First-in-Class Composite Angiotensin Receptor-Neprilysin Inhibitors (ARNI) in Practice.

Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) inhibits angiotensin II and neprilysin, enhancing circulating vasoactive peptides. It is recommended in heart failure with reduced ejection fraction (HFrEF) as a result of the PARADIGM-HF trial.1 This review discusses the rationale for neprilysin inhibition, data supporting efficacy, and practical tips for patient selection and utilization.

Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial.

AIMS: To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit. METHODS: In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression. RESULTS: The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints). CONCLUSIONS: The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.

T and Tk antigen activation in necrotising enterocolitis: manifestations, severity of illness, and effectiveness of testing.

AIMS: To determine if T or Tk antigen activation is associated with different and more severe manifestations of illness in infants with necrotising enterocolitis (NEC); and if a policy of testing infants with suspected sepsis or NEC for T and Tk antigen activation is effective. METHODS: A case-control study of infants with confirmed NEC, born after the introduction of screening, was undertaken:17 activated infants were compared with 28 non-activated controls, matched for gestation and weight. A historical control study compared the outcome of infants before and after the introduction of testing. RESULTS: Of 201 infants with confirmed NEC, 27 were T or Tk antigen activated-10 (9%) before and 17 (19%) after the introduction of testing. T or Tk antigen activated infants had a significantly higher mortality (35% vs 7%); more frequent (71% vs 21%) and severe haemolysis, hyperkalaemia, renal impairment, acidosis; and they received more colloid for resuscitation. While only known activated infants in both time periods were managed with the use of low titre T antibody blood products, there was a significant increase in mortality (odds ratios 2.6; 95% CI 1.2, 5.6) and incidence of surgery (OR 2.7; 1.5, 4.9) after the introduction of testing. The increased mortality (OR 2.6; 0.8, 5.2) and incidence of surgery (OR 1.8; 0.9, 3.7) were no longer significant after adjustment for several perinatal risk factors. CONCLUSIONS: In a retrospective case-control study, routine testing of at risk infants increased the detection rate of T and Tk antigen activation. The use of low titre T plasma products in these patients did not reduce mortality compared with historical controls. A randomised controlled trial of testing in at risk infants, or of the use of low titre T plasma products in babies with NEC and T activation, is warranted.

Persistence of Japanese encephalitis virus in the human nervous system.

Immunological and virological evidence for persistence of Japanese encephalitis virus (JEV) in the human nervous system is described in 16/323 (5%) laboratory-confirmed cases of Japanese encephalitis. In 9/16 patients, JEV specific IgM antibodies were detected in the CSF even at 50-180 days after the onset of symptoms. Similarly, in 7/16 patients, apart from IgM antibodies, viral antigen was also present in the CSF beyond the third week of illness and in one patient it could be detected even at 117 days. Infectious virus could be isolated from the CSF beyond the third week of illness in 3/16 patients. In one patient, JEV was isolated from the CSF on three consecutive occasions at 90, 110, and 117 days after onset of clinical symptoms. These findings suggest that JEV persists in the nervous system of a small proportion of patients.