Cho, Christine; Goto, Michihiko
doi: 10.1056/NEJMicm1803513pmid: 30354953
A 62-year-old man presented with low back pain, fevers, chills, night sweats, and weight loss. MRI revealed spondylitis and large psoas abscesses. Cultures grew Brucella melitensis.
doi: 10.1056/NEJMc1811048pmid: 30354956
To the Editor: The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial conducted by Johnston et al. (July 19 issue)1 showed that the combination of clopidogrel and aspirin was superior to aspirin alone and led to a lower risk of major ischemic events in the first 90 days among patients with minor ischemic stroke or high-risk transient ischemic attack (TIA). According to the eligibility criteria, the trial did not exclude patients who were receiving antiplatelet therapy (Table 1 of the article shows that more than half the patients were using aspirin at presentation). Thus, patients who had . . .
doi: 10.1056/NEJMc1810872pmid: 30354955
To the Editor: Kishore et al. (July 12 issue)1 used household surveys to estimate the number of excess deaths (4645; 95% confidence interval [CI], 793 to 8498) that occurred in Puerto Rico during the 102 days following Hurricane Maria in 2017. To test the robustness of their findings, we conducted time-series forecasting2 with the use of monthly mortality data in Puerto Rico between January 2010 and September 2017 to forecast the number of expected deaths had Hurricane Maria not occurred (Fig. 1). We then compared the forecast estimates with the survey-based mortality estimates. Using an average of a state-space and . . .
Dzau, Victor J.; Johnson, Paula A.
doi: 10.1056/NEJMp1809846pmid: 30207831
A National Academies report shows that sexual harassment is more likely to occur in environments that are male-dominated and where sexually harassing behaviors are tolerated, hierarchical relationships are enforced, and training environments may be isolating.
Choo, Esther K.; van Dis, Jane; Kass, Dara
doi: 10.1056/NEJMp1809351pmid: 30207825
Putting an end to the culture of gender-based harassment is key to recruiting, retaining, and realizing the full potential of nearly half the medical workforce. Doing so will depend on our willingness to undergo a complete transformation in how we approach this problem.
Pham, Hoangmai; Ginsburg, Paul B.
doi: 10.1056/NEJMp1805593pmid: 30230961
To truly redesign our health care payment and delivery system, we will have to take a holistic approach and move multiple levers in concert, rather than fiddling with individual factors serially and hoping for a coordinated effect.
doi: 10.1056/NEJMtwj181025pmid: N/A
Issue Highlights, October 25, 2018Combination Therapy for Cystic FibrosisPhase 2b Trial of a TB VaccineDiverticulitisAplastic AnemiaEnding Sexual Harassment in Medicine
doi: 10.1056/NEJMp1808397pmid: 30354957
Sooner than the medical student had expected, a certain cynicism began to creep into his thoughts. Why didn’t patients simply follow their doctors’ orders and avoid complications? And then the aging car he’d inherited from his mother started acting up.
Davies, Jane C.; Moskowitz, Samuel M.; Brown, Cynthia; Horsley, Alexander; Mall, Marcus A.; McKone, Edward F.; Plant, Barry J.; Prais, Dario; Ramsey, Bonnie W.; Taylor-Cousar, Jennifer L.; Tullis, Elizabeth; Uluer, Ahmet; McKee, Charlotte M.; Robertson, Sarah;
Keating, Dominic; Marigowda, Gautham; Burr, Lucy; Daines, Cori; Mall, Marcus A.; McKone, Edward F.; Ramsey, Bonnie W.; Rowe, Steven M.; Sass, Laura A.; Tullis, Elizabeth; McKee, Charlotte M.; Moskowitz, Samuel M.; Robertson, Sarah; Savage, Jessica; Simard, Christopher;
Showing 1 to 10 of 21 Articles
doi: 10.1056/NEJMoa1807119pmid: 30334693
BackgroundThe next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659–tezacaftor–ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.MethodsWe evaluated the effects of VX-659–tezacaftor–ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659–tezacaftor–ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1).ResultsVX-659–tezacaftor–ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659–tezacaftor–ivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del–MF genotypes; in patients with the Phe508del–Phe508del genotype already receiving tezacaftor–ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised improved in both patient populations.ConclusionsRobust in vitro activity of VX-659–tezacaftor–ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del–MF or Phe508del–Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455.)
doi: 10.1056/NEJMoa1807120pmid: 30334692
BackgroundVX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445–tezacaftor–ivacaftor).MethodsWe evaluated the effects of VX-445–tezacaftor–ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445–tezacaftor–ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del) after tezacaftor–ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline.ResultsIn vitro, VX-445–tezacaftor–ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del–MF group (P<0.001). In patients in the Phe508del–Phe508del group, who were already receiving tezacaftor–ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire–Revised.ConclusionsThe use of VX-445–tezacaftor–ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471; and EudraCT number, 2017-000797-11.)