Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is ...associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.
Surgery is the only potentially curative treatment for localized soft-tissue sarcomas. However, for sarcomas arising in the retroperitoneum, locoregional recurrence rates are 35% to 59% despite ...resection. Doxorubicin (DOX) is the standard first-line systemic chemotherapy for advanced soft-tissue sarcoma, yet its intravenous administration yields limited clinical efficacy and results in dose-limiting cardiotoxicity. We report the fabrication and optimization of a novel electrospun poly(caprolactone) (PCL) surgical mesh coated with layers of a hydrophobic polymer (poly(glycerol monostearate-co-caprolactone), PGC-C18), which delivers DOX directly to the operative bed following sarcoma resection. In xenograft models of liposarcoma and chondrosarcoma, DOX-loaded meshes (DoM) increased overall survival 4-fold compared with systemically administered DOX and prevented local recurrence in all but one animal. Importantly, mice implanted with DoMs exhibited preserved cardiac function, whereas mice receiving an equivalent dose systemically displayed a 23% decrease from baseline in both cardiac output and ejection fraction 20 days after administration. Collectively, this work demonstrates a feasible therapeutic approach to simultaneously prevent post-surgical tumor recurrence and minimize cardiotoxicity in soft-tissue sarcoma.
A proof-of-principle study in animal models shows that a novel local drug delivery approach can prevent tumor recurrence as well as drug-related adverse events following surgical resection of soft-tissue sarcomas.
Drug-loaded meshes offer a promising delivery strategy for the prevention of local recurrence. Patient-derived xenograft (PDX) models are representative of individual patient tumors and predictive of ...clinical outcomes.
A PDX model was established in NSG (NOD-scid IL2Rgammanull) mice using tumor tissue from a patient with aggressive lung adenocarcinoma. Polyglycolic acid (PGA) meshes loaded with paclitaxel (PGA+PTX) were electrospun. Tumor-bearing mice were randomized into 4 groups after macroscopic complete resection: (1) no treatment (n = 10); (2) intraperitoneal PTX at 20 mg/kg (n = 10); (3) PGA mesh without drug (n = 14); and (4) PGA+PTX mesh at 12 mg/kg (n = 14). A 1-cm2 mesh was placed onto the tumor resection beds. Groups were observed for local recurrence for 120 postoperative days.
PDX mice treated with PGA+PTX meshes after resection exhibited a >5-fold increase in recurrence-free survival (P < .0001) compared with systemically treated and untreated control groups. Median recurrence-free survival was 24 days for untreated and intraperitoneal PTX groups, 28 days for unloaded PGA mesh group, and undefined for the PGA+PTX mesh group.
Development of a PDX surgical resection model of non-small cell lung cancer permits robust assessment of postresection local recurrence for preclinical studies of patient-derived tumors. Intraoperative placement of drug-loaded meshes demonstrates superior local disease treatment, suggesting that this approach may improve recurrence-free survival in early-stage non-small cell lung cancer patients undergoing limited resection.
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Substantial advances in biotherapeutics are distinctly lacking for musculoskeletal diseases. Musculoskeletal diseases are biomechanically complex and localized, highlighting the need for novel ...therapies capable of addressing these issues. All frontline treatment options for arthrofibrosis, a debilitating musculoskeletal disease, fail to treat the disease etiology-the accumulation of fibrotic tissue within the joint space. For millions of patients each year, the lack of modern and effective treatment options necessitates surgery in an attempt to regain joint range of motion (ROM) and escape prolonged pain. Human relaxin-2 (RLX), an endogenous peptide hormone with antifibrotic and antifibrogenic activity, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, RLX has previously faltered through multiple clinical programs because of pharmacokinetic barriers. Here, we describe the design and in vitro characterization of a tailored drug delivery system for the sustained release of RLX. Drug-loaded, polymeric microparticles released RLX over a multiweek time frame without altering peptide structure or bioactivity. In vivo, intraarticular administration of microparticles in rats resulted in prolonged, localized concentrations of RLX with reduced systemic drug exposure. Furthermore, a single injection of RLX-loaded microparticles restored joint ROM and architecture in an atraumatic rat model of arthrofibrosis with clinically derived end points. Finally, confirmation of RLX receptor expression, RXFP1, in multiple human tissues relevant to arthrofibrosis suggests the clinical translational potential of RLX when administered in a sustained and targeted manner.
Risk of locoregional recurrence after sarcoma resection is high, increasing both morbidity and mortality. Intraoperative implantation of paclitaxel (PTX)-eluting polymer films locally delivers ...sustained, supratherapeutic PTX concentrations to the tumor bed that are not clinically feasible with systemic therapy, thereby reducing recurrence and improving survival in a murine model of recurrent sarcoma. However, the biology underlying increased efficacy of PTX-eluting films is unknown and provides the impetus for this work. In vitro PTX efficacy is time and dose dependent with prolonged exposure significantly decreasing PTX IC50 values for human chondrosarcoma (CS-1) cells (153.9 nmol/L at 4 hours vs. 14.2 nmol/L at 30 hours, P = 0.0001). High-dose PTX significantly inhibits proliferation with in vivo PTX films delivering a dose >130 μmol/L directly to the tumor thereby irreversibly arresting cell cycle and inducing apoptosis in CS-1 as well as patient-derived liposarcoma (LP6) and leiomyosarcoma (LMS20). Supratherapeutic PTX upregulates the expression of p21 in G2-M arrested cells, and irreversibly induces apoptosis followed by cell death, within 4 hours of exposure. Microarray analyses corroborate the finding of poor DNA integrity commonly observed as a final step of apoptosis in CS-1 cells and tumor. Unlike low PTX concentrations at the tumor bed during systemic delivery, supratherapeutic concentrations achieved with PTX-eluting films markedly decrease sarcoma lethality in vivo and offer an alternative paradigm to prevent recurrence.
Many displaced young people enter secondary schools with limited mother tongue literacy and low proficiency in the language of instruction, but little is known about how teachers respond to this ...challenge. This article presents an investigation of the approaches to teaching low- literacy refugee-background students reported by 61 teachers in Victorian secondary schools in receipt of targeted funding. Teachers were surveyed using a questionnaire designed to measure adoption of current popular approaches advocated in influential language and literacy pedagogy frameworks. Over half of the practices the authors asked about were used routinely by a majority of teachers. The findings suggest that most teachers make routine use of at least some strategies for developing language and literacy but may not always work towards building learner autonomy. Lack of attention to autonomous learning is explained in part by a lack of resources and time. Author abstract
ObjectivesTo investigate mortality rates and associated factors, and avoidable mortality in children/young people with intellectual disabilities.DesignRetrospective cohort; individual record-linked ...data between Scotland’s 2011 Census and 9.5 years of National Records for Scotland death certification data.SettingGeneral community.ParticipantsChildren and young people with intellectual disabilities living in Scotland aged 5–24 years, and an age-matched comparison group.Main outcome measuresDeaths up to 2020: age of death, age-standardised mortality ratios (age-SMRs); causes of death including cause-specific age-SMRs/sex-SMRs; and avoidable deaths.ResultsDeath occurred in 260/7247 (3.6%) children/young people with intellectual disabilities (crude mortality rate=388/100 000 person-years) and 528/156 439 (0.3%) children/young people without intellectual disabilities (crude mortality rate=36/100 000 person-years). SMRs for children/young people with versus those without intellectual disabilities were 10.7 for all causes (95% CI 9.47 to 12.1), 5.17 for avoidable death (95% CI 4.19 to 6.37), 2.3 for preventable death (95% CI 1.6 to 3.2) and 16.1 for treatable death (95% CI 12.5 to 20.8). SMRs were highest for children (27.4, 95% CI 20.6 to 36.3) aged 5–9 years, and lowest for young people (6.6, 95% CI 5.1 to 8.6) aged 20–24 years. SMRs were higher in more affluent neighbourhoods. Crude mortality incidences were higher for the children/young people with intellectual disabilities for most International Statistical Classification of Diseases and Related Health Problems, 10th Revision chapters. The most common underlying avoidable causes of mortality for children/young people with intellectual disabilities were epilepsy, aspiration/reflux/choking and respiratory infection, and for children/young people without intellectual disabilities were suicide, accidental drug-related deaths and car accidents.ConclusionChildren with intellectual disabilities had significantly higher rates of all-cause, avoidable, treatable and preventable mortality than their peers. The largest differences were for treatable mortality, particularly at ages 5–9 years. Interventions to improve healthcare to reduce treatable mortality should be a priority for children/young people with intellectual disabilities. Examples include improved epilepsy management and risk assessments, and coordinated multidisciplinary actions to reduce aspiration/reflux/choking and respiratory infection. This is necessary across all neighbourhoods.
This case study profiles eight international PhD students and describes the process of the construction and negotiation of their social and institutional identities in an Australian university. ...Audio-recorded informal conversations of the students highlight the role of social membership, staffroom interactions and language in the construction of institutional identities. The impact of multiple identity transitions experienced by new international students is described. The data analysis uses a sociocultural perspective of second language in use, which reflects the negotiation of power, space and identity in informal multicultural institutional encounters. The article provides insight into the ways transitions are experienced by international postgraduate students. Findings also include a critique of the negatively loaded stereotype of the 'international student' in Australian universities and the way it underplays the heterogeneity of student experience.
To evaluate the clinical role of a novel, noncontact, low-intensity, low-frequency ultrasound therapy (MIST Therapy) in the treatment of nonhealing leg and foot ulcers associated with chronic ...critical limb ischemia.
Prospective, parallel-group, randomized, controlled trial.
A multidisciplinary, vascular wound-healing clinic.
Thirty-five patients who received MIST Therapy plus the standard of wound care (treatment group) and 35 patients who received the standard of wound care alone (control group).
Standard of wound care alone or standard of wound care plus MIST Therapy for 12 weeks or until fully healed. MIST Therapy was administered 3 times per week for 5 minutes per treatment.
Percentage of patients with greater than 50% reduction in wound size from the index measurement after 12 weeks of treatment. The relationship of transcutaneous oximetry pressure in the supine and dependent position was evaluated as a factor in assessing the potential to heal ischemic ulcerations of the foot and leg.
A significantly higher percentage of patients treated with the standard of care plus MIST Therapy achieved greater than 50% wound healing at 12 weeks than those treated with the standard of care alone (63% vs 29%; P < .001). Thus, failure to achieve the minimum wound healing requirement occurred in 37% of patients in the treatment group and 71% of patients in the control group. The predictive value of baseline transcutaneous oxygen pressure may benefit the clinician when assessing the potential to heal ischemic wounds.
The rate of healing of cutaneous foot and leg ulcerations in patients with chronic critical limb ischemia improved significantly when MIST Therapy was combined with the standard of wound care.
Much of the limited literature on organ donation has focused on the demographic and psychographic profiles of people who are willing to become organ donors. More information about the relationship of ...attitudes, values, knowledge, and actual behavior among adults is needed if targeted communication campaigns promoting organ donation are to succeed. The results of a mail survey of 798 adults sampled (via stratified random sampling procedures) from two local sites of a national corporation suggest that attitudes toward donation, knowledge about organ donation, altruism, and perceived social norms are significantly associated with both actual behavior (having signed an organ donor card) and behavioral intent (among non-donors) to sign a card in the future. These findings support the major models of organ donation willingness, especially those advanced by Horton and Horton (1991) and Kopfman (1994). This study also advances current knowledge of organ donation willingness by 1) using a large, relatively diverse population of adults rather than relying on a student sample; and 2) focusing on specific knowledge barriers that distinguish donors from non-donors.
