Search Results (228)

Hot-fluid injection in thermal-enhanced oil recovery (thermal-EOR, TEOR) imposes temperature-driven volumetric strains that can substantially alter in situ stresses, fracture geometry, and wellbore/reservoir integrity, yet existing TEOR modeling has not fully captured coupled thermo-poroelastic (thermo-hydro-mechanical) effects on fracture aperture, fracture-tip behavior, and stress rotation within a displacement discontinuity method (DDM) framework. This study aims to examine the influence of sustained hot-fluid injection on stress redistribution, hydraulic-fracture deformation, and fracture stability in thermal-EOR by accounting for coupled thermal, hydraulic, and mechanical interactions. This study develops a fully coupled thermo-poroelastic DDM formulation in which fracture-surface normal and shear displacement discontinuities, together with fluid and heat influx, act as boundary sources to compute time-dependent stresses, pore pressure, and temperature, while internal fracture fluid flow (Poiseuille-based volume balance), heat transport (conduction–advection with rock exchange), and mixed-mode propagation criteria are included. A representative scenario considers an initially isothermal hydraulic fracture grown to 32 m, followed by 12 months of hot-fluid injection, with temperature contrasts of ΔT = 0–100 °C and reduced pumping rate. Results show that the hydraulic-fracture aperture increases under isothermal and modest heating (ΔT = 25 °C) and remains nearly stable near ΔT = 50 °C, but progressively narrows for ΔT = 75–100 °C despite continued injection, indicating potential injectivity decline driven by thermally induced compressive stresses. Hot injection also tightens fracture tips, restricting unintended propagation, and produces pronounced near-fracture stress amplification and re-orientation: minimum principal stress increases by 6 MPa for ΔT = 50 °C and 10 MPa for ΔT = 100 °C, with principal-stress rotation reaching 70–90° in regions adjacent to the fracture plane and with markedly elevated shear stresses that may promote natural-fracture activation. These findings show that temperature effects can directly influence injectivity, fracture containment, and the risk of unintended fracture or natural-fracture activation, underscoring the importance of temperature-aware geomechanical planning and injection-strategy design in field operations. Incorporating these effects into project design can help operators anticipate injectivity decline, improve fracture containment, and reduce geomechanical uncertainty during long-term hot-fluid injection. Full article

Long-acting cabotegravir and rilpivirine (LA-CAB/RPV) have been incorporated into the treatment of people living with HIV (PLWH), but evidence on their metabolic impact in real-world settings remains limited. This retrospective study analyzed the lipid profiles of 39 PLWH who switched from daily oral antiretroviral therapy to LA-CAB/RPV. Lipid parameters were compared before and seven months after the switch. No significant differences were observed in total cholesterol, LDL cholesterol, or triglycerides, indicating that LA-CAB/RPV did not worsen the lipid profile. However, HDL cholesterol increased significantly from 49.4 ± 11.5 mg/dL to 53.0 ± 11.9 mg/dL (p = 0.0065). Viral suppression and CD4 counts remained stable throughout the study period. These findings suggest that switching to long-acting injectable cabotegravir and rilpivirine maintains virological and immunological control without adversely affecting the total cholesterol, LDL cholesterol, or triglycerides, and is associated with an improvement in HDL cholesterol. LA-CAB/RPV therefore appears to be a metabolically safe therapeutic option for PLWH, with a potentially favorable effect on cardiovascular risk factors. Full article

Background: With modern antiretroviral regimens, durable viral suppression is now achieved in most people with HIV (PWH), whose life expectancy approaches that of the general population. Consequently, recent guidelines emphasise, beyond virological and immunological control, health-related quality of life and patient-reported outcomes (PROs) as targets of HIV care, including for dual regimens. Methods: We conducted a narrative review of clinical trials and observational studies evaluating PROs in adults treated with dual antiretroviral therapies, either oral or long-acting injectable. We also examined guideline documents and implementation studies addressing the role, feasibility, and interpretation of PROs in routine HIV care. Results: Trials of dual regimens reported high treatment satisfaction, convenience, and stable or improved quality of life, with some concerns related to injection-site reactions and visit burden for long-acting formulations. Emerging real-world data broadly confirm these findings but remain heterogeneous, with variability in instruments, assessment timing, and analytic approaches, limiting comparability and clinical use. Conclusions: PROs may support shared decision-making and optimise the use of dual therapies in PWH, but their uptake in clinical practice is still limited. Standardised tools, clearer interpretative frameworks, and pragmatic implementation strategies are needed to better integrate PROs into everyday HIV care. Full article

Background: Childhood growth hormone deficiency (GHD) and idiopathic short stature (ISS) are endocrine disorders characterized by impaired linear growth due to insufficient or ineffective growth hormone (GH) activity. While daily recombinant human GH (rhGH) therapy effectively restores growth, treatment adherence remains suboptimal owing to the burden of daily injections. Long-acting formulations such as pegylated recombinant human GH (PEG-rhGH) have been developed to improve convenience and compliance while maintaining therapeutic efficacy. This systematic review and meta-analysis aimed to evaluate the comparative effectiveness and safety of once-weekly PEG-rhGH versus daily rhGH and to assess dose–response outcomes between higher- and lower-dose PEG-rhGH regimens in pediatric GHD and ISS. Methods: This study followed PRISMA 2020 guidelines. Comprehensive searches were conducted in PubMed, Web of Science, and Scopus from inception to September 2025 using MeSH terms and free-text keywords for “PEGylated recombinant human growth hormone,” “long-acting growth hormone,” and “growth hormone deficiency.” Eligible studies included randomized controlled trials (RCTs) and cohort studies evaluating PEG-rhGH in children (≤18 years) with GHD or ISS, comparing either once-weekly PEG-rhGH with daily rhGH or different PEG-rhGH doses. Data extraction included study design, participant characteristics, intervention details, and key outcomes (height SDS, height velocity, IGF-1 SDS). Meta-analysis was conducted using Review Manager with a random-effects model, and heterogeneity was quantified using the I² statistic. Results: Eight studies, comprising 2549 children, met the inclusion criteria. Once-weekly PEG-rhGH demonstrated comparable short-term growth outcomes to daily rhGH at 6 and 12 months, with modest but significant superiority in height SDS (MD = 0.10, 95% CI 0.01–0.19) and height velocity (MD = 0.74 cm/year, 95% CI 0.42–1.05) by 24 months. IGF-1 SDS did not differ significantly at 6 or 12 months. In dose comparisons, 0.2 mg/kg/week PEG-rhGH produced substantially greater gains in height SDS and IGF-1 SDS than 0.1 mg/kg/week, with a time-dependent increase in the magnitude of the effect. Safety analyses revealed no increase in adverse or serious adverse events with PEG-rhGH compared to daily rhGH; reactions were generally mild and transient. Conclusions: Once-weekly PEG-rhGH is as effective as daily rhGH for promoting growth in pediatric GHD and ISS, with possible long-term advantages in growth outcomes and similar safety. The higher PEG-rhGH dose (0.2 mg/kg/week) appears to optimize efficacy without compromising tolerability. Weekly administration may enhance adherence and quality of life, supporting PEG-rhGH as a viable alternative to daily GH therapy. Full article

Background/Objectives: Oral donepezil, an acetylcholinesterase (AChE) inhibitor for Alzheimer’s disease, faces adherence challenges. Long-acting injectable (LAI) formulations like GB-5001 aim to enhance adherence by reducing dosing frequency. This Phase 1, open-label, active-controlled, dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GB-5001 in healthy male adults. Methods: Participants were assigned to cohorts receiving GB-5001A or GB-5001D (LAI formulations) via intramuscular (IM) or subcutaneous (SC) injection, or oral Aricept^®. Safety, PK, and PD (AChE inhibition) were assessed. The influence of CYP2D6 phenotype was explored, and modeling/simulation was performed. Results: Fifty healthy male participants completed the study. After IM administration, GB-5001A (70 mg, 140 mg, 280 mg) showed dose-dependent increases in exposure (AUC_inf and C_max), resulting in significantly extended exposure compared to oral Aricept^® 10 mg. No serious adverse events were reported; the most common AEs were mild injection site reactions, which occurred in all treatment groups except the GB-5001A IM 70 mg group and the Aricept group. GB-5001A also demonstrated sustained AChE inhibition. Conclusions: GB-5001A, an LAI donepezil, showed favorable safety, dose-proportional PK, and sustained plasma exposure. It achieved a 3–4-fold longer half-life than oral donepezil. These findings, supported by modeling, highlight GB-5001A’s potential as a once-monthly IM alternative for Alzheimer’s disease treatment. Full article

Background: Long-acting injectable antiretroviral therapy (LA-ART) with cabotegravir and rilpivirine (CAB + RPV) has emerged as a promising alternative to daily oral regimens for people living with HIV (PLWH), particularly those facing adherence challenges. While clinical trials have demonstrated its efficacy, real-world evidence remains limited. Methods: This retrospective, multicenter study evaluated the efficacy and safety of CAB + RPV in 160 virologically suppressed PLWH across eight Italian infectious disease units. Participants received intramuscular CAB (600 mg) and RPV (900 mg) every eight weeks without an oral lead-in phase. Clinical, immunological, and biochemical parameters were assessed at baseline and after 24 weeks. Results: At week 24, 96.25% of participants maintained virological suppression, and the proportion of individuals with target-not-detected viral load increased from 71% to 76%. Only one case of virological failure was observed. Significant immunological improvements included an increase in the CD4+/CD8+ ratio (p = 0.0038) and a reduction in CD8+ T-cell count (p = 0.0150). Biochemical analysis showed a decrease in serum creatinine (p < 0.0001) and an increase in HDL cholesterol (p = 0.0223). Treatment discontinuation occurred in 3.75% of participants, primarily due to adverse events or psychological factors. Conclusions: CAB + RPV demonstrated high efficacy and tolerability in a real-world setting, with favorable immunological and metabolic outcomes. These findings support its use as a viable therapeutic option for PLWH, especially those with adherence barriers. Further long-term studies are warranted to confirm these results across broader populations. Full article

Poly(lactic-co-glycolic acid) (PLGA) sustained-release systems for intra-articular (IA) delivery aim to extend joint residence time and reduce the reinjection frequency of conventional IA therapies. This review synthesizes current understanding of PLGA degradation, the acidic microenvironment inside degrading microspheres, and release behavior in joints, and surveys clinical experience with extended-release corticosteroid depots alongside emerging platforms for nonsteroidal and biologic agents. To situate PLGA within the broader IA field, we briefly summarize selected non-PLGA sustained-release approaches—such as multivesicular liposomes, hyaluronic acid conjugates, and hybrid matrices—to contextualize comparative performance and safety. For proteins and peptides, central barriers include acidification inside degrading microspheres, aggregation during fabrication and storage, and incomplete or delayed release, as illustrated by glucagon-like peptide-1 analog formulations. Mitigation strategies span pH buffering, excipient-based stabilization, and gentler manufacturing that improve encapsulation efficiency and preserve bioactivity. Translation hinges on manufacturing scale-up and quality systems that maintain critical particle attributes and enable informative in vitro–in vivo interpretation. Clinically, prolonged symptom relief after single dosing has been demonstrated for corticosteroid depots (e.g., ~50% pain reduction over 12 weeks with a single PLGA–triamcinolone injection), whereas repeat-dose safety and indication expansion beyond the knee remain active needs best addressed through multicenter trials incorporating imaging and patient-reported outcomes. Consistent real-world performance will depend on controlling batch-to-batch variability and implementing pharmacovigilance approaches suited to long dosing intervals, enabling broader clinical adoption. Full article

Carbon dioxide (CO₂)-enhanced coalbed methane recovery involves a complex process of mixed-gas adsorption, desorption, and diffusion–transport. The literature suggests that an appropriate range of CO₂ injection pressure and an optimal injection time window are critical for coal seams with varying reservoir conditions. That is, higher pressure and longer injection periods do not necessarily lead to better displacement performance. Therefore, in this study, experimental research was conducted on the time-varying characteristics of the displacement–replacement effect of CO₂-enhanced methane (CH₄) extraction from coal seams, and the following results were obtained. (1) The process of displacement–replacement of CH₄ by CO₂ in coal seams can be divided into five stages: a stage of spontaneous CH₄ desorption caused by partial-pressure effects, a replacement-dominated stage, a stage where replacement and displacement act jointly, a displacement-dominated stage, and a stabilization stage. (2) For all three coal samples (anthracite, coking coal, and long-flame coal), cumulative CH₄ desorption increases with increasing CO₂ injection pressure below 5 MPa and finally stabilizes. However, when CO₂ injection pressure exceeds 5 MPa, the effect weakens, possibly due to the dynamic changes in CO₂ partial pressure. (3) The displacement–replacement ratio decreases with increasing CH₄ equilibrium pressure. Additionally, the larger the difference between the CO₂ injection pressure and the CH₄ equilibrium pressure, the better the displacement–replacement effect. Full article

Background: Adolescence is a vulnerable period for the onset of severe psychiatric conditions, such as psychotic spectrum disorders. Non-adherence to antipsychotics is a common problem in young people with these conditions and paves the way for relapse, rehospitalization, and functional impairment. Co-occurring substance use disorders (SUDs) further undermine adherence and worsen outcomes. Long-acting injectable antipsychotics (LAIs) improve adherence and outcomes in adults, but none are licensed for use in individuals under 18. This review seeks to distill the available evidence on LAIs’ use in adolescents, from efficacy to safety, and to outline clinical practice recommendations. Methods: A narrative review was conducted. The evidence was organized by drug class: risperidone, paliperidone, aripiprazole, and other antipsychotics (olanzapine, haloperidol, first-generation depots). Results: Evidence in adolescents remains sparse and heterogeneous. Risperidone LAI has shown improvements in symptom severity, functioning, and behavioral control in bipolar disorder and schizophrenia, though commonly associated with side effects. Paliperidone palmitate demonstrated benefit in first-episode schizophrenia and autism spectrum disorder with intellectual disability, reducing hospital use but carrying risks of EPS and hyperprolactinemia. Aripiprazole LAI showed functional gains, short-term tolerability, and encouraging acceptance in case reports. Other LAIs were used in highly resistant cases with some clinical benefit, though extrapyramidal adverse events were common. Conclusions: The current literature provides limited data, and no clinical guidelines exist for the use of LAI in adolescents. Nonetheless, off-label use is reported in selected cases in clinical practice. Best practice is to start with oral stabilization, then use the lowest effective LAI with psychosocial support and close monitoring. When SUD co-occurs, LAIs may also help mitigate risks related to misuse/diversion of oral medication, provided that care includes systematic SUD screening and early intervention. Prospective controlled studies are urgently needed to establish long-term efficacy and safety in this vulnerable population. Full article

Background: Respiratory syncytial virus (RSV) is a major cause of infant respiratory illness, leading to significant hospitalizations. Two preventive strategies exist: maternal vaccination and a long-acting monoclonal antibody for neonates. In The Netherlands, neonatal immunization is planned to start from autumn 2025 onward, contingent on acceptance by parents and healthcare professionals. Maternal vaccination is already available at own costs. Understanding acceptance, perceptions, and barriers is critical for effective implementation. This study explores these factors to inform strategies for optimal uptake. Methods: This mixed-method study involved semi-structured online interviews with 21 (expectant) mothers (EMs) and 32 healthcare professionals (HCPs) involved in maternal and neonatal care (e.g., pediatricians, youth doctors/nurses, obstetricians, midwives, and general practitioners) and a quantitative descriptive analysis of factors influencing EM choices. Interviews were transcribed and thematically analyzed. Results: Both EMs and HCPs showed strong support for RSV immunization, with a preference for maternal vaccination or a combined approach. Concerns about neonatal injections during the sensitive postpartum period and unfamiliarity with newborn injections (e.g., vitamin K) influenced preferences. EMs noted hesitation about additional pregnancy/postpartum vaccinations, emphasizing the importance of well-timed interventions. HCPs highlighted logistical challenges, such as defining responsibilities, navigating National Immunization Program (NIP) changes, and ensuring readiness. All interviewed individuals value the option to choose between strategies, necessitating informed decision-making and respect for preferences. EMs make their final decision together with their partner, supported by expert information and their personal environment. Conclusions: Support for RSV immunization is high, with maternal vaccination preferred, though neonatal immunization is accepted if appropriately timed. Providing clear personalized and consistent information, heightened public awareness of RSV’s impact, respecting individual choices, and offering options are key to maximizing uptake. Full article

Hydrogels are hydrophilic, soft polymer networks with high water content and mechanical properties that are tunable; they are also biocompatible. Therefore, as biomaterials, they are of interest to modern medicine. In this review, the main applications of hydrogels in essential clinical applications are discussed. Chemical, physical, or hybrid crosslinking of either synthetic or natural polymers allow for the precise control of hydrogels’ physicochemical properties and their specific characteristics for certain applications, such as stimuli-responsiveness, drug retention and release, and biodegradability. Hydrogels are employed in gynecology to regenerate the endometrium, treat infections, and prevent pregnancy. They show promise in cardiology in myocardial infarction therapy through injectable scaffolds, patches in the heart, and medication delivery. In rheumatoid arthritis, hydrogels act as drug delivery systems, lubricants, scaffolds, and immunomodulators, ensuring effective local treatment. They are being developed, among other applications, as antimicrobial coatings for stents and radiotherapy barriers for urology. Ophthalmology benefits from the use of hydrogels in contact lenses, corneal bandages, and vitreous implants. They are used as materials for chemoembolization, tumor models, and drug delivery devices in cancer therapy, with wafers of Gliadel presently used in clinics. Applications in abdominal surgery include hydrogel-coated meshes for hernia repair or Janus-type hydrogels to prevent adhesions and aid tissue repair. Results from clinical and preclinical studies illustrate hydrogels’ diversity, though problems remain with mechanical stability, long-term safety, and mass production. Hydrogels are, in general, next-generation biomaterials for regenerative medicine, individualized treatment, and new treatment protocols. Full article

Background: Synthetic cannabinoid receptor agonists (SCRAs, commercially known as “Spice”) have become a leading cause of substance-induced psychosis worldwide. These compounds show strong associations not only with acute psychotic episodes but also, in a subset of patients, with persistent or relapsing psychotic disorders, patterns that raise concern about progression to schizophrenia. Yet clinicians still lack clear, evidence-based guidance, and the optimal management of SCRA-induced psychosis remains inadequately defined. Methods: We carried out a systematic search of PubMed, Scopus, and Web of Science on 2 April 2025, identifying 35 primary studies that together describe roughly 4600 clinical presentations (≈77% male; mean age: 24.7 years). Results: Across diverse settings a convergent three-step pharmacological strategy emerged. First, rapid tranquillization with parenteral benzodiazepines consistently controlled severe agitation and autonomic instability. Second, when florid psychosis persisted beyond 30–60 min, clinicians introduced a second-generation antipsychotic—most commonly olanzapine, risperidone, or aripiprazole—often at doses exceeding those used for primary psychoses. Third, for the minority of refractory or relapse-prone cases, escalation to long-acting injectable formulations or low-dose clozapine achieved symptom control, even at plasma levels below those required in treatment-resistant schizophrenia. Although the evidence base consists largely of uncontrolled clinical descriptions, across studies, a recurrent clinical pattern was observed: initial benzodiazepines for agitation, followed by antipsychotics when psychosis persisted and escalation to clozapine or long-acting injectables in refractory cases. This approach appears to be associated with symptom improvement, although the certainty of the evidence is low to very low. Conclusions. Prospective, comparative studies are urgently needed to refine dosing, directly compare antipsychotic classes, and evaluate emerging cannabinoid-modulating interventions. Full article

Long-acting injectable cabotegravir/rilpivirine (CAB/RPV-LA) is currently approved as a maintenance therapy for people with HIV (PWH) who are virologically suppressed. However, growing real-world evidence highlights its potential role in more complex viremic populations traditionally considered ineligible. We present a case series of eight PWH treated at two tertiary centers in Italy, all of whom faced persistent viremia, adherence difficulties, malabsorption syndromes, or psychosocial barriers. Following the switch to CAB/RPV-LA, all patients, despite heterogeneous clinical profiles and baseline virological status, achieved and maintained virologic suppression, demonstrated improved adherence, and experienced no serious adverse events. Full article

Despite the progress of antiretroviral therapy, there are still some patients with (MDR) HIV infection. In this case, international guidelines suggest using new-generation drugs, such as Ibalizumab (IBA) or Lenacapavir (LEN), in combination with an optimized background regimen. Our clinical case concerns a Heavily Treatment-Experienced (HTE) patient with MDR HIV-1 infection. Rescue therapy began in April 2022, combining residual drugs with low-level resistance and IBA. At this time, HIV-RNA results included 37.800 copies/mL, and CD4+ included 147 cells/µL. IBA was administered intravenously every 15 days. After 12 months, to optimize adherence, IBA was re-placed by LEN, which has long-acting posology, with subcutaneous injections every 6 months. IBA achieved viral suppression in only one month with an improvement in the CD4+ count and showed a progressive disappearance of viral mutations in the reservoir. It was well tolerated except for the onset of hypertension after infusions. After 12 months, IBA was switched to LEN, which showed good tolerability, preserving efficacy and stable pressure on HIV-DNA. Our case report about an HTE patient shows that IBA was efficacious in the rescue regimen, while also acting on the reservoir. LEN, adopted in a switch strategy which differed from that described in the literature, preserved efficacy and stable pressure on HIV-DNA. Full article

The aim of this study was to design a poorly water-soluble electrostatic nanocomplex of semaglutide (SMG) with protamine sulfate (PS) and zinc ions (Zn) for prolonged subcutaneous delivery. Complexation of SMG with the cationic peptide PS increased the lipophilicity (logP) proportionally from −4.7 to 0.3, particularly in the presence of Zn. The optimized nanocomplex exhibited spherical morphology, an amorphous state, a particle size of 196.0 nm, and a zeta potential of −45.7 mV. In an in vitro dissolution test under sink conditions, native SMG showed rapid drug release with 98% dissolution within 24 h. In contrast, the nanocomplexes showed markedly delayed release, with a concentration-dependent relationship between PS/Zn contents and SMG release rate, exhibiting 19% drug release over 7 days in the optimized formula. These findings suggest that the proposed nanocomplex is a promising system for long-acting injectable delivery of SMG, potentially enhancing patient compliance in patients with obesity or type 2 diabetes. Full article