Representation of Low- and Middle-Income Countries in CKD Drug Trials: A Systematic Review.

RATIONALE & OBJECTIVE: Almost 80% of individuals with chronic kidney disease (CKD) reside in low- and middle-income countries (LMICs) and are potentially underrepresented in randomized controlled clinical trials (RCTs). We assessed the global distribution of RCTs comparing pharmacological treatments for CKD over the past 2 decades, as well as the magnitude and evolution of participation by LMICs. STUDY DESIGN: Systematic review. SETTING & STUDY POPULATIONS: RCTs evaluating pharmacological interventions in adults with CKD. SELECTION CRITERIA FOR STUDIES: RCTs published between 2003-2023 and indexed in MEDLINE. DATA EXTRACTION: Each trial was reviewed and extracted independently by 2 investigators with disagreements settled by consensus or a third reviewer. ANALYTICAL APPROACH: RCT participation of World Bank-defined income groups and geographic regions were described, and the representation indices (RI) according to RCT participants and estimated CKD prevalences were calculated. RCTs were also categorized as global, regional, or national in scope. RESULTS: Among 7,760 identified studies, we included 1,366 RCTs conducted in 84 countries with 301,158 participants. National, regional, and global RCTs represented 85.4%, 3.5%, and 11.1% of studies, respectively. LMICs were included in 34.7% of RCTs. No RCTs included participants from low-income countries, and lower-middle-income countries participated in 13.2%. Of participants from RCTs with available information, 25.4% (n=64,843 of 255,237) were from LMICs. According to the RI, 6 LMICs were overrepresented (>1.25), 7 were adequately represented (0.75-1.25), and 26 were underrepresented (<0.75). Most global CKD RCTs (80.2%) included LMICs; however, LMIC participants constituted only 32.9% of the global trial population. We observed a positive trend in LMIC inclusion over time, rising from 22.9% (n=71of 310) in 2003-2007 to 45.5% (n=140of 308) in 2018-2023. LIMITATIONS: The use of an income-group dichotomy, exclusion of nonrandomized studies of intervention, and studies identified in 1 database. CONCLUSIONS: Despite an increase in participation over the past 2 decades, individuals with CKD from LMICs remain significantly underrepresented in RCTs. These findings suggest that increased efforts are warranted to increase LMIC representation in pharmacological CKD RCTs. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) substantially affects people from low- and middle-income countries (LMICs). However, the participation of these countries in randomized controlled trials (RCTs) remains uncertain. To assess the global distribution and representation of these countries in kidney disease research, we reviewed 1,366 CKD drug RCTs published from 2003-2023, conducted in 84 countries involving more than 300,000 participants. LMICs were included in approximately a third of these studies, with their participants making up approximately one-quarter of the total; lower-middle-income countries were poorly represented, and low-income countries were absent. LMICs constituted a third of participants in multinational RCTs. Most LMICs were underrepresented relative to the prevalence of CKD. We observed an increasing inclusion of LMICs, particularly in the last decade. Nonetheless, individuals with CKD from LMICs remain underrepresented in drug RCTs, suggesting that increased efforts are warranted to include representation of these populations in these studies.

Diagnostic accuracy of the BioFire® FilmArray® pneumonia panel in COVID-19 patients with ventilator-associated pneumonia.

BACKGROUND: Ventilator-Associated pneumonia (VAP) is one of the leading causes of morbidity and mortality in critically ill COVID-19 patients in lower-and-middle-income settings, where timely access to emergency care and accurate diagnostic testing is not widely available. Therefore, rapid microbiological diagnosis is essential to improve effective therapy delivery to affected individuals, preventing adverse outcomes and reducing antimicrobial resistance. METHODS: We conducted a cross-sectional study of patients with suspected VAP and COVID-19, evaluating the diagnostic performance of the BioFire® FilmArray® Pneumonia Panel (FA-PP). Respiratory secretion samples underwent standard microbiological culture and FA-PP assays, and the results were compared. RESULTS: We included 252 samples. The traditional culture method detected 141 microorganisms, and FA-PP detected 277, resulting in a sensitivity of 95% and specificity of 60%, with a positive predictive value of 68% and negative predictive value of 93%. In samples with high levels of genetic material (> 10^5 copies/mL), the panel had a sensitivity of 94% and specificity of 86%. In addition, 40% of the culture-negative samples had positive FA-PP® results, of which 35% had > 10^5 copies/mL of genetic material. The most prevalent bacteria were Gram-negative bacilli, followed by Gram-positive cocci. The panel identified 98 genes associated with antimicrobial resistance, predominantly extended-spectrum beta-lactamases (28%). CONCLUSION: The FA-PP is a sensitive assay for identifying bacteria causing VAP in patients with COVID-19, with a greater capacity to detect bacteria than the conventional method. The timely microbiological recognition offered by this panel could lead to optimized decision-making processes, earlier tailored treatment initiation, and improved antibiotic stewardship practices.

Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.

We recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment. To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680). The validation of novel biomarkers of susceptibility to therapy is critical to elucidate the efficacy signal of therapeutic agents. This is especially important in the context of glioblastoma, where therapeutic benefit is variable and unpredictable, leading to negative trials, yet the outcome of subset of patients has outperformed expectations.

Overview of hyperprolactinemia: General approach and reproductive health implications.

Prolactin (PRL) is a polypeptide hormone produced by the lactotrope cells of the anterior pituitary gland. Among its myriads of biological functions, PRL is the main regulator of mammary gland growth and development, as well as of the production and secretion of milk. Hyperprolactinemia represents a frequent consultation cause in medical practice. Nevertheless, elevations in serum PRL are not always pathological. Drug induced hyperprolactinemia is the most common cause, mainly by antipsychotics, followed by other causes such as pituitary neuroendocrine tumors, physiologic conditions, and systemic diseases such as chronic kidney disease and hypothyroidism. When evaluating a patient with hyperprolactinemia it is of utmost importance to consider the diverse etiologies of this condition in order to avoid unnecessary diagnostic workup and treatment. Regarding reproductive health, hyperprolactinemia is a well-documented cause of infertility, as approximately 15-20% of women undergoing infertility evaluation have hyperprolactinemia, which causes secondary amenorrhea, and other menstrual irregularities. Similarly, in men it is a cause of hypogonadism.

Diagnosis and Treatment of Pituitary Apoplexy, A True Endocrine Emergency.

Pituitary apoplexy (PA) is a clinical syndrome resulting from a hemorrhagic infarction of the pituitary gland. It is characterized by the sudden onset of visual disturbances, nausea, vomiting, headache and occasionally, signs of meningeal irritation and an altered mental status. The exact pathogenesis of PA remains to be elucidated, although tumor overgrowth of its blood supply remains the most popular theory. Main risk factors for the development of PA include systemic, iatrogenic, and external factors as well as the presence of an underlying pituitary tumor. The diagnostic approach of PA includes both neuroimaging and evaluation of pituitary secretory function. PA is a potentially life-threatening condition which should be managed with hemodynamic stabilization, correction of electrolyte abnormalities and replacement of hormonal deficiencies. PA treatment should be individualized based on the severity of the clinical picture which may vary widely. Treatment options include conservative management with periodic follow-up or neurosurgical intervention, which should be decided by a multidisciplinary team. We conducted a systematic review of the literature to unveil the frequency of PA predisposing factors, clinical and biochemical presentations, management strategies and outcomes.

The molecular biology of sporadic acromegaly.

GH-secreting tumors represent 15 % to 20 % of all pituitary neuroendocrine tumors (pitNETs), of which 95 % occur in a sporadic context, without an identifiable inherited cause. Recent multi-omic approaches have characterized the epigenomic, genomic, transcriptomic, proteomic and kynomic landscape of pituitary tumors. Transcriptomic analysis has allowed us to discover specific transcription factors driving the differentiation of pituitary tumors and gene expression patterns. GH-secreting, along with PRL- and TSH-secreting pitNETs are driven by POU1F1; ACTH-secreting tumors are determined by TBX19; and non-functioning tumors, which are predominantly of gonadotrope differentiation are conditioned by NR5A1. Upregulation of certain miRNAs, such as miR-107, is associated with tumor progression, while downregulation of others, like miR-15a and miR-16-1, correlates with tumor size reduction. Additionally, miRNA expression profiles are linked to treatment resistance and clinical outcomes, providing insights into potential therapeutic targets. Specific somatic mutations in GNAS, PTTG1, GIPR, HGMA2, MAST and somatic variants associated with cAMP, calcium signaling, and ATP pathways have also been associated with the development of acromegaly. This review focuses on the oncogenic mechanisms by which sporadic acromegaly can develop, covering a complex series of molecular alterations that ultimately alter the balance between proliferation and apoptosis, and dysregulated hormonal secretion.

Genomics, Transcriptomics, and Epigenetics of Sporadic Pituitary Tumors.

Pituitary tumors (PT) are highly heterogeneous neoplasms, comprising functioning and nonfunctioning lesions. Functioning PT include prolactinomas, causing amenorrhea-galactorrhea in women and sexual dysfunction in men; GH-secreting adenomas causing acromegaly-gigantism; ACTH-secreting corticotrophinomas causing Cushing disease (CD); and the rare TSH-secreting thyrotrophinomas that result in central hyperthyroidism. Nonfunctioning PT do not result in a hormonal hypersecretion syndrome and most of them are of gonadotrope differentiation; other non-functioning PT include null cell adenomas and silent ACTH-, GH- and PRL-adenomas. Less than 5% of PT occur in a familial or syndromic context whereby germline mutations of specific genes account for their molecular pathogenesis. In contrast, the more common sporadic PT do not result from a single molecular abnormality but rather emerge from several oncogenic events that culminate in an increased proliferation of pituitary cells, and in the case of functioning tumors, in a non-regulated hormonal hypersecretion. In recent years, important advances in the understanding of the molecular pathogenesis of PT have been made, including the genomic, transcriptomic, epigenetic, and proteomic characterization of these neoplasms. In this review, we summarize the available molecular information pertaining the oncogenesis of PT.

Langerhans Cell Histiocytosis Presented as Persistent Diaper Dermatitis: A Case Report.

Langerhans cell histiocytosis presents most frequently in pediatric patients with cutaneous manifestations such as erythematous and scaly papules in the trunk or scalp and macerated plaques in intertriginous sites. We present a case of a seven-month-old patient who was brought with complaints of persistent diaper rash. The patient presented with skin fissures in intertriginous areas and pink color papules dispersed widely in the trunk and perineum. The skin biopsy revealed infiltration of abundant histiocytes, eosinophils, lymphocytes, and plasma cells, being CD207, CD1a, and S-100 positive by immunohistochemistry. Due to the diversified presentations of Langerhans cell histiocytosis and its propensity to mimic other dermatological conditions, physicians should have a clinical suspicion of this disease and consider it as a differential diagnosis among common skin diseases in pediatric patients.

Bilateral carotid body tumor case: A novel preoperative management.

Paragangliomas are rare neuroendocrine neoplasms. The most common form of these tumors in head and neck are non-functional carotid body tumors. These neoplasms may present an extensive growth and compromise vital neurovascular structures in the neck, such as carotid vessels. Carotid body tumors usually present clinically as painless neck masses and occur most frequently in adults averaging 45 to 50 years, being the majority of these tumors unilateral and only 5% of all cases bilateral. The main treatment for carotid body paragangliomas is surgical resection, which can be extremely challenging due to tumor hypervascularity and significant blood loss. We present a bilateral carotid body tumor case in a 61-year-old woman who presented due to a pulsatile and painless mass in the right carotid region of the neck of 1-year of evolution. The tumor was found encasing the external carotid artery and classified as Shamblin II. A novel approach for preoperative management was performed, placing a covered graft-stent in the right common and proximal (C1) internal carotid arteries in order to splint and provide structural protection for carotid vessels during surgical resection and temporarily reduce blood flow of the carotid body tumor.

Mirtazapine Risk of Hyponatremia and Syndrome of Inappropriate Antidiuretic Hormone Secretion in Adult and Elderly Patients: A Systematic Review.

Hyponatremia is the most common fluid and electrolyte imbalance in hospitalized patients. Among hyponatremia causes, syndrome of inappropriate antidiuretic hormone secretion is a condition characterized by excessive release of antidiuretic hormone from the pituitary gland or nonpituitary sources. One of the most common drugs associated with hyponatremia is selective serotonin reuptake inhibitors, especially in elderly patients. Therefore, distinct therapeutic alternatives are essential for patients having risk factors for hyponatremia or syndrome of inappropriate antidiuretic hormone secretion development.  The present article aims to review the available literature evaluating mirtazapine-induced hyponatremia or syndrome of inappropriate antidiuretic hormone secretion in adult or elderly patients in order to determine the incidence of these adverse effects and analyze the existence of any correlation between the administered dose of mirtazapine and serum sodium levels. A systematic search was conducted, using key terms from the research topic, their synonyms, and Boolean/logic operators. From this evidence pool, inclusion and exclusion criteria were applied. We abstracted population characteristics and clinical endpoints. Relevant data from selected studies was abstracted and subject to statistical analysis.  A total sample size of 30,851 patients treated with mirtazapine was included. Mirtazapine-induced hyponatremia incidence was 3.26% (95% CI 3.06-3.45%), with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) the most probable underlying cause. Among case series and case reports evaluated (n=7), hyponatremia and SIADH were more frequent in female patients (71.4%) and the most frequent clinical manifestations included confusion (57%), somnolence (42%), and altered speech (28%). Mean serum sodium levels were (117 mEq/L, ranging from 113-130 mEq/L). The average time lapse between mirtazapine administration and clinical findings was 34 days. The Spearman's rank correlation coefficient between mirtazapine dosage and serum sodium levels was -0.3181 with a p-value >0.05.  In conclusion, mirtazapine presents a moderate risk of hyponatremia and should be considered as an alternative therapy in patients requiring antidepressants with risk factors for this preventable adverse effect.

Dysentery as the First Manifestation of Severe COVID-19.

The presence of dysentery as the first manifestation of coronavirus disease 2019 (COVID-19) is highly atypical and it may present with concomitant respiratory symptoms or as a single manifestation. Diagnosis is often difficult due to its clinical presentation similar to gastrointestinal diseases, such as infectious diarrhea. We present a case of a 35-year-old male who presented with dysentery as the first manifestation of severe COVID-19.

Atypical Cutaneous Leishmaniasis Variant.

Leishmaniasis is a complex group of parasitic infectious diseases caused by intracellular protozoa of the genus Leishmania. It is a zoonosis mainly transmitted by the bite of infected female Phlebotomus or Lutzomyia sandflies. Clinical manifestations of leishmaniasis are diverse and can range from asymptomatic presentations to disseminated systemic disease. Cutaneous leishmaniasis is endemic in more than 80 countries in the world, having a predominance in tropical and subtropical regions. Although the majority of cases follow a classic development, an increasing number of new and rare variants of cutaneous leishmaniasis have been reported. These variants should be suspected as a cause of diverse clinical presentations, especially in endemic regions and travelers, being a diagnostic challenge for physicians. We present a case of atypical cutaneous leishmaniasis found as a single verrucous plaque of eight months of evolution in the left posterior thigh of a 35-year-old man, who presented mild pruritus. The patient reported shrimp farming as his main occupational activity and was living in a rural region surrounded by forest on the Pacific coast of Ecuador. On dermatological examination, a single 4 x 5 cm verrucous plaque with irregular borders and a scaly erythematous violaceous aspect was found. Histopathological analysis revealed the presence of lymphohistiocytic inflammatory infiltrate with plasmocytes and granulomatous inflammation. On the Giemsa stain, intracellular amastigotes (Leishman-Donovan bodies) were observed. The treatment consisted of intramuscular meglumine antimoniate, presenting significant improvement on follow-up.

Pharyngeal-Cervical-Brachial Variant of Guillain-Barré Syndrome.

Guillain-Barré syndrome (GBS) represents the main cause of flaccid paralysis worldwide. Although most cases have a typical clinical presentation of symmetric ascending flaccid paralysis with areflexia or hyporeflexia, this disease may present as multiple clinical entities, therefore representing a diagnostic challenge for physicians, who should consider these variants when assessing neuropathies. The pharyngeal-cervical-brachial (PCB) variant of Guillain-Barré syndrome is defined by rapidly progressive oropharyngeal and cervicobrachial weakness associated with hyporeflexia or areflexia in the upper limbs. It is present in 3% of all Guillain-Barré syndrome cases and is characterized by axonal rather than demyelinating neuropathy.  We present a pharyngeal-cervical-brachial variant case in a 55-year-old male who presented to the neurological emergency department with a three-day history of progressive and continuous dysarthria, dysphagia to solids, and tongue numbness, later developing paresthesia and weakness in the upper limbs. On physical examination, slight bilateral facial weakness, limited soft palate elevation, absent gag reflex, and limited tongue lateralization were found. Additionally, weakness was found bilaterally in the upper limbs and the flexor and extensor muscles of the neck with preserved muscle strength in the lower limbs. The patient presented upper limb hyporeflexia with lower limb hyperreflexia. A lumbar puncture was performed, revealing protein levels of 35 mg/dL and no cells in the cerebrospinal fluid. Nerve conduction studies reported acute motor and sensory axonal neuropathy (AMSAN). Management of the patient consisted of IgG administration and nasogastric tube insertion.