Allogeneic mesenchymal stromal cell therapy for nonregenerative anemia in a FeLV-infected cat: a case report.

When anaemia does not respond to vitamin and iron supplements and no genitourinary or gastrointestinal cause of blood loss is found, the patient requires a bone marrow examination to exclude rare causes like myelodysplastic syndrome (MDS). However, even the bone marrow examination and usual cytogenetic testing,including karyotyping and fluorescence in situ hybridisation (FISH), may be inconclusive. In such cases, where there is a diagnostic dilemma, next-generation sequencing (NGS) may be a ray of hope. Here, we report a few cases where bone marrow aspiration, biopsy, and cytogenetics were inconclusive, and NGS helped in re-classifying these patients as MDS. NGS served as a critical bridge between clinical suspicion and definitive diagnosis when other modalities failed.

Iron deficiency anemia remains a significant health problem in children. Gastrointestinal blood loss is a recognized cause of iron deficiency in this population. Although rare, hiatal hernia has been reported as a source of chronic gastrointestinal bleeding, potentially leading to iron refractory iron deficiency anemia (IDA). A 4-year-old male child with iron refractory IDA had previously received multiple blood transfusions for recurrent anemia. During evaluation for complicated pneumonia, a chest computed tomography scan incidentally revealed a hiatal hernia. Following surgical repair of the hernia, iron refractory IDA responded to iron supplementation and follow-up complete blood counts at 2 and 6 months demonstrated normalization of hemoglobin levels. Clinicians should be aware that hiatal hernia might represent a rare but significant cause of anemia in children with iron refractory IDA.

Background. One of the key pathogenetic mechanisms in myelodysplastic syndrome (MDS) is a disruption of the hematopoietic stem cell microenvironment, which is accompanied by changes in the secretion of pro-inflammatory cytokines, in particular tumor necrosis factor alpha (TNF). Given the immunoinflammatory nature of MDS pathogenesis, the use of immunomodulatory drugs, in particular lenalidomide, has shown clinical efficacy in low-risk patients. Objective: to assess the clinical and hematological status and colony-forming activity of bone marrow cells in patients with MDS and refractory anemia with excess blasts 1 (RANB-1) depen­ding on the concentration of TNF in the blood serum. Materials and methods. Twenty-seven patients receiving lenalidomide were examined. Serum TNF level was determined with enzyme-linked immunosorbent assay using standard production kits. The analysis was performed on an enzyme immunoassay analyzer Multiskan EX ( = 430 nm). Plasma from healthy donors served as a control. ­Results. It was found that a decrease in TNF is accompanied by clinical improvement, increased erythropoiesis and increased co­lony formation in vitro. Serum TNF concentration significantly decreases in patients with MDS and RANB-1 when achieving a complete or partial response to lenalidomide therapy. TNF level demonstrates high predictive accuracy (AUC = 1.00) for differentiating response to treatment. Functional activity of progenitor cells (CFU-GM) and the level of CD34+/CD117+ in the bone marrow are inversely related to TNF. It is noteworthy that in the group of patients with MDS and RANB-1 who did not respond to lenalidomide therapy, a deterioration in the general condition was noted due to worsening anemia, which can be assessed as a clinical situation for correction of the therapeutic route in order to prevent emergencies. Conclusions. The obtained results confirm the feasibility of including TNF and colony formation in the set of diagnostic markers for risk stratification and predicting the course of MDS.

BackgroundProton pump inhibitors (PPIs), known for their potent acid-suppressing effects, are widely used in various clinical settings, including treatment and prevention. Understanding their adverse effects is crucial. This study, utilizing the FDA Adverse Event Reporting System (FAERS) database, comprehensively analyzes PPI-related adverse events to guide clinical medication practices.MethodsThis study analyzed suspected adverse drug reactions (ADRs) related to specific PPI drugs using data from the FAERS database, covering Q1 2004 to Q4 2024. Multiple statistical methods, including ROR, PRR, IC025, and EBGM, were employed for evaluation, with ADRs defined according to System Organ Class (SOC) and Preferred Term (PT). A comparative analysis was conducted to assess potential differences in ADR profiles among different PPI drugs.ResultsThis study analyzed 176,680 cases of PPI-related adverse events, with a total of 632,468 adverse reaction reports recorded when PPIs were designated as the primary suspected drug (PS). PPIs showed significantly elevated risks in the renal/urinary and gastrointestinal systems, with other common adverse reactions including hypomagnesemia, hypocalcemia, and renal anemia. Most adverse reactions occurred either within the first 0–30 days of use or after prolonged exposure (>6 months), and elderly patients (≥65 years) were disproportionately affected.ConclusionsFor high-risk populations using PPIs long-term (such as elderly patients or those with pre-existing renal impairment), continuous monitoring is essential to mitigate potential complications. Unnecessary use should be strictly avoided, and long-term medication should be minimized to ensure safety and appropriateness.

Despite its use in the treatment of renal anemia, no adequately controlled studies have examined the impact of L-carnitine administration in the patient population for which it is indicated (i.e., those hyporesponsive to erythropoiesis-stimulating agents [ESAs]). This randomized, double-blind, placebo-controlled pilot study evaluated the potential benefit of L-carnitine supplementation for the treatment of renal anemia in chronic hemodialysis patients who were hyporesponsive to ESA treatment. Patients shown to be hyporesponsive to ESA treatment were administered intravenous L-carnitine (10-20 mg/kg/dialysis session) or placebo for 3 months, during which erythropoietin resistance index (ERI) was measured as an indicator of treatment effectiveness. Secondary validation was conducted using an independent dataset. L-carnitine supplementation was associated with a 25% reduction in ERI, significantly greater than that seen in placebo-treated patients (3% reduction). This was supported by a 42% reduction after 6 months of treatment in the validation dataset. Overall, 88% of L-carnitine-treated patients had a clinically significant improvement in ERI, compared to 0% of placebo-treated patients. These findings provide evidence to support the National Kidney Foundation's practice recommendations with respect to the clinical use of L-carnitine for renal anemia. While the exact mechanism is yet to be elucidated, it is proposed that L-carnitine treatment improves carnitine palmitoyltransferase activity via carnitine pool normalization, thereby resulting in stabilization of the erythrocyte membrane. If this is the case, then it is feasible that a dual approach to increase erythrocyte production and lifespan through co-administration of ESA and L-carnitine provides a viable treatment option for ESA-resistant patients.

Roxadustat effectively improves renal anemia, but its impact on residual kidney function (RKF) preservation in continuous ambulatory peritoneal dialysis (CAPD) patients is unclear. Our objective was to evaluate the impact of roxadustat on RKF decline in prevalent CAPD patients, with particular emphasis on identifying sex-specific differential outcomes. Retrospective cohort study. This study included 360 CAPD patients treated with either roxadustat (n=144) or erythropoiesis-stimulating agents (ESAs) (n=216) at our center between January 2021 and June 2024. CAPD patients diagnosed with renal anemia were treated with roxadustat or ESAs to achieve target hemoglobin levels. The primary endpoint was the decline in RKF during the 18-month follow-up period, measured by the average of 24-hour urinary urea and creatinine clearances adjusted for the body surface area (mL/min/1.73 m2). Secondary endpoints included changes in hemoglobin levels and lipid profiles, as well as the incidence of peritonitis. Propensity scores methods, including 1:1 propensity score matching with replacement and inverse probability of treatment weighting. Overall, neither propensity score matching nor inverse probability of treatment weighting models showed significant difference in RKF preservation between the roxadustat and ESA groups. However, in male patients, roxadustat was associated with a slower decline in RKF compared with ESAs (Δ-0.8 vs Δ-1.4 mL/min/1.73 m2; P = 0.04) at 18 months. Additionally, hemoglobin levels were comparable between groups. The roxadustat group exhibited lower triglycerides and low-density lipoprotein level than the ESA group. No significant difference in peritonitis incidence was observed between the 2 groups. The overall baseline RKF of our PD patients was exceptionally low. Roxadustat delays RKF decline in male CAPD patients while providing comparable anemia control and favorable lipid profile effects as ESAs. These sex-specific outcomes suggest underlying biological mechanisms, highlighting the need for larger, targeted studies to further elucidate the potential benefits of roxadustat in this population.

Red blood cells (RBCs) play a crucial role in delivering oxygen to tissues with their distinctive shape. However, the mechanisms underlying cellular deformation and rupture due to stress, which lead to diseases such as acute renal failure, pulmonary hypertension, anemia, and gallstone formation, remain poorly understood. Here, we investigate the mechanism of membrane protrusion and present a highly effective method to restore the morphology and function of damaged RBCs. We propose ultrasound-triggered nanodroplets loaded with oxygen and glucose to increase the local concentrations of these substances around RBCs and facilitate the rapid release of their payloads to repair fatigued RBCs under ultrasound. We identify a critical membrane protrusion length threshold of one-third the cell's diameter, beyond which the skeleton structure fractures and prevents repair. Our findings demonstrate how nanodroplets can efficiently deliver oxygen and glucose to expose membrane connection and trigger cytoskeleton reorganization to repair cellular structure. In an in vitro extracorporeal membrane oxygenation (ECMO) model, our method reduces the percentage of abnormal RBCs to 5% and decreases free hemoglobin concentration by 50%. This work offers new insights into RBC rejuvenation and strongly supports the potential of ultrasound-triggered nanodroplets for revitalizing fatigued RBCs, contributing to long-term health and well-being.

Roxadustat for Refractory Anemia Associated to Cytomegalovirus Infection in Kidney Transplantation.

Ferric carboxymaltose for third-trimester refractory anemia and perinatal outcomes: Retrospective cohort analysis.

Discovery of DS79540454 via fragment-based drug discovery strategy: New scaffolds of hypoxia-inducible factor prolyl hydroxylase inhibitor.

BACKGROUND Hypercapnia is a known complication of laparoscopic surgery involving carbon dioxide (CO₂) pneumoperitoneum and is usually managed intraoperatively with ventilatory adjustments. However, delayed-onset postoperative hypercapnia is uncommon. Anemia impairs hemoglobin-mediated buffering and clearance of CO₂, potentially increasing vulnerability to postoperative respiratory acidosis. This report describes 2 cases of delayed-onset postoperative hypercapnia in anemic patients following total laparoscopic hysterectomy with CO₂ pneumoperitoneum, in the absence of subcutaneous emphysema. CASE REPORT Case 1: A 43-year-old woman with American Society of Anesthesiologists (ASA) physical status I and severe anemia (hemoglobin 7.3 g/dL) underwent laparoscopic hysterectomy. One unit of blood was transfused intraoperatively. Fifteen minutes after extubation, she experienced prolonged postoperative unresponsiveness. Arterial blood gas (ABG) showed significant respiratory acidosis with a partial pressure of arterial CO₂ (PaCO₂) of 88 mmHg. She needed reintubation and 2 hours of mechanical ventilation before full recovery. Case 2: A 45-year-old woman with ASA I and refractory anemia (hemoglobin 8.1 g/dL) underwent laparoscopic hysterectomy with intraoperative blood transfusion. Despite intraoperative hyperventilation for rising end-tidal CO₂ (>75 mmHg), she developed extended unresponsiveness following extubation. ABG detected severe hypercapnia (PaCO₂ 88 mmHg). She recovered using manual ventilation without reintubation. Neither patient showed signs of subcutaneous emphysema. CONCLUSIONS Delayed-onset hypercapnia can occur in anemic patients following laparoscopic surgery, despite standard ventilation protocols. Reduced hemoglobin-mediated CO₂ buffering, combined with ongoing CO₂ absorption after pneumoperitoneum may contribute to this presentation. Anemia should therefore be considered as a modifiable risk factor, and in high-risk patients, enhanced postoperative monitoring and individualized ventilation strategies should be considered.

Patients with chronic kidney disease (CKD) develop anaemia in the setting of abnormal iron metabolism and reduced endogenous erythropoietin. Pure red cell aplasia (PRCA) is a condition that, in rare cases, has been associated with erythropoietin products, commonly prescribed in patients with CKD-related anaemia. We describe 14 cases of Epoetin-alfa associated PRCA which have resulted in significant morbidity. Our cases were predominantly male (71%) with a median age of onset 68 years old. Each presented with profound anaemia 4-48 months (median 9.5 months) after commencing subcutaneous Epoetin. Heterogeneous immunosuppression regimens were used, predominantly with either monotherapy prednisone or ciclosporin. Two patients did not receive immunosuppression. Of our 14 cases, eight have since been commenced and maintained on Roxadustat with six of these subsequently reaching target haemoglobin. Of the six not commenced on Roxadustat, only one has reached target haemoglobin. This is the first multi-patient report of Roxadustat in patients with ESA-PRCA. Our cluster of cases highlights the need for strong suspicion of acquired PRCA in patients treated with erythropoietin products who present with refractory anaemia. HIF stabilisers such as Roxadustat, which have otherwise not been licensed in New Zealand, seem to be beneficial in these cases, possibly minimising the need for heavy immunosuppression.

Parvovirus B19 (PVB19) is a clinically important cause of refractory anemia in kidney transplant recipients (KTRs). Data from low- and middle-income settings remain scarce despite high transplant volumes. This study evaluated the clinical spectrum, management practices, and outcomes of PVB19 infection across major transplant programs in India. We conducted a retrospective multicenter cohort study across 14 tertiary transplant centers. All KTRs with PCR-confirmed PVB19 infection and complete clinical data were included. Clinical features, bone marrow findings, immunosuppressive (IS) adjustments, intravenous immunoglobulin (IVIG) use, and patient and graft outcomes were analyzed. A total of 135 KTRs were identified. Median time to infection was 11 weeks posttransplant. Anemia was universal, not frequently accompanied by leukopenia (17.7%) or thrombocytopenia (14.8%). Bone marrow examinations (n=34) demonstrated giant proerythroblasts or pure red cell aplasia. IS reduction was implemented in all patients; most commonly, complete MMF withdrawal (61.5%). IVIG was administered to 90% (median cumulative dose 100g). Overall, 97% achieved hematologic recovery, with a median response time of 20 days. Recurrence occurred in 4.4%. At a median follow-up of 18 months, graft survival was 92.6%; graft loss (n=10) was primarily due to antibody-mediated rejection, and no deaths were attributable to PVB19. PVB19 infection represents an important consideration in the differential diagnosis of early posttransplant anemia in KTRs. Timely PCR testing and pragmatic treatment strategies can achieve favorable hematologic and graft outcomes in resource-constrained settings.

Oxygen is an essential element in the process of cellular oxidation, and hypoxia, a state of insufficient oxygen, can profoundly influence cellular adaptive responses through gene transcription, thereby impacting cell metabolism, angiogenesis, and inflammation. Hypoxia-inducible factor (HIF), particularly its alpha subunit (HIF-1α), is a critical transcription factor that orchestrates cellular adaptation to hypoxic environments and plays a multifaceted role in various cellular activities. In recent years, HIF-1α has been widely implicated in stimulating hematopoietic function and the good effect of roxadustat in treating renal anemia. However, the specific role of HIF-1α in bone metabolism remains unclear. More and more studies have shown that HIF-1α can not only directly affect osteoblasts, osteoclasts, osteocytes, and bone matrix during bone remodeling, but also locally and remotely regulate macrophages and various cytokines involved in bone remodeling. In addition, HIF-1α can indirectly regulate bone metabolism by promoting angiogenesis and regulating cell metabolism. This review comprehensively elucidates the intricate mechanisms by which HIF-1α influences bone metabolism. The aim is to provide a robust theoretical foundation for exploring the potential therapeutic application of roxadustat to improve bone metabolism in patients with Chronic Kidney Disease-related Osteoporosis (CKD-RO). It is important to note that, while this review highlights promising findings, the current evidence is primarily derived from preclinical animal studies and necessitates rigorous clinical validation.

Introduction. Activation of inflammatory cascades by the tumor microenvironment and the tumor cells themselves plays a key role in breast cancer (BC) progression. Interleukin 6 (IL-6), as one of the key factors of tumor-associated inflammation, is a promising target for therapeutic intervention in metastatic BC, especially in bone and bone marrow involvement. Material and methods. A woman with disseminated relapse of triple negative BC with total bone marrow carcinomatosis associated with deep pancytopenia received cyclic therapy with Eribulin 1.4 mg/m2, days 1 and 8 in combination with tocilizumab 80 mg, day 1 and lenalidomide 0.5 mg/day. The interval between cycles is 21 days. At the time of therapy initiation, the patient had ECOG-3, resistant fever 380C, grade 4 thrombocytopenia, grade 3 refractory anemia. IL6 level - 64.15 pg/mL, ferritin 2025 μg/L, LDH 1474 U/L, alkaline phosphatase 498 IU/L. Result. The normalization of the performance status (up to ECOG 1), disappearance of the inflammatory syndrome, normalization of the level of IL-6 and other inflammatory markers were noted/ The independence from blood transfusions was achieved. After 6 cycles of therapy, a decrease in the level of tumor markers and regression of metabolic activity on 18 F-FDG PET/CT in previously existing bone foci with normalization of the levels of alkaline phosphatase, parathyroid hormone and LDH were achieved. The toxicity of the therapy did not exceed grade 1. Six months after therapy start the patient was active, well, independent of blood product transfusions with no signs of tumor progression. Conclusions. Therapy including IL-6 blockade in combination with chemotherapy, immunotherapy or targeted drugs, seems to be a promising option for treating patients with aggressive forms of BC and may form the basis of new personalized treatment strategies.

AimsHypoxia-inducible factor (HIF) signalling influences cardiomyocyte differentiation, maturation, and metabolic adaptation under pathological conditions. HIF-Prolyl hydroxylase domain (HIF-PH) inhibitors, which target this pathway, have been introduced for the treatment of renal anaemia. Their precise effect or safety on cardiac function remains unclear because their pharmacokinetics and distribution are not well-understood. This study aimed to examine HIF signalling activation in adult cardiomyocytes (CMs).Methods and resultsWe used tamoxifen (TAM)-inducible, CM-specific von Hippel–Lindau (VHL) knockout (VHL-MCM) mice to activate CM HIF signalling. Then we subjected the mice to normal ageing or high-fat diet (HFD) and L-NAME feeding, a murine model of heart failure with preserved ejection fraction (HFpEF). In normal ageing group, there was no difference in the echocardiographic parameters or tissue fibrosis between VHL-MCM and control mice. VHL-MCM mice exhibited significantly increased capillary density and higher expression levels of HIF-target genes (P = 0.0248, two-way ANOVA). Under HFD + L-NAME treatment, VHL-MCM mice showed transient but significantly preserved global longitudinal strain (GLS) at 12 weeks post-TAM injection compared to controls (P = 0.0284, two-way ANOVA). Sirius red staining indicated a trend towards reduced whole-heart and interstitial fibrosis with significant increase in capillary density in VHL-MCM mice.ConclusionSustained HIF signalling activation in adult CM does not impair the cardiac structure and function in normal ageing process and shows transient yet beneficial effect in murine HFpEF model.

Myelodysplastic syndromes (MDSs) are a group of highly heterogeneous myeloid clonal diseases. Anemia is the most common clinical symptom, yet its pathogenesis remains incompletely understood. Preliminary evidence suggests an increase in macrophage infiltration and iron load in the bone marrow of patients with an MDS, alongside elevated interleukin-6 (IL-6) expression in bone marrow mesenchymal stem cells (BMSCs). The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a critical regulator of cellular antioxidant responses and inflammation, but its role in mediating the effects of iron overload in the microenvironment of patients with an MDS remains unclear. This study aims to investigate the hypothesis that iron-overloaded bone marrow macrophages promote BMSC senescence and IL-6 secretion via the Keap1-Nrf2-ARE pathway, thereby impairing the survival and differentiation of hematopoietic stem cells and hematopoietic progenitor cells and contributing to anemia. Specific objectives are to (1) quantify the macrophage iron load across major MDS subtypes and correlate it with anemia severity and prognosis; (2) define the phenotype of erythroid island macrophages (CD68+, CD169+, and vascular cell adhesion molecule 1+) and the expression of endothelial microparticles in bone marrow tissues of patients with an MDS; and (3) experimentally test whether iron-overloaded macrophages and their exosomes regulate IL-6 secretion and senescence in BMSCs via the Keap1-Nrf2-ARE pathway. Bone marrow samples will be collected from patients with key MDS subtypes (MDS with single-lineage dysplasia, refractory anemia with ring sideroblasts, MDS with multilineage dysplasia, and MDS with excess blasts; n=30 per subgroup) and control patients with iron-deficiency anemia (n=30). Methods will include histochemistry (Perls Prussian blue staining), immunohistochemistry and immunofluorescence (for macrophage and endothelial microparticle analysis), enzyme-linked immunosorbent assay, flow cytometry, quantitative polymerase chain reaction, and Western blotting. An in vitro model of iron-overloaded macrophages will be established using phorbol 12-myristate 13-acetate-differentiated THP-1 cells treated with ferric ammonium citrate. Exosomes will be isolated from these macrophages via ultracentrifugation. The effects of iron-overloaded macrophages and their exosomes on BMSC IL-6 secretion, senescence (senescence-associated β-galactosidase staining), and Keap1-Nrf2-ARE pathway activity will be assessed in coculture systems, with and without pharmacological inhibitors (5,6-dichloro-1-β-D-ribofuranosylbenzimidazole) or activators (dimethyl fumarate) of Nrf2. The study received ethics approval in December 2024. Patient recruitment and sample collection are in progress. As of December 2025, a total of 85 samples had been accrued. Pilot experiments to optimize macrophage differentiation and iron loading conditions have been completed. The full experimental workflow, including all sample analyses and in vitro experiments, is anticipated to be completed by May 2026. This study is expected to elucidate a novel molecular mechanism linking iron overload in macrophages to BMSC dysfunction and anemia in MDS. The findings could identify the Keap1-Nrf2-ARE pathway as a potential therapeutic target for managing MDS-related anemia. DERR1-10.2196/77936.

Renal anemia is a common complication in maintenance hemodialysis (MHD) patients, closely linked to higher cardiovascular event risk, reduced quality of life, and poor prognosis. This study explored the correlation between novel peripheral blood inflammatory markers and renal anemia in MHD patients. A total of 142 regular MHD patients (January 2022–June 2023) were divided into renal anemia group (Hb < 110 g/L, n = 75) and non-anemia group (Hb ≥ 110 g/L, n = 67) per 2017 Kidney disease guidelines; 74 healthy controls were included. Patients with hematologic disorders, recent acute blood loss, etc, were excluded. neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were measured/calculated. Age and gender were comparable across groups (P >.05). Mann–Whitney U test, Pearson correlation, and receiver operating characteristic curve analysis were used. neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, PLR, SII were higher in both MHD groups than controls; PLR and SII were higher in anemia group than non-anemia group. All 4 markers correlated negatively with Hb. PLR and SII had diagnostic value for MHD renal anemia, with PLR being optimal (AUC = 0.844, 95% CI: 0.774–0.899, P < .001; sensitivity = 76.0%, 95% CI: 65.2%–84.3%;specificity = 85.1%, 95% CI: 74.7%–91.7%;optimal cutoff = 143.4). PLR is associated with renal anemia in MHD patients, potentially serving as an accessible screening marker. However, single-center limitation requires validation in large-scale multi-center studies before clinical promotion.

Proton pump inhibitors (PPIs), known for their potent acid-suppressing effects, are widely used in various clinical settings, including treatment and prevention. Understanding their adverse effects is crucial. This study, utilizing the FDA Adverse Event Reporting System (FAERS) database, comprehensively analyzes PPI-related adverse events to guide clinical medication practices. This study analyzed suspected adverse drug reactions (ADRs) related to specific PPI drugs using data from the FAERS database, covering Q1 2004 to Q4 2024. Multiple statistical methods, including ROR, PRR, IC025, and EBGM, were employed for evaluation, with ADRs defined according to System Organ Class (SOC) and Preferred Term (PT). A comparative analysis was conducted to assess potential differences in ADR profiles among different PPI drugs. This study analyzed 176,680 cases of PPI-related adverse events, with a total of 632,468 adverse reaction reports recorded when PPIs were designated as the primary suspected drug (PS). PPIs showed significantly elevated risks in the renal/urinary and gastrointestinal systems, with other common adverse reactions including hypomagnesemia, hypocalcemia, and renal anemia. Most adverse reactions occurred either within the first 0-30 days of use or after prolonged exposure (>6 months), and elderly patients (≥65 years) were disproportionately affected. For high-risk populations using PPIs long-term (such as elderly patients or those with pre-existing renal impairment), continuous monitoring is essential to mitigate potential complications. Unnecessary use should be strictly avoided, and long-term medication should be minimized to ensure safety and appropriateness.