Preeclampsia and risk of maternal pulmonary hypertension at high altitude in Bolivia.

Women with a history of preeclampsia (PE) have a greater risk of pulmonary arterial hypertension (PAH). In turn, pregnancy at high altitude is a risk factor for PE. However, whether women who develop PE during highland pregnancy are at risk of PAH before and after birth has not been investigated. We tested the hypothesis that during highland pregnancy, women who develop PE are at greater risk of PAH compared to women undergoing healthy highland pregnancies. The study was on 140 women in La Paz, Bolivia (3640m). Women undergoing healthy highland pregnancy were controls (C, n = 70; 29 ± 3.3 years old, mean±SD). Women diagnosed with PE were the experimental group (PE, n = 70, 31 ± 2 years old). Conventional (B- and M-mode, PW Doppler) and modern (pulsed wave tissue Doppler imaging) ultrasound were applied for cardiovascular íííassessment. Spirometry determined maternal lung function. Assessments occurred at 35 ± 4 weeks of pregnancy and 6 ± 0.3 weeks after birth. Relative to highland controls, highland PE women had enlarged right ventricular (RV) and right atrial chamber sizes, greater pulmonary artery dimensions and increased estimated RV contractility, pulmonary artery pressure and pulmonary vascular resistance. Highland PE women had lower values for peripheral oxygen saturation, forced expiratory flow and the bronchial permeability index. Differences remained 6 weeks after birth. Therefore, women who develop PE at high altitude are at greater risk of PAH before and long after birth. Hence, women with a history of PE at high altitude have an increased cardiovascular risk that transcends the systemic circulation to include the pulmonary vascular bed.

Clinical practice guidelines on leptospirosis in children 2019

Executive Summary@#Leptospirosis is a disease prevalent mostly in tropical and subtropical countries. Its potential to be a concerning problem emerges with the onset of the rainy season, as flooding and heavy rainfall facilitate disease epidemics. Among those at risk of contracting the disease are field workers, veterinarians, sewer workers, military personnel and those who swim or wade in contaminated waters. In the absence of an existing evidence-based guideline for the pediatric age group, this first edition hopes to standardize approach to diagnosis, antibiotic management, and prevention of leptospirosis. The intended users are primary care physicians, family medicine physicians, pediatricians, and other healthcare workers involved in the management of leptospirosis in children. Ten priority questions were identified by a group of experts composed of an oversight committee, a guideline writing panel, and a technical review committee. The GRADE methodology was used to determine the quality of evidence of each recommendation. The draft recommendations (summarized below) were finalized after these were presented to and voted on by a panel of stakeholders.

Women in Neurosurgery: Historical Path to Self-Segregation and Proposal for an Integrated Future.

Despite the rising percentage of women accessing the medical profession over the last few decades, surgical specialties are still largely male-dominated; in particular, a remarkable gender disparity is evident in neurosurgery, where only 19% of practitioners are females. Although women may be reluctant to choose a challenging specialty like neurosurgery due to concerns around how to balance family and career, it must be admitted that prejudices against female neurosurgeons have been deeply rooted for long, prompting many to give up and switch track to less demanding subspecialties. Among those who have persisted, many, if not most, have experienced difficulties in career progression and received unequal treatment in comparison with their male counterparts. In 1989, a group of 8 female neurosurgeons founded Women in Neurosurgery (WINS), an organization that aimed to guarantee inclusivity in neurosurgery, encouraging a better and more egalitarian working environment. Thereafter, WINS sessions were regularly promoted at international conferences, offering female neurosurgeons a platform to report issues related to gender discrimination. Over recent years, the mission of WINS sessions in national and international conferences has taken an unexpected deviation; they have progressively become supplementary scientific sessions with only women neurosurgeons as speakers, thus paving the road to a form of self-segregation. This tendency has also resulted in the establishment of sections of only female neurosurgeons within some national societies. Although there remains a faction that fiercely supports the WINS mindset of reserved spaces for women, such segregation is an upsetting prospect for those who believe that science and professionalism have no gender; a growing part of the global neurosurgical community believes that the conception of a "female neurosurgery" and a "male neurosurgery" is misguided and counterproductive and consider the existence of the WINS as anachronistic and no longer necessary.

Grip Strength, Gait Speed and Plasma Markers of Neurodegeneration in Asymptomatic Middle-aged and Older Adults.

BACKGROUND: Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimer's Disease and neurodegeneration have not been elucidated. OBJECTIVES: To examine association between physical function measures and plasma markers of Alzheimer's Disease (AD) and neurodegeneration. DESIGN: Cross-sectional and longitudinal analyses. SETTING: Community-based cohort in the city of Framingham, Massachusetts. PARTICIPANTS: 2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61. MEASUREMENTS: Plasma Aß40 and Aß42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aß isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results: Grip strength at Exam-7 was associated with plasma Aß40 (ß -0.006, p-value 0.032) at Exam-7 and plasma total-tau (ß -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS: ß -0.009, p 0.0005; FWS: ß -0.226, p-value <0.0001). Chair stand speed was not associated with plasma markers; Aß42 was not associated with function. CONCLUSION: Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial.

Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).

Pediatric Case of Li-Fraumeni Syndrome in Honduras.

Li-Fraumeni syndrome is an inherited, autosomal dominant disease. It is categorized as a rare disease caused by mutations of the TP53 gene, which causes increased susceptibility of the patients and their children to many types of cancer. Choroid plexus tumor is rare, which occurs in 0.3 cases per 1,000,000 people, of which 40% turn out to be carcinomas. We present a 12-year-old boy with a history of worsening headaches of more than one month, gait disturbance, projectile vomiting, and right hemiparesis. An intraventricular tumor was identified in the occipital of the left lateral ventricle, which turned out to be a TP53-mutant choroidal plexus carcinoma.

Hábitos alimenticios en comerciantes del mercado campesino. Sucre, Bolivia. 2019 / Food habits in traders of the campesino marketplace. Sucre, Bolivia. 2019

OBJETIVO: describir los hábitos alimenticios y estilo de vida de los comerciantes del mercado Campesino. MÉTODOS: se realizó un estudio descriptivo, transversal con 170 personas comprendidas entre 14 a 80 años. Para la recolección de datos se aplicó una encuesta. RESULTADOS: la mayor parte de la población encuestada es del sexo femenino, comparando el número de veces durante la semana del consumo de comida chatarra entre hombres y mujeres se encontró que con más frecuencia las mujeres consumen de 1 a 3 veces por semana la comida chatarra. Hay más jóvenes de entre 14 y 21 años que realizan actividad deportiva que el resto de las edades, hay más sujetos en la población de entre 38 a 45 años que consumen sustancias como alcohol, nicotina y tabaco.

OBJECTIVE: describe the eating habits and lifestyle of the farmers of the peasant market. METHODS: a descriptive, cross - sectional study was carried out with 170 people between 14 and 80 years old. For data collection, a survey was applied. RESULTS: most of the surveyed population is female, comparing the number of times during the week of junk food consumption between men and women, it was found that women consume junk food more frequently 1 to 3 times a week. There are more young people between 14 and 21 years of age who perform sports activity than the rest of the ages, there are more subjects in the population between 38 and 45 years of age who consume substances such as alcohol, nicotine and tobacco.

Datasets acquired with correlative microscopy method for delineation of prior austenite grain boundaries and characterization of prior austenite grain size in a low-alloy high-performance steel.

Prior studies on martensitic steel microstructures have either delineated the prior austenite grain boundaries via chemical etching or reconstructed the prior austenite grains from crystallographic orientations measured with electron backscattered diffraction (EBSD). To appropriately validate the reconstruction algorithms, the EBSD data need to be collected on martensitic microstructures, where the prior austenite grain boundaries are delineated with techniques such as chemical etching that can serve as ground truth for comparison with the reconstructed prior austenite grains. In this article, the method of correlative microscopy is employed to collect scanning electron microscope (SEM) image and automated EBSD scan data from the same region of an appropriately etched steel specimen. The SEM images and automated EBSD scan data are presented for five different fields of view in the specimen. These datasets are analyzed and discussed in the accompanying article titled "Correlative microscopy for quantification of prior austenite grain size in AF9628 steel" [1].

NADH-linked mitochondrial respiration in the developing mouse brain is sex-, age- and tissue-dependent.

Mitochondria play a major role in the brain. Apart from energy production, mitochondria regulate key factors in the activation of cell signaling pathways such as survival, proliferation, and differentiation. While all these processes occur during the physiological development of the brain, it is surprising that the mitochondrial functions and functioning in the brain during the postnatal development remain poorly explored. In this work, we collected samples of brainstem and cortex of mice at postnatal ages 3 (P3), 21 (P21), and at adulthood (3 months old) and evaluated the mitochondrial oxygen consumption after complex I activation. To do so, we used our oxygraph-2 K system (OROBOROS) that measures the mitochondrial bioenergetics in saponin-permeabilized tissue punches of 2  mg weight. Furthermore, as sex dimorphism in the brain occurs since very early stages of development, we performed experiments in brain samples of male and female mice. Accordingly, the mitochondrial oxygen consumption rate (OCR) was evaluated under activation of complex I (NADH-linked respiration - mitochondrial state 3), and during the inhibition of the complex V (ATP synthase) with oligomycin (mitochondrial state 4). In following, the respiratory control ratio (RCR - state 3/state4) was calculated as an index of mitochondrial oxidative-phosphorylation coupling. Our results show that the activity of the mitochondrial complex I in the brain increases along with the postnatal development in a sex- and tissue-dependent manner, with males showing higher activity than females, and with brainstem tissue showing higher activity than cortex. Our data may contribute to a better understanding of the sex-dependent maturation of the cortex and the cardiorespiratory network located in the brainstem.

Long-term plasma pharmacokinetics of bedaquiline for multidrug- and extensively drug-resistant tuberculosis.

SETTING: Bedaquiline (BDQ) has been approved for the treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). For many patients treatment is prolonged beyond the recommended 6 months. The long-term pharmacokinetics of BDQ have yet to be elucidated. OBJECTIVE: To evaluate plasma concentrations of BDQ during treatment and its elimination after treatment discontinuation. DESIGN: This was a retrospective study conducted in two units in France that provide treatment for MDR/XDR-TB. Sociodemographic, clinical, biological and therapeutic parameters were collected from patients currently or formerly treated with BDQ. Plasma concentrations of BDQ and its active M2 (N-desmethyl) metabolite were determined using ultra-performance liquid chromatography with tandem mass spectrometry. RESULTS: Thirteen patients were recruited (35 samples): 10 (31 samples) during BDQ treatment and 3 (4 samples) after BDQ discontinuation. The median duration of treatment with BDQ was 11 months (interquartile range [IQR] 8-14). During treatment, the median plasma BDQ concentrations and M2 were respectively 1264 ng/ml (IQR 910-2244) and 252 ng/ml (IQR 134-290). In one patient, BDQ was detected in the plasma 200 days after treatment discontinuation (528 ng/ml). CONCLUSION: BDQ and M2 plasma concentrations were consistent with good drug efficacy/safety profiles, suggesting good treatment adherence with no relevant drug interactions. The long-term plasma detectability of BDQ after treatment discontinuation may raise the spectre of the emergence of resistance.

Evaluation of septal insertion of atrioventricular valves in fetuses by postmortem 4.7 Tesla cardiac MRI: A feasibility study.

PURPOSE: The purpose of this study was to compare non-invasive high-spatial-resolution postmortem cardiac magnetic resonance imaging (MRI) and autopsy findings for evaluating the septal insertion of atrioventricular valves in fetuses. MATERIALS AND METHODS: Five fetal heart specimens including two normal hearts, one heart with complete atrioventricular septal defect (AVSD) and two hearts with linear insertion of atrioventricular valves (LIAVV; gestational age 17 to 34 weeks) were studied with cardiac MRI using a 4.7 T MRI scanner without sample preparation. Three (3D) and two-dimensional (2D) turbo-RARE (rapid imaging with refocused echoes) sequences in four-chamber and left-ventricular long-axis planes were obtained with a minimal isotropic/in-plane resolution of 156µm. Nonparametric tests were performed to compare the distance between insertions of medial leaflets of the atrioventricular valves and the inlet/outlet distance ratio between MRI and autopsy findings in normal, complete AVSD and with linear insertion of atrioventricular valves (LIAVV) fetal hearts. RESULTS: Despite apparent differences between LIAVV/normal hearts, no significant differences were found between differential insertion of medial leaflets and inlet/outlet distance ratios with both techniques. Very good to excellent reliability between both techniques was found for differential insertion (ICC: 87.2%; 95% CI: -21.7%, 99.1%) (P=0.963) and inlet/outlet distance ratio (ICC 98.3%; 95%CI: 85.2%, 99.8%) (P=0.537) measurements. CONCLUSION: Postmortem cardiac MRI could replace autopsy for assessing normal or abnormal septal insertion of atrioventricular valves in fetuses without requiring specific preparation of the heart.

Phylogenetic analysis of Histoplasma capsulatum var duboisii in baboons from archived formalin-fixed, paraffin embedded tissues.

Histoplasma capsulatum var. duboisii (Hcd) infections have been well documented to cause chronic granulomatous disease, mainly involving the skin of baboons and humans in African countries primarily. This retrospective study classified the subspecies of Histoplasma and developed a phylogenetic tree utilizing DNA sequences extracted from formalin-fixed, paraffin embedded (FFPE) tissues from 9 baboons from a research colony in Texas histologically diagnosed with Hcd. Based on sequence analysis of ITS-2, Tub-1, and ARF, Hcd isolated from the archived samples closely aligns with the African clade and has 88% sequence homology with a sample isolated from an individual in Senegal.

MRI Features Can Predict 1p/19q Status in Intracranial Gliomas.

BACKGROUND AND PURPOSE: The 2016 revision of the World Health Organization Classification of Tumors of the Central Nervous System mandates codeletion of chromosomes 1p and 19q for the diagnosis of oligodendroglioma. We studied whether conventional MR imaging features could predict 1p/19q status. MATERIALS AND METHODS: Patients with previous 1p/19q testing were identified through pathology department records, typically performed on the basis of an oligodendroglial component on routine histology; 69 patients met the inclusion criteria. Preoperative imaging of patients with grade II or III gliomas was retrospectively assessed by 2 neuroradiologists, blinded to the 1p/19q status. Thirteen MR imaging features were first assessed in a small initial cohort (n = 10), after which the criteria were narrowed for the remaining patients as a validation cohort. RESULTS: There was 85% agreement between radiologists for the overall prediction of 1p/19q status in the validation cohort, with an accuracy of 84%. The presence of >50% T2-FLAIR mismatch and calcification was found to be the most useful for predicting 1p/19q status. The >50% T2-FLAIR mismatch variable was demonstrated in 14 tumors and had 100% specificity for identifying a noncodeleted tumor (P = .001), with 97% interobserver correlation. Calcification was visualized in 7 tumors, 6 of which were 1p/19q codeleted (specificity, 97%; P = .006), with 100% interobserver correlation. CONCLUSIONS: The presence of >50% T2-FLAIR mismatch is highly predictive of a noncodeleted tumor, while calcifications suggest a 1p/19q codeleted tumor. If formal 1p/19q testing is not possible, a combined MR imaging-histologic assessment may improve the diagnostic accuracy over histology alone.

Comparison Between Total IgG, C1q, and C3d Single Antigen Bead Assays in Detecting Class I Complement-Binding Anti-HLA Antibodies.

BACKGROUND: Complement-binding donor-specific antibodies (DSAs) are associated with antibody-mediated rejection and allograft loss. Novel single antigen bead (SAB) assays-that is, complement component 1q (C1q) and complement component 3d (C3d) assays-have been developed to specifically detect complement-binding DSA, but it remains unclear whether these assays have an improved ability to detect complement-binding DSA as compared with using the total IgG SAB assay with a high mean fluorescence intensity (MFI) cutoff. The aim of this study was to compare the ability of the total IgG, C1q, and C3d SAB assays in detecting complement-binding anti-HLA antibodies. METHODS: Twenty sera known to have complement-binding anti-HLA antibodies (serologic class I HLA typing by complement-dependent cytotoxicity method) were tested with 3 different SAB assays: total IgG (undiluted and 1:8 dilution), C1q, and C3d. Serologic anti-HLA specificities were compared with those obtained by IgG, C1q, and C3d SAB assays. RESULTS: IgG SAB was more sensitive in detecting complement-binding antibodies (sensitivity 24 of 24 = 1, odds ratio infinity). Pearson correlation showed the association between (1) C1q and IgG SAB assays (cutoff C1q SAB 1000 MFI, cutoff IgG SAB 5000 MFI: r = 0.347, P < .0001) and (2) C3d and IgG SAB assays (cutoff 500 MFI C3d SAB, 5000 MFI for IgG SAB: r = -0.173, P = .279). CONCLUSIONS: For class I anti-HLA antibodies, IgG SAB (cutoff MFI > 5000) was more sensitive in detecting complement-binding antibodies when compared with C1q and C3d SAB assays.

Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo.

Plasma cells (PCs) are a major source of alloantibody in transplant patients and are resistant to current therapy. Because receptor-ligand interactions in stromal microenvironments play important roles in the localization, development, and survival of normal PCs, we hypothesized that interfering with CXCR4/CXCL12 interactions with plerixafor might cause PC depletion and enhance the efficacy of the proteasome inhibitor bortezomib. PCs in mouse spleen, bone marrow, and peripheral blood demonstrated CXCR4 expression. We then treated with plerixafor in doses ranging from 240 µg/kg in a single dose to a 1-mg/kg daily dose for 10 days. CXCR4/CXCL12 blockade with plerixafor resulted in increased mobilization of PCs into the peripheral blood. Splenectomy completely abrogated this effect, suggesting that all plerixafor-mobilized cells were from the spleen. The total number of PCs in the spleen and marrow remained constant despite treatment with plerixafor. Bortezomib caused a reduction in PCs, but adding plerixafor did not increase killing. We conclude that CXCR4/CXCL12 interactions are important for the retention of a subpopulation of PCs in the spleen, but this interaction has minimal effect on PCs in the marrow. The lack of enhancement of bortezomib-mediated depletion suggests that factors other than CXCR4/CXCL12 interactions are responsible for drug resistance.

Mosaic-activating FGFR2 mutation in two fetuses with papillomatous pedunculated sebaceous naevus.

Papillomatous pedunculated sebaceous naevus (PPSN) has been described as a subtype of sebaceous naevus (SN), typically affecting the scalp and face. In contrast with Schimmelpenning syndrome, no cerebral, ocular or skeletal anomalies have hitherto been reported. We report two unrelated fetuses with PPSN, one with large pink exophytic tumours, the other with minor features but similar microscopic findings. We performed whole-exome sequencing in affected skin tissue from fetus 1, which identified a postzygotic de novo FGFR2 c.1144T>C (p.Cys382Arg) mutation in 34·6% of reads which was absent in the parents' blood. Targeted deep sequencing of FGFR2 confirmed its mosaic status in additional affected skin from fetus 1, and identified the same substitution in 26% of reads in affected skin from fetus 2. FGFR2 p.Cys382Arg is a known somatic driver mutation in human cancer, previously reported to result in activation of RAS signalling. A similar paralogous missense mutation in the transmembrane domain of FGFR3 (p.Gly380Arg) has been reported in keratinocytic epidermal naevi. Our findings define a distinct clinical and molecular subgroup of SN, beside HRAS or KRAS-related SN, and expand the spectrum of mosaic skin conditions associated with receptor tyrosine kinase mutations.

Meningococcal carriage in children and young adults in the Philippines: a single group, cross-sectional study.

This cross-sectional prevalence study investigates meningococcal carriage for the first time in a Southeast Asian population. Posterior pharyngeal swabs were collected between August 2013 and March 2014 from 937 healthy Filipinos aged 5-24 years attending school or university in Manila. Of these, 35 were found to be carriers giving an overall carriage prevalence of 3·7% [95% confidence interval (CI) 2·6-5·2]. Carriage was associated with age (P < 0·001) and was highest (9·0%, 95% CI 5·5-13·8) in subjects aged 10-14 years, but was comparatively low (<3%) in all other age groups considered. This suggests that an immunization programme in the Philippines designed to reduce carriage acquisition and induce herd immunity may require a vaccine dose before the age of 10 years. Serogroup B was most commonly carried (65·7%, 95% CI 47·8-80·9), with a small number of carriers for serogroups C, Y and W also present. Two individuals (5·7%, 95% CI 0·7-19·2) who were simultaneously carrying multiple serogroups were identified. This exploratory study provides valuable insight into the asymptomatic carriage of Neisseria meningitidis in a healthy subset of the Filipino population and illustrates the importance of generating local carriage data.

Sublingual Tacrolimus in Liver Transplantation: A Valid Option?

BACKGROUND: Oral tacrolimus (Tac) is currently the pillar of maintenance immunosuppression after solid organ transplantation. Recent studies proposed sublingual (SL) administration as an alternative; however, data regarding its use in adult liver transplant (LT) recipients are limited. METHODS: Three LT recipients were included. Two (patients 1 and 2) were transitioned from oral to SL Tac owing to persistently erratic serum concentrations and 1 (patient 3) because of severe oral intolerance. SL Tac was started in a 1:2 dose-conversion rate. RESULTS: All patients tolerated the SL Tac well without any side effects requiring dose reduction or discontinuation. In patients 1 and 2, the therapeutic trough concentrations improved significantly after switching to SL Tac: 20% (10/50) on oral Tac to 50% (7/14) on SL Tac in patient 1 (P = .04), and from 0% (0/15) oral Tac vs 40% (4/10) on SL Tac in patient 2 (P = .02). Patient 2, who had consistently subtherapeutic trough levels on oral Tac (mean trough of 2.6 ± 0.7 ng/mL), achieved a stable therapeutic level on SL Tac (mean trough 8.1 ± 2.7 ng/mL; P < .001). In patients 1 and 3, the mean trough levels remained unchanged: 5.1 ± 1.9 ng/mL on oral Tac versus 5.3 ± 1.6 ng/mL on SL Tac (P = .76), and 4.3 ± 1.3 ng/mL on oral Tac versus 4.2 ± 1.9 ng/mL on SL Tac (P = .76), respectively. CONCLUSIONS: Oral administration of Tac is the criterion standard route for drug delivery; however SL administration should be considered as a safe alternative when the oral method is not an option.