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Over the past few years, researchers have demonstrated the use of hydrogels to design drug delivery platforms that offer a variety of benefits, including but not limited to longer circulation times, reduced drug degradation, and improved targeting. Furthermore, a variety of strategies have been explored to develop stimulus-responsive hydrogels to design smart drug delivery platforms that can release drugs to specific target areas and at predetermined rates. However, only a few studies have focused on exploring how innate hydrogel properties can be optimized and modulated to tailor drug dosage and release rates. Here, we investigated the individual and combined roles of polymer concentration and crosslinking density (controlled using both chemical and nanoparticle-mediated physical crosslinking) on drug delivery rates. These experiments indicated a strong correlation between the aforementioned hydrogel properties and drug release rates. Importantly, they also revealed the existence of a saturation point in the ability to control drug release rates through a combination of chemical and physical crosslinkers. Collectively, our analyses describe how different hydrogel properties affect drug release rates and lay the foundation to develop drug delivery platforms that can be programmed to release a variety of bioactive payloads at defined rates.

Controlled delivery of proteins has immense potential for the treatment of various human diseases, but effective strategies for their delivery are required before this potential can be fully realized. Recent research has identified hydrogels as a promising option for the controlled delivery of therapeutic proteins, owing to their ability to respond to diverse chemical and biological stimuli, as well as their customizable properties that allow for desired delivery rates. This study utilized alginate and chitosan as model polymers to investigate the effects of hydrogel properties on protein release rates. The results demonstrated that polymer properties, concentration, and crosslinking density, as well as their responses to pH, can be tailored to regulate protein release rates. The study also revealed that hydrogels may be combined to create double-network hydrogels to provide an additional metric to control protein release rates. Furthermore, the hydrogel scaffolds were also found to preserve the long-term function and structure of encapsulated proteins before their release from the hydrogels. In conclusion, this research demonstrates the significance of integrating porosity and response to stimuli as orthogonal control parameters when designing hydrogel-based scaffolds for therapeutic protein release.

You may have already noticed some changes in your paper over the past few weeks. A bold new banner, bigger and better type, and a whiter and brighter paper are just a few of the improvements we've made to help make your paper more enjoyable and easier to use. Behind the scenes, we've also made additions to our newsroom, expanded our research capabilities and built an exceptional customer care team.

Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK. We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case–fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models. 319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case–fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40–49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15–2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case–fatality rate (2·25, 1·13–4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09–4·08; p=0·028). Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk–benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies. University of Birmingham and University of Oxford.

The intracellular retention of misfolded extracellular matrix proteins is a common disease mechanism in various rare skeletal diseases. This discovery has driven the study of ER stress and the unfolded protein response (UPR) as a promising therapeutic target in several skeletal dysplasias. In the case of COL10A1 mutations, targeting the UPR resulted in a clinical trial of the repurposed drug carbamazepine; however, for other closely related skeletal disorders, treatment with carbamazepine was ineffective, indicating the need for suitable markers for in vitro screenings of potential drug treatments. Mutations in cartilage oligomeric matrix protein (COMP), a cartilage structural protein, cause both multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH); together referred to as the COMPopathies, which result from the intracellular retention of mutant COMP to varying degrees. In contrast to other closely related skeletal disorders, caused by mutations in cartilage structural proteins, the involvement of the UPR is less clear, and so far, no common COMPopathy marker has been identified. Here, using cell models of COMPopathies, we identified MMP9 upregulation as a common feature of six pathogenic COMP variants that do not induce a prominent UPR. We further show that the archetypal p.V194D matrilin-3 MED variant (which causes MED) does not induce MMP9 expression, suggesting that MMP9 upregulation could serve as a specific marker of COMPopathies in vitro.

Bacteria must maintain the ability to modify and repair the peptidoglycan layer without jeopardising its essential functions in cell shape, cellular integrity and intermolecular interactions. A range of new experimental techniques is bringing an advanced understanding of how bacteria regulate and achieve peptidoglycan synthesis, particularly in respect of the central role played by complexes of Sporulation, Elongation or Division (SEDs) and class B penicillin-binding proteins required for cell division, growth and shape. In this review we highlight relationships implicated by a bioinformatic approach between the outer membrane, cytoskeletal components, periplasmic control proteins, and cell elongation/division proteins to provide further perspective on the interactions of these cell division, growth and shape complexes. We detail the network of protein interactions that assist in the formation of peptidoglycan and highlight the increasingly dynamic and connected set of protein machinery and macrostructures that assist in creating the cell envelope layers in Gram-negative bacteria.

Federal health agency leaders describe plans to develop infrastructure for generating high-quality evidence to improve care. They argue that it will be necessary to embed research in clinical care, create interoperable research data networks, and apply new research methods. Making better choices about health and health care requires the best possible evidence. Unfortunately, many of the decisions made today in our health care system are not supported by high-quality evidence 1 – 4 derived from randomized, controlled trials or well-designed observational studies. But as rich, diverse sources of digital data become widely available for research and as analytical tools continue to grow in power and sophistication, the research and health care communities now have the opportunity to quickly and efficiently generate the scientific evidence needed to support improved decision making about health and health care. The pursuit of high-quality, data-driven evidence . . .

IntroductionDespite the profound burden of disease, a strategic global response to optimise musculoskeletal (MSK) health and guide national-level health systems strengthening priorities remains absent. Auspiced by the Global Alliance for Musculoskeletal Health (G-MUSC), we aimed to empirically derive requisite priorities and components of a strategic response to guide global and national-level action on MSK health.MethodsDesign: mixed-methods, three-phase design.Phase 1: qualitative study with international key informants (KIs), including patient representatives and people with lived experience. KIs characterised the contemporary landscape for MSK health and priorities for a global strategic response.Phase 2: scoping review of national health policies to identify contemporary MSK policy trends and foci.Phase 3: informed by phases 1–2, was a global eDelphi where multisectoral panellists rated and iterated a framework of priorities and detailed components/actions.ResultsPhase 1: 31 KIs representing 25 organisations were sampled from 20 countries (40% low and middle income (LMIC)). Inductively derived themes were used to construct a logic model to underpin latter phases, consisting of five guiding principles, eight strategic priority areas and seven accelerators for action.Phase 2: of the 165 documents identified, 41 (24.8%) from 22 countries (88% high-income countries) and 2 regions met the inclusion criteria. Eight overarching policy themes, supported by 47 subthemes, were derived, aligning closely with the logic model.Phase 3: 674 panellists from 72 countries (46% LMICs) participated in round 1 and 439 (65%) in round 2 of the eDelphi. Fifty-nine components were retained with 10 (17%) identified as essential for health systems. 97.6% and 94.8% agreed or strongly agreed the framework was valuable and credible, respectively, for health systems strengthening.ConclusionAn empirically derived framework, co-designed and strongly supported by multisectoral stakeholders, can now be used as a blueprint for global and country-level responses to improve MSK health and prioritise system strengthening initiatives.

Active bone-conducting hearing devices (aBCHD; e.g., MEDEL Bonebridge® (BB)) and active middle ear implants (aMEI; e.g., MEDEL Vibrant Soundbridge® (VSB)) use radio frequency transmission to send information from an external microphone and sound processor to an internally implanted transducer. These devices potentially have an advantage over devices with percutaneous links because the skin is closed over the implantable components, which should reduce the risk of skin problems and infection. On the other hand, surgical procedures are more complex, with a greater risk of damage due to surgery. The objectives of this research were to quantify the reliability and long-term survival of MEDEL VSB and BB devices, determine the adverse and serious adverse device-related complications, and consider associated causes. A multi-center observational retrospective and prospective study was conducted at eleven auditory implant centers in the United Kingdom. Data was collected using a surgical questionnaire and audiological reports. Data were obtained from patient notes or from prospective cases that had a minimum follow-up of one year post-implant. Consecutive patient records were reviewed. Datasets from 109 BB and 163 VSB were reviewed. Of these, 205 were retrospective case note reviews, and 67 were prospective cases. The mean follow-up was 4 and 6 years, respectively, for BB and VSB. Kaplan–Meier Survival analyses indicated that the BB survival was 97% and 93.3% at 1 and 5 years, respectively, and the VSB was 92.1% and 87% at the same time points. This is a large cohort study for the field and has indicated that BB and VSB are safe interventions. Care should be taken to monitor magnet strength in the first few months. For the majority of device-related effects, there was no apparent association with etiology. However, an interesting pattern emerged for individuals who exhibited an inflammatory response, e.g., adhesions or device extrusion, and those with a history of chronic suppurative otitis media. This should be considered in future work and is not surprising given that many VSB recipients have a complicated hearing history, often associated with otitis media.