Safety, Tolerability, and Outcomes of Tafamidis for the Treatment of Acquired Amyloid Neuropathy in Domino Liver Transplant Recipients.

INTRODUCTION: Acquired amyloid neuropathy is an iatrogenic disease that appears years after a domino liver transplant. The objectives of our study are to analyze the efficacy and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. This post-authorization, prospective, longitudinal study included seven domino liver transplant recipients with acquired amyloid neuropathy who received treatment with tafamidis for 18 months. METHODS: The primary endpoints were the response rate, defined as those patients with an increase of < 2 points on the Neurological Impairment Score (NIS) from baseline, and the change in the NIS score from baseline. Secondary endpoints included the Quantitative Sensory Test, 10-m walk test, quality of life (Norfolk), and disability (Rasch-built Overall Disability Scale). As safety parameters, the evidence of graft rejection, changes in immunosuppressive trough levels and changes in antiviral and allogeneic cellular immunity before and 12 months after tafamidis treatment were also assessed. RESULTS: Six patients (85.7%) had responded at 18-months. Compared to baseline, we observed non-statistically significant improvement in mean NIS score at 6 months (- 2.54 points, CI - 5.92 to 0.84), 12 months (- 3.25 points; CI - 6.63 to 0.13), and 18 months (- 2.35 points; CI - 5.74 to 1.02). Changes in the Quantitative Sensory Test, 10-m walk tests and the quality of life and disability questionnaires were not statistically significant. The use of tafamidis did not induce relevant side effects or drug interactions. Also, no acute rejections events nor changes in functional adaptive immunity were observed. CONCLUSION: Our study supports the safety and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. Tafamidis shows promise as a useful treatment in the clinical management of these patients. Future randomized placebo-controlled clinical trials with longer follow-up durations are needed.

Hereditary Transthyretin Amyloidosis with Polyneuropathy: Monitoring and Management.

Our aim in this review is to discuss current treatments and investigational products and their effect on patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and provide suggestions for monitoring disease progression and treatment efficacy.

Treatment With Diflunisal in Domino Liver Transplant Recipients With Acquired Amyloid Neuropathy.

Objectives: To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. Methods: We performed a retrospective longitudinal study of prospectively collected data for all domino liver transplant recipients with acquired amyloid neuropathy who received diflunisal at our hospital. Neurological deterioration was defined as an score increase of ≥2 points from baseline on the Neurological Impairment Scale/Neurological Impairment Scale-Lower Limbs. Results: Twelve patients who had received compassionate use treatment with diflunisal were identified, of whom seven had follow-up data for ≥12 months. Five patients (71.4%) presented with neurological deterioration on the Neurological Impairment Scale after 12 months (p = 0.0382). The main adverse effects were cardiovascular and renal, leading to diflunisal being stopped in five patients and the dose being reduced in two patients. Conclusion: Our study suggests that most domino liver transplant recipients with acquired amyloid neuropathy will develop neurological deterioration by 12 months of treatment with diflunisal. This therapy was also associated with a high incidence of adverse effects and low treatment retention. The low efficacy and low tolerability of diflunisal treatment encourage the search for new therapeutic options.

Intestinal Paracoccidioidomycosis: Case report and literature review.

INTRODUCTION AND IMPORTANCE: Paracoccidioidomycosis (PCM) is a systemic fungal infection, primarily affecting the respiratory tract. Extra pulmonary presentation is rare, representing less than 1% of cases (about 1 in every 200 cases). CASE PRESENTATION: We present a case of a 73-year-old male with acute surgical abdomen secondary to Intestinal Paracoccidioidomycosis requiring intestinal resection and postoperative antifungal therapy. CONCLUSION: Intestinal Paracoccidioidomycosis represents a rare pathology with challenging diagnostic approach due to its frequency and nonspecific clinical manifestations. Extra pulmonary presentation is rare, but it should be considered in endemic regions.

Epigenome-wide association study of COVID-19 severity with respiratory failure.

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

Myasthenia gravis exacerbation after melatonin administration: case series from a tertiary referral centre.

BACKGROUND: Myasthenia gravis is an autoimmune disease mediated by antibodies against proteins associated with the postsynaptic membrane of the neuromuscular junction. Several drugs may trigger an exacerbation of the disease. Melatonin supplements are widely used for the treatment of insomnia as they are well tolerated with few side effects. The role of melatonin in the immune system and its effects in autoimmune disorders remain uncertain. CASE PRESENTATION: We identified three patients in our referral centre from 2014 to 2019 who presented a worsening within days or weeks of starting melatonin. Two of them stopped the treatment without clinical improvement in the next week. Increasing dose of corticosteroids did not lead to clinical improvement in the next month and one of the patients was finally administered intravenous immunoglobulins. CONCLUSION: Melatonin may trigger exacerbations of myasthenia gravis, probably due to an upregulation of the adaptive immune system and an interaction with the corticosteroids and other immunosuppressant treatments. We consider that melatonin should be administered with caution in these patients.

Intravenous immunoglobulins may prevent prednisone-exacerbation in myasthenia gravis.

Corticosteroids may produce a paradoxical worsening of myasthenia gravis (MG) symptoms within the first weeks of treatment. We therefore wanted to assess the hypothesis that a prior infusion of intravenous immunoglobulin (IVIG) may have a protective effect. Our primary objectives were to show that the coadministration of immunoglobulins and glucocorticoids is safe and effective for controlling myasthenic symptoms, and to compare the exacerbation rate with this approach and historical practice without IVIG. We recruited 45 patients with generalized MG who required corticosteroids for the first time and we gave all IVIG before starting the full doses of prednisone. Monitoring was performed with validated scales, questionnaires, and blood tests over a 6-week period. Only 4.4% had severe adverse effects related to IVIG and 86.7% improved clinically. Notably, only 2.2% had a paradoxical symptom exacerbation in the first weeks of starting prednisone, which was statistically lower than the 42% reported in a historical series. We conclude that adjuvant therapy with IVIG when starting prednisone for the first time in patients with generalized MG is safe and effective. Given that the rate of paradoxical worsening was lower than that previously reported, the addition of IVIG may have a protective effect against such exacerbations.

Eculizumab as a promising treatment in thymoma-associated myasthenia gravis.

Myasthenia gravis is a chronic autoimmune disorder caused by antibodies directed against the neuromuscular junction. Some patients may have an associated thymoma, which confers a worse prognosis. Eculizumab, a monoclonal antibody that inhibits the activation of terminal complement, has recently been approved for the treatment of refractory generalized myasthenia gravis. This is an early case report of thymoma-associated refractory myasthenia gravis successfully treated with eculizumab in a real-world setting.

Intracameral lidocaine as supplement to classic topical anesthesia for relieving ocular pain in cataract surgery.

AIM: To evaluate safety, efficacy, and patient adherence of intracameral lidocaine as supplement of classic topical anesthetic drops in cataract surgery. METHODS: A prospective and controlled trial including a large cohort of 1650 individuals suffering with bilateral cataract not complicated, in program by phacoemulsification surgery, were randomly assigned to 2 different groups for the type of anesthesia received, 0.4% oxybuprocaine hydrochloride (INN) drops, and INN drops associated to intracameral 1% lidocaine hydrochloride monohydrate. At the end of surgery, tables were assigned to each patient indicating the degree of pain (0-3) felt during the operation. RESULTS: Thirty-two percent of patients in group 1 declared to have not felt any pain against the 77% of patients in group 2. Fifty-nine percent of patients in group 1 complained about only a slight discomfort against 20% of group 2 patients. Only a small percentage of patients in group 1 (5%) admitted severe pain, while no patient in group 2 admitted severe pain. Four patients of group 2 reported an episode of transient amaurosis, lasting several hours after surgery. CONCLUSION: Intracameral administration of lidocaine is a simple and secure method able to increase the analgesia during the cataract surgery, eliminating the discomfort and increasing also the cooperation of the patients during the steps of manipulation.

Effects of combined hormonal contraception on health and wellbeing: women's knowledge in northern Italy.

OBJECTIVES: We investigated levels of knowledge of the effects of combined hormonal contraceptives (CHCs) on general/reproductive health and physical/psychosexual wellbeing. METHODS: A cross-sectional study was conducted in two university hospitals in northern Italy. Healthy current-, past- and never CHC users (n = 545; age 18-44 years) completed a self-administered questionnaire. RESULTS: Ninety-three percent of current-, 74% of past-, and 56% of never users believed they were sufficiently informed (χ(2): 67.1; p = 0.001) about the benefits and risks of CHCs. Respondents mentioned: (i) a reduced risk of ovarian (67%) and endometrial (53%) cancer; (ii) an increased risk of thrombosis (82%); (iii) an increased risk of breast cancer (45%); (iv) a decreased fertility (19%) and no influence on risk of sexually transmitted infections (48%); (v) a reduced risk of menstrual abnormalities (77%) and acne (79%); (vi) less dysmenorrhoea (83%) and more headache (56%), weight gain (74%), increased appetite (51%), leg cramps (77%), mood swings (45%), vaginal dryness (47%), and low sex drive (48%). Beliefs about diseases/conditions and symptoms were influenced by CHC use. CONCLUSIONS: CHC use is linked to good knowledge of risks and benefits. Our data suggest HCPs must be proactive in providing relevant information so that women can choose their contraception with a balanced insight of side effects.

Robotic single-site surgery for female-to-male transsexuals: preliminary experience.

Hysterectomy with bilateral salpingo-oophorectomy is a part of gender reassignment surgery for the treatment of female-to-male transsexualism. Over the last years many efforts were made in order to reduce invasiveness of laparoscopic and robotic surgery such as the introduction of single-site approach. We report our preliminary experience on single-site robotic hysterectomy for cross-sex reassignment surgery. Our data suggest that single-site robotic hysterectomy is feasible and safe in female-to-male transsexualism with some benefits in terms of postoperative pain and aesthetic results.

Dorzolamide chlorhydrate versus acetazolamide in the management of chronic macular edema in patients with retinitis pigmentosa: description of three case reports.

AIMS: To assess the efficacy of topical dorzolamide for treating cystoid macular edema in patients with retinitis pigmentosa and minimize the secondary effects of maintenance therapy in patients with retinitis pigmentosa (RP) who present with chronic microcystic macular edema. METHODS: To replace acetazolamide systemic treatment, with a topical treatment using 2% dorzolamide in three patients. The methods performed were OCT scan with a Spectralis HRA-OCT, for the measurement of macular thickness and morphology; best corrected visual acuity was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS), was assessed slit-lamp biomicroscopy, ocular tonometry, fundus biomiocrosopy, and color fundus photography. This therapeutic protocol has been applied and described in three patients. RESULTS: In all three tested patients, following the administration of dorzolamide in eye drop, we observed a remarkable decrease in macular edema, almost comparable to that obtained with acetazolamide per os. CONCLUSION: The study confirms the anti-edematogenic effect of topical dorzolamide in RP with recurring macular cysts, as this can have a favorable response with topical dorzolamide. In all the three examined patients, the instillation of topical dorzolamide caused a remarkable reduction in their macular edema, as highlighted on OCT.

Effect of a contraceptive pill containing estradiol valerate and dienogest (E2V/DNG) in women with menstrually-related migraine (MRM).

BACKGROUND: Combined hormonal contraception might worsen migraine in sensitive women, especially during the free-hormone interval, and raise concerns about the vascular risk. The characteristics of a contraceptive pill containing estradiol valerate/dienogest (E2V/DNG) might be of potential benefit in women with menstrually related migraine (MRM) who choose to use oral contraception for birth control. STUDY DESIGN: This was a prospective diary-based pilot study. Thirty-two women (age >35 years) [n=18 who had never used combined oral contraceptives (COCs) and n=14 who had previously used COCs] diagnosed with MRMs according to the International Headache Society criteria were included. During the observational period, women filled in a diary with the clinical characteristics of migraine attacks. After a three-cycle run-in period, each subject received a COC containing E2V/DNG (Qlaira®/Natazia®; Bayer HealthCare, Berlin, Germany) administered using an estrogen step-down and progestogen step-up approach. Follow-up evaluations were scheduled at the last cycle of run-in and at the third and sixth cycles of treatment. RESULTS: The number of migraine attacks was significantly reduced at the third (p<.001) and sixth cycles (p<.001) in comparison with the run-in period. A similar result was evident for the duration (p<.001 at the third and p<.001 at the sixth cycle) as well as for the severity of head pain (p<.001 at the third and p<.001 at the sixth month). Indeed, a significantly lower number of analgesics were used at the third cycle (p<.001) in comparison with baseline, and a further decrease was evident at the sixth cycle (p<.001) in comparison with the third cycle of E2V/DNG use. Interestingly, duration and severity of head pain were significantly correlated with the number of days of dysmenorrhea at the third cycle (r=.89, p=.000 and r=.67, p=.02; respectively) and at the sixth cycle (r=.76, p=.000 and r=.62, p=.04; respectively) in women without complete remission of menstrual cramps during the study period. CONCLUSIONS: The present diary-based pilot study indicates that the use of a pill containing EV2/DNG for six cycles has a positive effect in women with MRM and suggests an association between dysmenorrhea with COCs use as a potential feature of refractory head pain.

Menopause and sexual desire: the role of testosterone.

The present short review underlines the role of testosterone (T) in the motivational and satisfaction components of women's sexuality and critically discusses the strategies to treat hypoactive sexual desire disorder (HSDD), a condition of low desire associated with personal and/or interpersonal difficulties, which is more common in surgical menopausal women. There are multiple ways androgens target the brain regions (hypothalamic, limbic and cortical) involved in sexual function and behaviour. Even though circulating available androgens have been implicated in several domains of sexual response, they seem to be related weakly to symptoms, such as low sexual desire, poor sexual arousal, orgasm and diminished well-being in postmenopausal women. The possibilities of treating low sexual desire/HSDD are multifaceted and should include the combination of pharmacological treatments able to maximize biological signals driving the sexual response, and individualized psychosocial therapies in order to overcome personal and relational difficulties. Transdermal T has been shown to be effective at a dose of 300 µg/day both in surgically and naturally menopausal women replaced with estrogen or not, without any relevant side-effects. However, the decision to treat postmenopausal women with HSDD with T is mainly based on clinical judgement, after informed consent regarding the unknown long-term risks.

Hormonal and psycho-relational aspects of sexual function during menopausal transition and at early menopause.

OBJECTIVE: The aim of the present observational, cross-sectional study was to examine the effects of hormonal and psycho-relational variables on sexual function during menopausal transition and at early postmenopause in women with hot flushes. STUDY DESIGN: The sample comprised 138 women referred to a clinic for the treatment of hot flushes. They were categorised according to their stage of menopausal transition using the STRAW criteria: early menopausal transition (EMT) if their menstrual cycle was 7 or more days different from normal; late perimenopause (LMT) if they had experienced 60 days or more of amenorrhoea; and early postmenopause (EPM) if their amenorrhoea had lasted for at least 12 months but less than 4 years. MAIN OUTCOME MEASURES: Sexual function was measured by using the Female Sexual Function Index (FSFI), while anxiety (state and trait), depression, eating disorder and marital adjustment were evaluated by validated self-report questionnaires. Levels of free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS) and estradiol (E2) were also measured. RESULTS: Overall sexual function varied significantly with stage of menopause, with total FSFI score less in EPM than in EMT (p=.009). A similar pattern was evident on FSFI sub-scales for sexual desire (p=.02), arousal (p=.01) orgasm (p=.01) and also pain (p=.02), but not for lubrication and satisfaction. Ratings for anxiety, depression and eating disorder did not differ across the menopausal sub-groups, and neither did ratings of marital adjustment. Both FT (p=.01) and DHEAS (p=.03) levels were slightly reduced at EPM in comparison with EMT, as were E2 levels (p=.001 EMT versus LMT; p=.0001 LMT versus EPM). In multiple regression analyses, plasma FT level was the only factor to predict FSFI full score (beta=.48; p=0.004) in women at EMT, while in women at LMT the depression score was the only factor to do so (beta=-.62; p=0.0001). The best model predicting FSFI full score at EPM included levels of DHEAS and E2 levels and state anxiety score. CONCLUSIONS: Hormonal and some psychological variables are relevant to sexual function in symptomatic women during menopausal transition and at early menopause but their role differs with the specific stage of reproductive ageing.

Mood disorders and sexual functioning in women with functional hypothalamic amenorrhea.

OBJECTIVE: To investigate the sexual function of women with functional hypothalamic amenorrhea (FHA) and to test the mediating effects of depression and anxiety on the sexual functioning of women with FHA. DESIGN: In this cross-sectional study, participants completed questionnaires on sexual function, depression, and anxiety. SETTING: Tertiary care university hospital. PATIENT(S): Women with (n=41) and without (n=39) FHA recruited from a gynecologic endocrinology unit. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The McCoy Female Sexuality Questionnaire assessed sexual function, and the Zung Scale measured depression and anxiety. RESULT(S): Women with FHA experienced more sexual function problems and significantly higher depression and anxiety compared to women without menstrual dysfunction. In addition, depression offered a significant explanation for the sexual problems experienced by women with FHA. CONCLUSION(S): The psychologic symptoms that contribute to the onset of FHA partially mediate the relationship between FHA and sexual dysfunction.

Psychosexual well-being in women using oral contraceptives containing drospirenone.

Considerable advances have been made in hormonal contraception in recent years, geared at maximizing compliance and minimizing discontinuation. In oral contraceptive (OC) formulations, the estrogenic component, generally ethinyl estradiol (EE), has been reduced significantly and newer progestins like dienogest and drospirenone (DRSP), compounds with different molecular structures, have been introduced; in addition, new regimens (extended, flexible, 24/4 formats instead of the standard 21/7 format) and innovative delivery systems (vaginal rings, transdermal patches, subcutaneous implants and intrauterine devices) are available. The multitude of choices allows hormonal contraception to be tailored to the individual woman in order to obtain non-contraceptive benefits, without significant side effects, and also a favorable risk/benefit profile for her general and reproductive health. Over the past few years, new OC formulations combining DRSP (3 mg), a unique progestin with both antimineralocorticoid and antiandrogenic activities, with estrogen (30 mcg or 20 mcg EE), in two regimens (24/4 and 21/7) of active pills in a 28-day cycle, have shown positive effects on water retention-related weight gain and physical, emotional and psychosexual well-being. It seems likely that the use of a low-dose, well-balanced OC and the shorter 4-day hormone-free interval may minimize the side effects that can impair quality of life and thus increase women's compliance with hormonal contraception therapy.