Richard Giovane

Lumacaftor/ivacaftor, a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation

ABSTRACT Introduction: Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF. Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation. This article reviews the pharmacologic features, clinical efficacy, and safety of LUM/IVA and summarize the available pre-clinical and clinical data of LUM/IVA use. Expert commentary: LUM/IVA showed modest, but significant improvements from baseline in percent predicted FEV1 (ppFEV1) as well as a reduction in pulmonary exacerbations by 35% It was shown to be safe for short- and long-term use. Currently, LUM/IVA is the only oral agent in its class available and represents a milestone the development of therapies for the management of CF. Nonetheless, pharmacoeconomic data are necessary to justify its high cost before is use becomes standard of care.

Itraconazole or Amphotericin B for Talaromycosis

n engl j med 377;14 nejm.org October 5, 2017 1402 sion of the RDW-SD in a Cox proportional-hazards model for the development of coronary heart disease did not affect the risk estimate associated with CHIP (hazard ratio, 1.99; 95% confidence interval, 1.26 to 3.13), after adjustment for RDW-SD, age, sex, hypertension, type 2 diabetes status, smoking history, and levels of high-density lipoprotein cholesterol and total cholesterol. On the basis of this limited sample, we found no evidence that red-cell anisocytosis, as indicated by an elevated RDW-SD, mediates the association between CHIP and atherosclerotic cardiovascular disease. Siddhartha Jaiswal, M.D., Ph.D.n engl j med 377;14 nejm.org October 5, 2017 1400 (ventricular asymmetry) that were thought to be unrelated to ZIKV infection. Our findings suggest that prenatal ultrasonography in ZIKV-infected pregnant women can detect ZIKV-associated morphologic changes in the fetus and thus may inform decision making among such women who may be considering pregnancy termination.5 Long-term functional outcome studies correlated to imaging findings are warranted.Jaiswal et al. report the results of four case–control studies that confirm a near doubling in the risk of coronary heart disease in patients with CHIP,1 a finding that was first reported in the Journal in 2014.2 The authors postulate that two mechanisms may be involved: the promotion of inflammatory responses, as supported in a study involving Tet2 knockout mice, and an increase in the number of myeloid cells, a finding that appears to be more relevant for patients with JAK2 mutations, which confer a much larger risk than the more common DNMT3A, TET2, and ASXL1 mutations, in which blood counts remain normal. However, the authors do not provide data relating to red-cell distribution width, which is the only blood-cell index that has been shown to have a significant association with CHIP2 and which has been associated with an unexplained increase in all-cause mortality in an aging population. 3,4 In understanding how CHIP promotes atherosclerosis, it is important to explore the causal relationship between clonal hematopoiesis and red-cell anisocytosis to determine whether these are independent or associated risk factors for cardiovascular disease.

Treatment for and Clinical Characteristics of Granulomatous Mastitis.

There are no randomized controlled trials demonstrating efficacy of any treatment modalities (glucocorticoids, antibiotics, or surgical interventions) in treatment of idiopathic granulomatous mastitis. Sheybani et al report their experience with oral corticosteroids and methotrexate. They should be congratulated on comprehensive reporting of their treatment outcomes. Although they achieved very excellent treatment outcomes, there are many important points that should be clarified. The authors report a low recurrence rate of three (13.6%) patients after steroid cessation. In our clinic, we treated nine patients with idiopathic granulomatous mastitis (age range 21–39 years) with initial steroid therapy (1 mg/kg for 3 weeks and tapered in 2 months). All patients had recurrence after steroid tapering within 3 months, except one patient who got pregnant and recovered spontaneously. The tuberculin skin test is not a reliable marker to make a differential diagnosis between idiopathic granulomatous mastitis and tuberculosis mastitis in moderate or high tuberculosis endemic countries. The authors state that almost all patients received previous antibiotic therapy with several antibiotics, but they did not clarify details of treatment at presampling time. Antibiotics and duration of treatment are very important before Gram staining and routine culture evaluation in idiopathic granulomatous mastitis. Although the role of Corynebacterium species in the pathogenesis of idiopathic granulomatous mastitis has not been clearly confirmed, remarkable supporting evidence has been reported by Taylor et al. Also, we treated two patients with idiopathic granulomatous mastitis (confirmed with presence of granuloma) with teicoplanin and doxycycline after revealed Corynebacterium species from their mammarian abscesses after a 2-week antibioticfree period with full recovery. All of our patients had received several antibiotics before presentation to the clinic. Therefore, we conclude that screening for Corynebacterium species is important before making a diagnosis of idiopathic granulomatous mastitis and starting steroid therapy.

Laparoendoscopic Single-Site Surgery for Management of Heterotopic Pregnancy: A Case Report and Review of Literature

Background Heterotopic pregnancy occurs when two pregnancies occur simultaneously in the uterus and an ectopic location. Treatment includes removal of the ectopic pregnancy with preservation of the intrauterine pregnancy. Treatment is done laparoscopically with either a Laparoendoscopic Single-Site Surgery (LESS) or a multiport laparoscopic surgery. Case We present a case of a first trimester heterotopic pregnancy in a 42-year-old gravida 5, para 0-1-3-1 female with previous history of left salpingectomy, who underwent laparoscopic right salpingectomy and lysis of adhesions (LOA) via Single-Incision Laparoscopic Surgery (SILS). Conclusion Although LESS for benign OB/GYN cases is feasible, safe, and equally effective compared to the conventional laparoscopic techniques, studies have suggested no clinically relevant advantages in the frequency of perioperative complications between LESS and conventional methods. No data on the cost effectiveness of LESS versus conventional methods are available. LESS utilizes only one surgical incision which may lead to decreased pain and better cosmetic outcome when compared to multiport procedure. One significant undesirable aspect of LESS is the crowding of the surgical area as only one incision is made. Therefore, all instruments go through one port, which can lead to obstruction of the surgeons vision and in some cases higher rate of procedure failure resulting in conversion to multiport procedure.

Psychotherapy With Somatosensory Stimulation for Endometriosis-Associated Pain: A Randomized Controlled Trial

We applaud the work done by Meissner et al,1 in which their results demonstrate the potential for the use of psychotherapy with somatosensory stimulation in treating endometriosis. Although their results are encouraging, the authors did not discuss or control for comorbid conditions that can lead to confounding variables. Meissner et al did not screen patients with comorbid conditions that can affect their pain tolerance such as fibromyalgia. Fibromyalgia in the presence of endometriosis has been described by Sinaii et al.2 In conditions such as this, the patient’s perception of pain might be drastically different because fibromyalgia is a chronic condition of pain. This altered perception of pain could affect data regarding the subjective feeling of the patient’s perceived pain; this can therefore alter the patient’s perceived outcome of how somatosensory stimulation improved their pain. We ask Meissner et al their rationale for using an unblinded randomized control trial in lieu of a crossover randomized prospective trial. We believe that this study should have been a crossover randomized prospective trial, because all participants would have been exposed to the treatment for a certain duration and, more importantly, it would control for confounding variables or even draw other associations, such as comorbid conditions that affect the patient’s perception of pain.

A Simple Anesthetic Technique to Eliminate Pain and Optimize Patient Satisfaction for Chalazion Incision and Curettage

A chalazion is a localized area of granulomatous inflammation associated with lipid deposits and swelling of the eyelid. It occurs due to the obstruction of sebaceous glands, meibomian or Zeis, of which the former is more common. The meibomian gland may be obstructed due to varying etiologies including infection, inflammation, or neoplastic lesions. Chalazia may have a slow, insidious onset with minimal symptoms. Most commonly, localized inflammation occurs in the upper lid, with an immobile, hard, mass in the tarsal plate. If large enough, an upper lid chalazion can induce visual disturbances by creating mechanical ptosis or causing increased corneal astigmatism [1]. The chalazion may produce pain if it grows large enough to cause distention of the terminal branches of the ophthalmic (V1) or maxillary (V2) sensory nerve endings. Terminal branches of the ophthalmic division supply the upper eyelid as the lacrimal, supraorbital, and supratrochlear nerves. Terminal branches of the maxillary division supply the lower eyelid as the zygomaticofacial and infraorbital nerves. In addition, sensation of both upper and lower lids results from innervations of the infratrochlear nerve.

The Anachronistic Terminology of Gestational Hypertension: Time for a Change.

In Reply: We thank the authors for their interest in our study examining the effect of maternal overweight and obese status on pregnancy outcomes in women with gestational diabetes mellitus. They raise several important points, and we are in agreement that the preponderance of evidence suggests that there is an association among maternal obesity, excess gestational weight gain, and both large-forgestational-age birth weight and preeclampsia. However, as we were writing our article, we were struck by how little we understand about the mechanisms relating both maternal obesity and excess gestational weight gain to adverse pregnancy outcomes. Gestational weight gain consists of gains in maternal and fetal fat mass and fat-free mass as well as the placenta and amniotic fluid, but there are limited data describing the relationship among baseline maternal characteristics, body composition changes, and eventual pregnancy outcomes. In addition, whether excess weight gain is related to metabolic alterations such as dyslipidemia and inflammation independent of the baseline maternal metabolic state is relatively unknown. The timing of weight gain also may be important; recent studies have shown that excess weight gain even early in pregnancy may increase the risk for large-forgestational-age neonates. Strategies to limit weight gain in pregnancy have had mixed results, and some of this may stem from the fact that, when pregnant women gain weight, we have only partial knowledge of what is occurring and the temporal pattern between weight gain and outcomes may also be relevant. Women with gestational diabetes are at high risk for preeclampsia, and we hope that future studies will elucidate whether changing the trajectory of maternal weight gain after a diagnosis of gestational diabetes mellitus can affect the risk for preeclampsia.