaf curl virus and the duranta leaf curl virus. Interestingly, this newly identified virus is composed of open reading frames (ORFs) from different origins. Phylogenetic networks and complementary recombination detection methods revealed extensive recombination among the sequences. The infectious clone of the newly detected virus was found to be fully infectious in C. album and Nicotiana benthamiana as the viral DNA was successfully reconstituted from systemically infected tissues of inoculated plants, thus fulfilling Koch’s postulates. Our study reveals a new speciation of an emergent ssDNA plant virus associated with C. album through recombination and therefore, proposed the tentative name ‘Chenopodium leaf distortion virus’ (CLDV).     

Synthesis of two potent glucocorticoid receptor agonists labeled with carbon‐14 and stable isotopes

Two potent glucocorticoid receptor agonists were prepared labeled with carbon‐14 and with stable isotopes to perform drug metabolism, pharmacokinetics, and bioanalytical studies. Carbon‐14 labeled (1) was obtained from an enantiopure alkyne (5) via a Sonogashira coupling to a previously reported 5‐amino‐4‐iodo‐[2‐¹⁴C]pyrimidine [¹⁴C]‐(6), followed by a base‐mediated cyclization (1) in 72% overall radiochemical yield. Carbon‐14 labeled (2) was prepared in five steps employing a key benzoic acid intermediate [¹⁴C]‐(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine–magnesium exchange and then electrophile trapping reaction with [¹⁴C]‐carbon dioxide. A chiral auxiliary (S)‐1‐(4‐methoxyphenyl)ethylamine was then coupled to this acid to give [¹⁴C]‐(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [¹⁴C]‐(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [¹⁴C]‐(18) and finally removal of the chiral auxiliary gave [¹⁴C]‐(2) in 7% overall yield. For stable isotope syntheses, [¹³C₆]‐(1) was obtained in three steps using [¹³C₄]‐(6) and trimethylsilylacetylene‐[¹³C₂] in 26% yield, while [²H₅]‐(2) was obtained by first preparing the iodopyridine [²H₅]‐(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [²H₅]‐(2) in 42% overall yield.