Mortality from Congenital Zika Syndrome - Nationwide Cohort Study in Brazil.

BACKGROUND: Prenatal exposure to Zika virus has potential teratogenic effects, with a wide spectrum of clinical presentation referred to as congenital Zika syndrome. Data on survival among children with congenital Zika syndrome are limited. METHODS: In this population-based cohort study, we used linked, routinely collected data in Brazil, from January 2015 through December 2018, to estimate mortality among live-born children with congenital Zika syndrome as compared with those without the syndrome. Kaplan-Meier curves and survival models were assessed with adjustment for confounding and with stratification according to gestational age, birth weight, and status of being small for gestational age. RESULTS: A total of 11,481,215 live-born children were followed to 36 months of age. The mortality rate was 52.6 deaths (95% confidence interval [CI], 47.6 to 58.0) per 1000 person-years among live-born children with congenital Zika syndrome, as compared with 5.6 deaths (95% CI, 5.6 to 5.7) per 1000 person-years among those without the syndrome. The mortality rate ratio among live-born children with congenital Zika syndrome, as compared with those without the syndrome, was 11.3 (95% CI, 10.2 to 12.4). Among infants born before 32 weeks of gestation or with a birth weight of less than 1500 g, the risks of death were similar regardless of congenital Zika syndrome status. Among infants born at term, those with congenital Zika syndrome were 14.3 times (95% CI, 12.4 to 16.4) as likely to die as those without the syndrome (mortality rate, 38.4 vs. 2.7 deaths per 1000 person-years). Among infants with a birth weight of 2500 g or greater, those with congenital Zika syndrome were 12.9 times (95% CI, 10.9 to 15.3) as likely to die as those without the syndrome (mortality rate, 32.6 vs. 2.5 deaths per 1000 person-years). The burden of congenital anomalies, diseases of the nervous system, and infectious diseases as recorded causes of deaths was higher among live-born children with congenital Zika syndrome than among those without the syndrome. CONCLUSIONS: The risk of death was higher among live-born children with congenital Zika syndrome than among those without the syndrome and persisted throughout the first 3 years of life. (Funded by the Ministry of Health of Brazil and others.).

My Dog, My Hero: Assessing the Feasibility of a Cross-Generational Digital Storytelling Intervention for Veterans.

During the COVID-19 pandemic, social isolation had a devastating effect on well-being. Veterans were among the most vulnerable given their high rates of military trauma-related conditions. Research supports that dogs can provide veterans with a sense of purpose, social support, and stress management. Digital storytelling provided a unique perspective with focus on a recognized hero, the veteran's dog, and an opportunity for engagement with other veterans during COVID-19. The purpose of the study was to assess the feasibility of this digital storytelling intervention based on Story Theory framework and tailored to encompass components of cross-generational collaboration in combination with individual and group virtual sessions as a mechanism to promote social engagement. The research was conducted using a descriptive exploratory design. Veterans (N = 8) were paired with a trained student and grouped in sets of four. There were eight guided 1-hour weekly virtual sessions to create their digital story. Demographic and pre-post intervention survey data were also collected. Based on eight established criteria, this article systematically evaluates the feasibility of the digital storytelling intervention for veterans. The findings suggest practical considerations to ensure viability of digital storytelling as a therapeutic intervention for veterans and other populations at-risk for suboptimal well-being.

Pre-surgical socket analysis for immediate implant placement.

BACKGROUND: Traditional protocols for implant surgery suggest a healing period of 2-3 months from dental extraction to implant placement. Based on all the volumetric modifications produced by that approach, there are authors who advocate for immediate implantology. The aim of the present study was to determine the prevalence of different sockets, and the dimensions of the bone around the upper anterior incisors and canines, to determine the predictability of immediate implants in our population. MATERIAL AND METHODS: This is an observational, cross-sectional study based on cone-beam computed tomography images of the anterior maxila of patients attending the Odontological Hospital of the University of Barcelona (OHUB) and requesting for implant treatment. Different measurements were performed on every analyzed tooth, and also they were categorized by using the main dental sockets classifications. RESULTS: Bone attachment levels and cortical thickness are lower in women compared to men in all three types of teeth (the difference in the bone attachment levels ranges from 4.68%-8.63% and in the bone thickness goes from 0.02-0.58mm). Bone attachment level gradually reduces with age. The reductions observed in all the measurements are higher in the case of canines, compared with the other teeth. The differences from patients <45 years old and patients between 55-64 years old are 13.58±14.55mm in the case of central incisors, 10.04±5.52 in the case of lateral incisors and 22.39±13.65mm in the case of canines. CONCLUSIONS: According to our results, the canines are the teeth with the greatest complexity when it comes to immediate implantology treatments. Furthermore, that kind of treatment is more complex as age increases, since we observed a gradual percentage of unfavourable sockets in older patients.

Association of vitamin D levels and oral lichen planus. Systematic review and meta-analysis.

BACKGROUND: Oral lichen planus (OLP) is an inmuno-mediated mucocutaneous chronical inflammatory disease. Multiple predisposing factors are considered, such as autoimmune response, microorganisms, medications, dental materials, psychological stress, genetic predisposition or nutritional deficiencies. The deficiency of vitamin D has been related to various autoimmune diseases like OLP. MATERIAL AND METHODS: The electronic search was conducted in the MEDLINE (Pubmed), Scopus, Cochrane Library and Web of Science databases. To assess any potential risk of bias, the authors critically appraised each study by the Newcastle-Ottawa Scale for cohort and case-control studies. Pooled analyses were performed using a random-effects model. Heterogeneity of the studies was assessed by the I2 statistics. Forest Plots were performed to graphically represent the difference between vitamin D concentrations in the OLP compared to healthy group, with a 95% confidence interval. RESULTS: After applying our inclusion and exclusion criteria, 7 articles were included in our review. The median concentration vitamin D in ng/ml found in serum for patients with OLP was of 26,6311,75ng/ml and for healthy patients was of 31,438,7ng/ml. Regarding the quantitative analysis, 7 studies were included. The difference in the concentration of vitamin D in healthy patients and patients with OLP statistically significant (Weighted Mean Difference (WMD): -6.20, 95% CI: -11.24 to -1.15, p=0.02 and I2 heterogeneity: 94%, p<0.00001). CONCLUSIONS: The patients with OLP have statistically lower vitamin D levels than healthy patients.

Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: A phase 2 study from GELTAMO.

Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory (RR) disease have poor outcomes with current salvage regimens. We conducted a phase 2 trial to analyse the safety and efficacy of adding lenalidomide to R-ESHAP (LR-ESHAP) in patients with RR DLBCL. Subjects received 3 cycles of lenalidomide 10 mg/day on days 1-14 of every 21-day cycle, in combination with R-ESHAP at standard doses. Responding patients underwent autologous stem-cell transplantation (ASCT). The primary endpoint was the overall response rate (ORR) after 3 cycles. Centralized cell-of-origin (COO) classification was performed. Forty-six patients were included. The ORR after LR-ESHAP was 67% (35% of patients achieved complete remission). Patients with primary refractory disease (n = 26) had significantly worse ORR than patients with non-refractory disease (54% vs. 85%, p = 0.031). No differences in response rates according to the COO were observed. Twenty-eight patients (61%) underwent ASCT. At a median follow-up of 41 months, the estimated 3-year PFS and OS were 42% and 48%, respectively. The most common grade ≥3 adverse events were thrombocytopenia (70% of patients), neutropenia (67%) and anaemia (35%). There were no treatment-related deaths during LR-ESHAP cycles. In conclusion, LR-ESHAP is a feasible salvage regimen with promising efficacy results for patients with RR DLBCL.

Canonical Wnt/ß-catenin activity and differential epigenetic marks direct sexually dimorphic regulation of Irx3 and Irx5 in developing mouse gonads.

Members of the Iroquois B (IrxB) homeodomain cluster genes, specifically Irx3 and Irx5, are crucial for heart, limb and bone development. Recently, we reported their importance for oocyte and follicle survival within the developing ovary. Irx3 and Irx5 expression begins after sex determination in the ovary but remains absent in the fetal testis. Mutually antagonistic molecular signals ensure ovary versus testis differentiation with canonical Wnt/ß-catenin signals paramount for promoting the ovary pathway. Notably, few direct downstream targets have been identified. We report that Wnt/ß-catenin signaling directly stimulates Irx3 and Irx5 transcription in the developing ovary. Using in silico analysis of ATAC- and ChIP-Seq databases in conjunction with mouse gonad explant transfection assays, we identified TCF/LEF-binding sequences within two distal enhancers of the IrxB locus that promote ß-catenin-responsive ovary expression. Meanwhile, Irx3 and Irx5 transcription is suppressed within the developing testis by the presence of H3K27me3 on these same sites. Thus, we resolved sexually dimorphic regulation of Irx3 and Irx5 via epigenetic and ß-catenin transcriptional control where their ovarian presence promotes oocyte and follicle survival vital for future ovarian health.

The Role of Nutrients and Nutritional Signals in the Pathogenesis of Vibrio cholerae.

Vibrio cholerae, the agent of cholera, is a natural inhabitant of aquatic environments. Over the past decades, the importance of specific nutrients and micronutrients in the environmental survival, host colonization, and pathogenesis of this species has become increasingly clear. For instance, V. cholerae has evolved ingenious mechanisms that allow the bacterium to colonize and establish a niche in the intestine of human hosts, where it competes with commensals (gut microbiota) and other pathogenic bacteria for available nutrients. Here, we discuss the carbon and energy sources utilized by V. cholerae and what is known about the role of nutrition in V. cholerae colonization. We examine how nutritional signals affect virulence gene regulation and how interactions with intestinal commensal species can affect intestinal colonization.

Tropical tree foliage supplementation in ruminants improves rumen fermentation and the bacterial profile and decreases methane production.

The main of this study was to evaluate the effect of supplementation of tropical tree foliage in ruminant diets on the in vitro fermentation, bacterial population, volatile fatty acids (VFAs), and enteric CH4 production. Seven experimental diets were evaluated: a control treatment of Pennisetum purpureum (T7) and six treatments of P. purpureum supplemented (30%) with the foliage of Neomillspaughia emargiata (T1), Tabernaemontana amygdalifolia (T2), Caesalpinia gaumeri (T3), Piscidia piscipula (T4), Leucaena leucocephala (T5), and Havardia albicans (T6). The T2, T7, and T5 treatments had the highest (p < 0.05) digestibility of dry matter. Overall, supplementation increased (p < 0.05) the concentrations of propionic and butyric acid and decreased acetic acid. Methanogenic bacteria decreased (p < 0.05) in T1, T2, T5, and T6. Ruminococcus albus decreased in T1, T2, T3, and T5 and Selenomonas ruminiantum increased in T3. Fibrobacter succinogenes increased, except in T5. Methane production decreased (p < 0.05) in T1, T4, T5, and T6. The supplementation with Leucaena leucocephala, Tabernaemontana amygdalifolia, Neomillspaughia emargiata, Piscidia piscipula, Havardia albicans, and Caesalpinia gaumeri is a potential alternative nutritional strategy for ruminants that results in positive changes in VFAs profile, a decrease on CH4 production and methanogenic bacteria, and changes on fibrolytic and non-fibrolytic bacteria composition.HIGHLIGHTSTropical tree foliage supplementation increased propionic and butyric acid and decreased acetic acid concentrations.Fibrolytic, non-fibrolytic, and Methanogenic bacteria were selectively modulated with the supplementation of tropical tree foliage.The enteric methane (CH4) production decreased with the supplementation of tree foliage.The supplementation of Tabernaemontana amygdalifolia and Leucaena leucocephala had the highest digestibility and is a potential alternative nutritional strategy for ruminants.

Role of thyroid hormones in burning mouth syndrome. Systematic review.

BACKGROUND: Burning mouth syndrome is an idiopathic condition characterized by burning pain in a normal-appearing oral mucosa lasting at least four to six months. In the case of secondary burning mouth syndrome is associated with local or systemic factors (such as thyroid disorders) that can cause these symptoms. The aim of this review was to study the relationship between thyroid disorders and burning mouth syndrome. MATERIAL AND METHODS: The present study followed the PRISMA guidelines. An electronic search strategy was developed for PubMed/Medline, Scopus and Cochrane. The following combination of keywords and Boolean operators were used: Thyroid AND burning mouth; Thyroid AND burning mouth syndrome; Hypothyroidism AND burning mouth; Hypothyroidism AND burning mouth syndrome; Hyperthyroidism AND burning mouth; Hyperthyroidism AND burning mouth syndrome. The results were processed by existing free software in https://www.graphpad.com/. To evaluate the association of the categorical variables we used the Fisher test at a level of significance of p-value ≤ 0,05. As a primary summary measure the Odds Ratio (OR) has been used. To analyze the risk of bias the guidelines of the GRADE guide were used and the grade of evidence was analyzed by the guide of Joanna Briggs Institute: Levels of Evidence and Grades of Recommendations. RESULTS: After applying the inclusion and exclusion criteria, 5 studies were selected for review. The Chi-square was 10.92 and the Odds Ratio was 3.31 with respect to TSH values with p <0.0001 (Fisher's test). The population of patients with TSH alterations is increased in 80.49% and decreased in 19.51%. CONCLUSIONS: It can be concluded that thyroid hormone abnormalities are a factor in secondary burning mouth syndrome; specially in patients with hypothyroidism.

Treatment of recurrent aphtous stomatitis: A systematic review.

BACKGROUND: Recurrent Aphtous Stomatitis (RAS) is the most common process affecting the oral mucosa. It is painful, multifactorial and generally recurrent. The aim of this systematic review is to know the last treatment approaches and their effectivity. MATERIAL AND METHODS: we compared the outcome of different kind of treatments in terms of the improvement of the lesions, reduction of the size of those lesions and the time needed for their healing. Inclusion criteria were: clinical trials, articles written in English or Spanish and published less than 5 years ago. RESULTS: we used the following keywords: "treatment", "aphtous stomatitis", "canker sores"; combined with Boolean operators AND y OR. We selected 28 articles for reading the whole text, and after applying the eligibility criteria, we selected 17 articles for our revision. Among all the treatments, we emphasize the barrier method based in compound of cellulose rubber and a calcium/sodium copolymer PVM/MA, with which the difference in the 3rd and 7th day was of -6,29 ± 0,14 points in the pain score. The treatment with insulin and chitosan gel, brought a pain suppression on the third day, with no reactivation of the pain during the whole study. The application of a film composed of polyurethane and sesame oil with chitosan, brought a reduction in the size of the lesions of 4,54 ± 2,84mm on the 6th day compared with the situation before the beginning of the treatment. The different kinds of laser, which produced a reduction in the pain score just at the beginning of the treatment up to 8,1 ± 1,6 points, and a reduction of the size of the lesions of 4,42 ± 1,02mm on the 7th day. CONCLUSIONS: Besides the classic treatments for RAS, we have to take into account other treatment modalities, above all the different kinds of laser.

Role of selected salivary inflammatory cytokines in the diagnosis and prognosis of oral squamous cell carcinoma. A Systematic Review and Meta-analysis.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is gradually increasing its incidence in our society. Unfortunately, this entity is diagnosed at an advanced stage in most patients, a fact that implies greater difficulty in its treatment and a worse prognosis. This systematic review aims to assess whether the cytokines IL-6, IL-8 and TNF-α are potential salivary biomarkers that allow early diagnosis of cancer. MATERIAL AND METHODS: An electronic search was performed in three databases (Pubmed, Scopus and Web of Science). We used the following keywords: "salivary cytokines", "saliva cytokines", "salivary interleukins", "biomarkers", "oral squamous cell carcinoma" and "diagnosis", combined with the Boolean operators "AND" and "OR". RESULTS: 128 publications were found and finally 23 articles were included in the review and 15 in the meta-analysis. It has been observed that the majority of OSCC patients express higher salivary concentrations of IL-6, IL-8 and TNF-α compared to the control (CL) and premalignant lesion (OPML) groups. It has also been observed that the different premalignant lesions do not have statistically significant differences in the salivary concentration of the cytokines, and on the other hand, differences have been observed between the different TNM stages. The meta-analysis has shown that the difference in concentration of IL-6, IL-8 and TNF-α is statistically significant between the CL group and the OSCC, and also between the CL group and OPML. CONCLUSIONS: There is sufficient evidence to affirm that IL-6, IL-8 and TNF-α are useful salivary cytokines in the early diagnosis and prognosis of OSCC. Although future studies are necessary to establish greater reliability of these biomarkers and thus be able to develop a valid diagnostic test.

Population-based surveillance for congenital zika virus syndrome: a latent class analysis of recorded cases from 2015-2018.

OBJECTIVE: This study aims to describe clinical findings and determine the medium-term survival of congenital zika syndrome (CZS) suspected cases. METHODS: A retrospective cohort study using routine register-based linked data. It included all suspected cases of CZS born in Brazil from January 1, 2015, to December 31, 2018, and followed up from birth until death, 36 months, or December 31, 2018, whichever came first. Latent class analysis was used to cluster unconfirmed cases into classes with similar combinations of anthropometry at birth, imaging findings, maternally reported rash, region, and year of birth. Kaplan-Meier curves were plotted, and Cox proportional hazards models were fitted to determine mortality up to 36 months. RESULTS: We followed 11,850 suspected cases of CZS, of which 28.3% were confirmed, 9.3% inconclusive and 62.4% unconfirmed. Confirmed cases had almost two times higher mortality when compared with unconfirmed cases. Among unconfirmed cases, we identified three distinct clusters with different mortality trajectories. The highest mortality risk was observed in those with abnormal imaging findings compatible with congenital infections (HR = 12.6; IC95%8.8-18.0) and other abnormalities (HR = 11.6; IC95%8.6-15.6) compared with those with normal imaging findings. The risk was high in those with severe microcephaly (HR = 8.2; IC95%6.4-10.6) and macrocephaly (HR = 6.6; IC95%4.5-9.7) compared with normal head size. CONCLUSION: Abnormal imaging and head circumference appear to be the main drivers of the increased mortality among suspected cases of CZS. We suggest identifying children who are more likely to die and have a greater need to optimise interventions and resource allocation regardless of the final diagnoses.

CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.

XX and XY fetal gonads are initially bipotential, poised between the ovary and testis fate. Multiple lines of evidence suggest that commitment to testis fate requires the repression of genes associated with ovary fate. It was previously shown that loss of CBX2, the subunit of the Polycomb Repressive Complex 1 (PRC1) that binds H3K27me3 and mediates silencing, leads to ovary development in XY mice and humans. While it had been proposed that CBX2 is an activator of the testis-determining gene Sry, we investigated the alternative possibility that CBX2 has a direct role as a repressor of the antagonistic ovary-promoting pathway. To investigate this possibility, we developed a quantitative genome-wide profile of the repressive histone mark H3K27me3 and its active counterpart H3K4me3 in isolated XY and XX gonadal supporting cells before and after sex determination. We show that testis and ovary sex-determining (SD) genes are bivalent before sex determination, providing insight into how the bipotential state of the gonad is established at the epigenetic level. After sex determination, many SD genes of the alternate pathway remain bivalent, possibly contributing to the ability of these cells to transdifferentiate even in adults. The finding that many genes in the Wnt signaling pathway were targeted for H3K27me3-mediated repression in Sertoli cells led us to test whether deletion of Wnt4 could rescue testis development in Cbx2 mutants. We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice. Furthermore, we show that CBX2 directly binds the downstream Wnt signaler Lef1, an ovary-promoting gene that remains bivalent in Sertoli cells. Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development.

Gonadal supporting cells acquire sex-specific chromatin landscapes during mammalian sex determination.

Cis-regulatory elements are critical for the precise spatiotemporal regulation of genes during development. However, identifying functional regulatory sites that drive cell differentiation in vivo has been complicated by the high numbers of cells required for whole-genome epigenetic assays. Here, we identified putative regulatory elements during sex determination by performing ATAC-seq and ChIP-seq for H3K27ac in purified XX and XY gonadal supporting cells before and after sex determination in mice. We show that XX and XY supporting cells initiate sex determination with similar chromatin landscapes and acquire sex-specific regulatory elements as they commit to the male or female fate. To validate our approach, we identified a functional gonad-specific enhancer downstream of Bmp2, an ovary-promoting gene. This work increases our understanding of the complex regulatory network underlying mammalian sex determination and provides a powerful resource for identifying non-coding regulatory elements that could harbor mutations that lead to Disorders of Sexual Development.

High activation and skewed T cell differentiation are associated with low IL-17A levels in a hu-PBL-NSG-SGM3 mouse model of HIV infection.

The humanized NOD/SCID/IL-2 receptor γ-chainnull (NSG) mouse model has been widely used for the study of HIV pathogenesis. Here, NSG mice with transgenic expression of human stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 (NSG-SGM3) were injected with peripheral blood leukocytes (PBL mice) from two HIV-infected (HIV+ ) patients who were under anti-retroviral therapy (ART; referred as HIV+ mice) or one HIV-seronegative healthy volunteer (HIV- ). Such mice are either hu-PBL-NSG-SGM3 HIV+ or HIV- mice, depending on the source of PBL. The kinetics of HIV replication and T cell responses following engraftment were evaluated in peripheral blood and secondary lymphoid tissues. High HIV replication and low CD4 : CD8 ratios were observed in HIV+ mice in the absence of anti-retroviral therapy (ART). Consistent with high activation and skewed differentiation of T cells from the HIV-infected donor, HIV+ mice exhibited a higher T cell co-expression of human leukocyte antigen D-related (HLA-DR) and CD38 than HIV- mice, as well as a shifted differentiation to a CCR7- CD45RA+ terminal effector profile, even in the presence of ART. In addition, HIV replication and the activation/differentiation disturbances of T cells were associated with decreased plasma levels of IL-17A. Thus, this hu-PBL-NSG-SGM3 mouse model recapitulates some immune disturbances occurring in HIV-infected patients, underlying its potential use for studying pathogenic events during this infection.

Descriptive study of naevus involution in a series of 74 patients with atypical naevus syndrome under SIAscopy digital follow-up.

BACKGROUND: Characterization of nevi involution could help to understand the biological behaviour of melanocytic neoplasms. OBJECTIVE: To describe the frequency and morphology of naevus involution in a series of patients with atypical naevus syndrome under digital follow-up with a SIAscopy program and, in a small sample of fading nevi, to analyse histopathological features and immunohistochemical biomarkers. METHODS: Seventy-four patients registered from April 2007 to July 2014 in the SIAscopy system of the Department of Dermatology of Hospital Arnau de Vilanova of Lleida, Spain, were reviewed. Fourteen naevus cases with fading features were prospectively excised during follow-up. Eleven already excised naevus controls were randomly selected from our archive. RESULTS: We observed that 81% of patients showed, at least, one involutive naevus and 25% of recorded nevi presented this phenomenon; the mean time of involution was 46.7 months. The predominant structural pattern was reticular (>70%), and the most frequently observed regression structures were vascular (33.8%). Histopathological significant higher intensity of inflammatory infiltrate in controls and higher presence of laminar and compact fibrosis and increase of vessels in cases were demonstrated. Regarding immunohistochemical biomarkers, only higher expression of cytoplasmic activated caspase 3 in controls was significant. CONCLUSIONS: Naevus involution is a common phenomenon in patients with dysplastic naevus syndrome. It is usually a slow process, more frequent in naevus with reticular pattern. SIAscopy regression structures are uncommon, with the exception of vascular ones. Histologically, fading involutive pattern is characterized by scarce inflammatory infiltrate and melanophages, delicate fibrosis and increase of vessels.

Evaluation of kidney function in HIV-infected patients receiving an antiretroviral regimen containing one or two inhibitors of the tubular secretion of creatinine.

OBJECTIVES: The aim of this study was to determine the evolution of renal function in patients receiving one or two inhibitors, according to different baseline factors. Some antiretroviral drugs such as rilpivirine (RPV), dolutegravir (DTG), or cobicistat (COBI), interact with the tubular secretion of creatinine, but there are no data about their impact in renal function evaluation in patients with renal disease or when these drugs are used concomitantly. METHODS: A prospective cohort study was carried out in HIV-infected patients who switched to a dual regimen including DTG, RPV or darunavir/COBI, separately or in combination. The primary endpoint was the evolution of the serum creatinine-based estimated glomerular filtration rate (eGFR-scr). A control group not receiving any transporter inhibitor was included. RESULTS: A total of 288 patients on different dual regimens were included (DTG + RPV, 92; DTG + darunavir/COBI, 23; DTG, 26; COBI, 19; control group, 128). In patients receiving two transporter inhibitors, eGFR-scr decreased by a mean of -8.4 mL/min/1.73 m2 , similar to that observed with the separate use of DTG or COBI (mean of both groups, -8.6 mL/min/1.73 m2 ), while eGFR-scr improved in the control group. Similar evolution of proteinuria and tubular dysfunction was observed in all the groups, and there were no significant changes in the cystatin C-based eGFR. Mean eGFR-scr change inversely correlated with baseline eGFR-scr value (r = -0.39; P < 0.01), with a lower eGFR-scr decrease in patients with chronic kidney disease. CONCLUSIONS: Similar eGFR-scr decreases were observed in patients using different antiretroviral drugs inhibiting the tubular transport of creatinine, separately or in combination, with no alterations in proteinuria or cystatin C-based eGFR. The lack of additional changes when the drugs were used in combination, and the lower impact in cases of previous chronic kidney disease, suggest that there are compensatory mechanisms for creatinine secretion.

Two-drug vs. three-drug combinations for HIV-1: Do we have enough data to make the switch?

Three-drug combination antiretroviral therapy (ART) became available in 1996, dramatically improving the prognosis of people living with HIV. The clinical benefits of ART are due to the sustained viral load suppression and CD4 T cell gains. Major drawbacks of the first ART regimens were adverse events, and high pill burden, which led to the reduction of drug adherence resulting in frequent treatment discontinuations and the development of drug resistance. Due to increased viral potency of new antiretroviral drugs consideration of a two-drug combination therapy repositioning occurred in an effort to reduce adverse events, drug-drug interactions and cost, while maintaining a sustained antiviral effect. Various combinations of two-drug regimens have been studied, and non-inferiority compared to a three-drug regimen has been shown only for some of them. In addition, a two-drug combination regimen may not be suitable for every patient, especially those who are pregnant, those with tuberculosis or coexisting HBV infection. Furthermore no information has been generated concerning the secondary transmission of HIV from patients who have undetectable plasma viral load on two-drug regimens. Additional studies of two-drug combinations are also necessary to evaluate the debated existence of low viral replication in tissues and on immune activation. While there is no urgent need to routinely switch patients to two-drug combination therapy, due to the availability of drug combinations without significant toxicities, dual regimens represent a suitable option that deserve long-term evaluation before being introduced to clinical practice.

Aerosolized Lipid Amphotericin B for Complementary Therapy and/or Secondary Prophylaxis in Patients with Invasive Pulmonary Aspergillosis: A Single-Center Experience.

BACKGROUND: Experience with aerosolized lipid amphotericin B (aeLAB) as therapy or secondary prophylaxis in patients with invasive pulmonary aspergillosis (IPA) is anecdotal. METHODS: We performed a single-center retrospective cohort study to evaluate the efficacy of systemic antifungal therapy with and without aeLAB in patients with proven or probable IPA. Complete or partial response at 3 months was the primary end-point. Clinical response and mortality at 12 months, occurrence of adverse drug reactions and respiratory fungal colonization were secondary end-point. RESULTS: Eleven patients (39%) received aeLAB in addition to systemic antifungal therapy (group A), and 22 (61%) received systemic antifungal therapy only (group B). The use of aeLAB was not standardized. Amphotericin B lipid complex was used in all patients but one, who received liposomal amphotericin B. Five patients received aeLAB as antifungal complementary therapy and 6 received it as secondary prophylaxis. Except for the requirement of inhaled corticosteroids and home oxygen therapy, more frequent in group A, both groups were similar in baseline conditions. A better (nonsignificant) clinical outcome was observed at 3 months in patients receiving aeLAB. Only uncontrolled baseline condition was associated with one-year mortality in univariate analysis (p = 0.002). A multivariate Cox regression analysis suggests that aeLAB, corrected for uncontrolled underlying disease, reduces mortality at 12 months (HR 0.258; 95% CI 0.072-0.922; p = 0.037). CONCLUSION: Although no significant difference was observed in the main variable (3-month clinical response) and in spite of methodological limitations of the study, the possible survival benefit of aeLAB, adjusted for the control of the underlying disease, could justify the performance of well-controlled studies with a greater number of patients.