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Can Organs Be Generated from a Patient’s Own Stem Cells?
No full textThe global shortage of transplantable organs represents a critical medical challenge, with current organ donation systems meeting less than 10% of the worldwide need. This situation has spurred intensive research into regenerative medicine, particularly focusing on the potential of generating organs from a patient’s own stem cells. This review examines the current state of stem cell research and its applications in organ generation, analyzing both the progress made and the challenges that remain. Through a comprehensive analysis of recent literature and clinical trials, the study explores the fundamental principles of stem cell biology, current therapeutic applications, and the role of supporting technologies such as bioscaffolding and organoid development. The findings indicate significant advances in stem cell manipulation and tissue engineering, particularly in areas such as insulin-producing beta cells and cardiac tissue repair. However, substantial challenges persist, including organ structural complexity, functional integration, and potential tumorigenesis. While complete organ generation remains elusive, incremental successes in stem cell applications suggest a promising trajectory toward this goal. This review concludes that while current technology cannot yet generate fully functional organs, continued research advances and investment in this field may eventually transform transplantation medicine
Novel Case of Pediatric Basal Ganglia Abscess Due to Streptococcus Intermedius Amid a Rise in Neuroinvasive Infections During the COVID-19 Pandemic: Illustrative Case
No full textBACKGROUND Pediatric basal ganglia abscesses are extremely rare, with only 2 other published cases in the literature. To the authors’ knowledge, this is the first case of a primary bacterial abscess caused by Streptococcus intermedius in the basal ganglia of a pediatric patient. OBSERVATIONS This case coincides with a rise in neuroinvasive streptococcal infections among children during the COVID-19 pandemic. Prompt MRI with diffusion and attenuation analyses allowed for abscess identification and treatment with neurosurgical drainage, leading to full recovery. Although intracranial abscesses in deep parenchymal locations are extremely rare in healthy children, the recently increased incidence of neuroinvasive infections and the devastating sequelae of delayed or missed diagnosis make early recognition and treatment essential. To this end, reporting and recognition of the varied presentations of this pathology is crucial. LESSONS Herein, the authors highlight that in light of the surge in cases in recent years, patients suspected of having an intracranial abscess should not be delayed in receiving cranial imaging and treatment, as rapid identification and management of abscesses are crucial to reduce the likelihood of long-term complications
Prognostic Significance of Frailty in Chronic Subdural Hematoma: Implications for Treatment Selection in the Era of Middle Meningeal Artery Embolization
No full textPurpose: Middle meningeal artery embolization (MMAE) as a standalone or adjunctive therapy has emerged as an efficacious and safe treatment for chronic/subacute subdural hematoma (csaSDH). The objective of this study is to compare the prognostic significance of frailty in csaSDH patients treated with MMAE alone or with craniotomy/burr hole (CBH). Methods: Hospitalization records were identified in the National Inpatient Sample (2016–2020) and the cohort was stratified by increasing frailty thresholds, quantified by the Risk Analysis Index (RAI). Effect sizes of frailty tiers for poor outcome (defined as non-routine discharge disposition) produced from multivariable logistic regression models and discrimination (c-statistic) were evaluated separately in the MMAE only and CBH sub-cohorts. Results: This analysis identified 13,390 csaSDH hospitalizations, of which 595 (5%) documented treatment with MMAE only. Although all frailty tiers of the categorical RAI were significantly associated with poor outcome in the CBH cohort, lower effect sizes were observed in the MMAE cohort. Discrimination of RAI for poor outcome was significantly greater in the CBH cohort compared to the MMAE only cohort. Conclusion: In comparison to surgical evacuation, frailty demonstrated lower effect sizes and worse discrimination for poor outcomes in patients treated with MMAE, suggesting that frail patients may be more likely to achieve better outcomes following this less invasive therapy. MMAE may be considered as a first-line or standalone treatment in certain patients
TNF Inhibits NKCC2 Phosphorylation by a Calcineurin-Dependent Pathway
No full textWe previously demonstrated that tumor necrosis factor-alpha (TNF) inhibits Na+-K+-2Cl- cotransporter (NKCC2) phosphorylation in the thick ascending limb (TAL); however, the underlying mechanism remains unclear. We tested the hypothesis that the induction of calcineurin (CN) activity and the expression of CN isoforms contribute to the mechanism by which TNF inhibits phosphoNKCC2 (pNKCC2) expression. CN activity increased by approximately twofold in primary cultures of medullary (m)TAL cells challenged with mouse recombinant TNF. In contrast, silencing TNF production in mTAL cells using lentivirus U6-TNF-ex4 reduced CN activity. pNKCC2 expression decreased in mTAL cells challenged with TNF, whereas inhibition of CN activity with cyclosporine A (CsA) increased pNKCC2 expression. Although mTAL cells express both the calcineurin A subunit (CNA) a and b isoforms, only CNA b isoform mRNA increased after mTAL cells were challenged with TNF. In vivo, both TNF and CNA b expression increased in outer medulla (OM) from mice given 1% NaCl in the drinking water for 7 days and intrarenal lentivirus silencing of TNF selectively reduced expression of CNA b. Intrarenal injection of a lentivirus that specifically silenced CNA b (U6-CNAb-ex6) increased pNKCC2 expression and attenuated the inhibitory effects of TNF on pNKCC2 expression in freshly isolated TAL tubules. Collectively, the study is the first to demonstrate that TNF increases CN activity and specifically induces b-isoform expression in the kidney. Since NKCC2 is a known target of the CNA b isoform, these findings suggest that a CN-dependent signaling pathway involving this isoform contributes to the mechanism by which TNF inhibits pNKCC2 expression
Efficacy and Safety of Switching to Daily Bictegravir Plus Lenacapavir From a Complex HIV Treatment Regimen: A Randomized, Open-Label, Multicenter Phase 2 Study (ARTISTRY-1)
No full textBackground: Complex antiretroviral therapy (ART) regimens, such as those requiring multiple tablets, several doses per day, or both, can negatively affect quality of life and treatment adherence among people with human immunodeficiency virus (HIV). Methods: ARTISTRY-1 is a phase 2/3, operationally seamless, randomized, open-label, multicenter, active-controlled study (GS-US-621-6289; NCT05502341). Phase 2 of the study enrolled adults with plasma HIV-1 RNA \u3c50 copies/mL receiving a complex ART regimen for ≥6 months. Efficacy and safety outcomes were evaluated after a switch to bictegravir (BIC) (75-mg) + lenacapavir (LEN) (25- or 50-mg) regimens, compared with continuing on a complex ART regimen through 24 weeks. Results: Overall, 128 participants were assigned randomly to begin BIC 75 mg + LEN 25 mg (n = 51) or BIC 75 mg + LEN 50 mg (n = 52) or continue on their complex ART regimen (n = 25). At week 24, HIV-1 RNA was ≥50 copies/mL in 0 of 51, 1 of 52 (1.9%), and 0 of 25 participants in the 3 groups, respectively. CD4 cell counts and percentages remained stable through week 24; the median change from baseline in CD4 cell count (interquartile range) was 18 (-39 to 70), -16 (-80 to 93), and 42 (-36 to 90) cells/μL, respectively. There were no study discontinuations due to a serious adverse event through week 24. Both BIC + LEN dosing regimens were well tolerated, with similar safety profiles observed between groups. Conclusions: These data support the continued evaluation of the combination of BIC and LEN to optimize treatment in people with HIV and virologic suppression who are receiving complex ART regimens
Istaroxime: A Novel Therapeutic Agent for Acute Heart Failure
No full textAcute decompensated heart failure (ADHF) is a multifactorial process that is associated with high morbidity and mortality. Treatment with inotropes can rapidly improve hemodynamic status; however, their use has been associated with increased mortality and incidence of arrhythmias. Istaroxime is a first-in-class intravenous agent currently undergoing clinical trials for acute heart failure. It has the unique mechanism of action of both Na+/K+ ATPase inhibition and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a stimulation. Notably, its action on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a improves calcium handling, which is known to be abnormal in heart failure. Clinical trials have shown that istaroxime has beneficial hemodynamic effects; in particular, its ability to increase systolic blood pressure without causing significant increases in heart rate or clinically significant arrhythmias differentiates it from inotropes currently utilized for ADHF treatment, such as milrinone. While initial studies are encouraging, additional trials are needed to assess outcomes and to compare their performance to standard inotropes in patients hospitalized with ADHF. This article will review the relevant preclinical and clinical trials for istaroxime, as well as the relevant pharmacology
Adjunctive Cariprazine for the Treatment of Major Depressive Disorder: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed
No full textBackground: The number needed to treat (NNT) for efficacy and number needed to harm (NNH) for tolerability/safety were evaluated for adjunctive cariprazine in major depressive disorder (MDD). Methods: Data were extracted from five randomized, double-blind, placebo-controlled trials of adjunctive cariprazine in MDD. NNTs (response, remission, severity shift) and NNHs (discontinuations due to adverse events [AEs], AEs, laboratory shifts) were determined in dose groupings; likelihood to be helped/harmed (LHH) was calculated. Results: NNTs (95 % CI) for adjunctive cariprazine versus placebo were statistically significant at week 6/early termination for response on the Montgomery–Åsberg Depression Rating Scale (MADRS), as defined by a decrease in total score ≥ 50 % (doses ≥ 1 mg/d = 12 [9–21]; 1–2 mg/d = 12 [8–25]; 2–4.5 mg/d = 14 [9–43]) and other response/remission outcomes. NNHs for cariprazine versus placebo were generally ≥ 10 for AEs that were statistically significant; an apparent dose-response was seen for akathisia (lower dose = 24 [17–43]; higher dose = 9 [7–11]). LHHs were ≥ 1 (acceptable benefit/harm ratio) for MADRS total score response versus most important cariprazine AEs in most dose groupings. For response versus discontinuation because of an AE, adjunctive cariprazine 1–2 mg/d had a more favorable response/tolerability profile in indirect comparison with other approved atypical antipsychotics. Limitations: Post hoc analysis; indirect comparisons. Conclusions: Patients receiving adjunctive cariprazine encountered benefits more often than harms; NNT values at week 6/early termination were statistically significant versus placebo on response/remission outcomes across dose groupings from the five pooled studies. Adjunctive cariprazine was well tolerated; NNH values versus placebo were generally \u3e 10, with better akathisia tolerability in the lower-dose range
