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Radiotherapy (XRT) is often utilized to improve the immune checkpoint blockade response in cancer management. Such combination treatment can enhance the abscopal effect, facilitating a prolonged and durable systemic response. However, despite intense research efforts, only a minority of patients respond to this approach, and novel strategies to increase the abscopal effect are urgently needed. Here, the development of an intratumoral (i.t.) injectable nanofiber (NF)-based tumor immune niche (TIN) that converts XRT-treated tumors into an in situ cancer vaccine, eliciting robust systemic antitumor immunity, is reported. This NF-based immune niche incorporates redox-degradable anti-CTLA-4 (α-CTLA-4) nanogels (NGs) and interleukin-2 (IL-2) NGs for controlled release in hypoxic irradiated tumors, reversing the immunosuppressive tumor microenvironment into a pro-inflammatory microenvironment, and expanding the tumor-infiltrating CD8 + T cell population. Additionally, it is functionalized with polyinosinic-polycytidylic acid (poly(I:C)) to promote antigen-presenting cell maturation and prime neoantigen-specific CD8 + T cells. In vitro studies demonstrate TIN's ability to prime antigen-specific CD8 + T cells and increase antigen-specific cell-killing efficiency under in vitro immunosuppressive conditions. In vivo studies confirm TIN's ability to elicit robust systemic anticancer activity in mouse melanoma and colorectal cancer models without inducing severe immune-related adverse events., (© 2024 Wiley‐VCH GmbH.)

As a chronic autoinflammatory condition, ulcerative colitis is often managed via systemic immunosuppressants. Here we show, in three mouse models of established ulcerative colitis, that a subcutaneously injected colon-specific immunosuppressive niche consisting of colon epithelial cells, decellularized colon extracellular matrix and nanofibres functionalized with programmed death-ligand 1, CD86, a peptide mimic of transforming growth factor-beta 1, and the immunosuppressive small-molecule leflunomide, induced intestinal immunotolerance and reduced inflammation in the animals' lower gastrointestinal tract. The bioengineered colon-specific niche triggered autoreactive T cell anergy and polarized pro-inflammatory macrophages via multiple immunosuppressive pathways, and prevented the infiltration of immune cells into the colon's lamina propria, promoting the recovery of epithelial damage. The bioengineered niche also prevented colitis-associated colorectal cancer and eliminated immune-related colitis triggered by kinase inhibitors and immune checkpoint blockade., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Multiple Sclerosis (MS) is an autoimmune condition targeting the central nervous system (CNS) characterized by focal demyelination with inflammation, causing neurodegeneration and gliosis. This is accompanied by a refractory period in relapsing MS or chronic progression in primary progressive MS. Current MS treatments target disease relapses and aim to reduce further demyelination and disability. These include the treatment of acute exacerbations through global immunomodulation upon corticosteroid administration, which are accompanied by adverse reactions. Disease modifying therapies (DMTs) which provide targeted immunosuppression of T and B cells, and sequestration of leukocytes out of CNS, have led to further improvements in demyelination prevention and disease burden reduction. Despite their efficacy, DMTs are ineffective in remyelination, pathology reversal and have minimal effects in progressive MS. The advent of modern biomedical engineering approaches in combination with a better understanding of MS pathology, has led to the development of novel, regenerative approaches to treatment. Such treatments utilize neural stem cells (NSCs) and can reduce disease relapses and reverse damage caused by the disease through localized tissue regeneration. While at initial stages, pre-clinical and clinical studies utilizing NSCs and immune modulation have shown promising outcomes in tissue regeneration, creating a potential new era in MS therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Andrew Z. Wang has patent ENGINEERED CELLS FUNCTIONALIZED WITH IMMUNE CHECKPOINT MOLECULES AND USES THEREOF issued to The University of North Carolina at Chapel Hill. Kin Man Au has patent ENGINEERED CELLS FUNCTIONALIZED WITH IMMUNE CHECKPOINT MOLECULES AND USES THEREOF pending to The University of North Carolina at Chapel Hill. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Family group conferences (FGCs) in child welfare bring immediate and wider family members together to decide on the best way to meet a child's needs. Unlike professionally led meetings, the aim is for decisions to be made by or with family members. Qualitative and mixed-method research with FGC participants tends to show positive experiences: most participants feel their voices are heard; FGCs facilitate family-driven solutions and closer relationships-within families and with social workers. Although there is existing literature on FGCs, there is a paucity of robust comparative UK evaluations, i.e., randomised controlled trials or quasi-experimental studies. Comparative studies internationally have focused on a narrow range of outcomes, not recognised the importance of context, and paid little attention to the quality of delivery. Some qualitative studies have considered process and context but there is scant measurement of these. The aims of this study are, firstly, to establish how FGCs improve outcomes for families and what factors vary their quality, and, secondly, to assess longer-term outcomes in terms of service use and associated costs., Methods: Given the importance of process and context, evaluation informed by realist and complex systems approaches is needed. This multi-method evaluation includes a survey of FGC services in all UK local authorities (n = 212) to map service provision; co-design of programme theory and evaluation measures with family members who have experienced an FGC (n = 16-24) and practitioners (n = 16-24) in two sites; a prospective single-arm study of FGC variability and outcomes after six months; and comparison of service use and costs in FGC participants (n≥300 families) and a control group (n≥1000) after two years using a quasi-experiment., Discussion: This is a pragmatic evaluation of an existing intervention, to identify what mechanisms and contexts influence effective process and longer-term outcomes. The study is registered with Research Registry (ref. 7432)., Competing Interests: Jonathan Scourfield is a trustee of the Family Rights Group, a charity that promotes better family participation in the child welfare process, and family group conferences as one way of achieving this. This non-financial interest does not alter our adherence to PLOS ONE policies on sharing data and materials, with the provisos in the data sharing statement., (Copyright: © 2024 Scourfield et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Failure to establish immune tolerance leads to the development of autoimmune disease. The ability to regulate autoreactive T cells without inducing systemic immunosuppression represents a major challenge in the development of new strategies to treat autoimmune disease. Here, a translational method for bioengineering programmed death-ligand 1 (PD-L1)- and cluster of differentiation 86 (CD86)-functionalized mouse Schwann cells (SCs) to prevent and ameliorate multiple sclerosis (MS) in established mouse models of chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE) is described. It is shown that the intravenous (i.v.) administration of immune checkpoint ligand functionalized mouse SCs modifies the course of disease and ameliorates EAE. Further, it is found that such bioengineered mouse SCs inhibit the differentiation of myelin-specific helper T cells into pathogenic T helper type-1 (T h 1) and type-17 (T h 17) cells, promote the development of tolerogenic myelin-specific regulatory T (T reg ) cells, and resolve inflammatory central nervous system microenvironments without inducing systemic immunosuppression., (© 2021 Wiley-VCH GmbH.)

Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by autoreactive T cells targeting the insulin-producing beta (β) cells. Despite advances in insulin therapy, T1DM still leads to high morbidity and mortality in patients. A key focus of T1DM research has been to identify strategies that re-establish self-tolerance and suppress ongoing autoimmunity. Here, we describe a strategy that utilizes pretargeting and glycochemistry to bioengineer β cells in situ to induce β-cell-specific tolerance. We hypothesized that β-cell-targeted Ac 4 ManNAz-encapsulated nanoparticles deliver and establish β cells with high levels of surface reactive azide groups. We further theorized that administration of a dibenzylcyclooctyne (DBCO)-functionalized programmed death-ligand 1 immunoglobulin fusion protein (PD-L1-Ig) can be readily conjugated to the surface of native β cells. Using nonobese diabetic (NOD) mice, we demonstrated that our strategy effectively and selectively conjugates PD-L1 onto β cells through bioorthogonal stain-promoted azide-alkyne cycloaddition. We also showed that the in vivo functionalized β cells simultaneously present islet-specific antigen and PD-L1 to the engaged T cells, reversing early onset T1DM by reducing IFN-gamma expressing cytotoxic toxic T cells and inducing antigen-specific tolerance.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that results from autoreactive T cells destroying insulin-producing pancreatic beta (β) cells. The development of T1DM is associated with the deficiency of co-inhibitory immune checkpoint ligands (e.g., PD-L1, CD86, and Gal-9) in β cells. Here, a new translational approach based on metabolic glycoengineering and bioorthogonal click chemistry, which bioengineers β cells with co-inhibitory immune checkpoint molecules that induce antigen-specific immunotolerance and reverse early-onset hyperglycemia is reported. To achieve this goal, a subcutaneous injectable acellular pancreatic extracellular matrix platform for localizing the bioengineered β cells while creating a pancreas-like immunogenic microenvironment, in which the autoreactive T cells can interface with the β cells, is devised., (© 2021 Wiley-VCH GmbH.)

Chemoradiotherapy with cisplatin and etoposide is a curative management regimen for both small and non-small cell lung cancers. While the treatment regimen is effective, it also has a high toxicity profile. One potential strategy to improve the therapeutic ratio of chemoradiation is to utilize nanotherapeutics. Nanoparticle formulation of cisplatin and etoposide, however, is challenging due to the significant mismatch in chemical properties of cisplatin and etoposide. Herein we report the formulation of a polymeric nanoparticle formulation of cisplatin and etoposide using a prodrug approach. We synthesized a hydrophobic platinum prodrug, which was then co-delivered with etoposide using a nanoparticle. Using mouse models of lung cancer, we demonstrated that dual-drug loaded nanoparticles are significantly more effective than small molecule chemotherapy in chemoradiotherapy. These results support further investigation of nanoparticle-based drug formulations of combination chemotherapies and the use of nanotherapeutics in chemoradiotherapy. STATEMENT OF SIGNIFICANCE: The treatment of lung cancer often involves a combination of chemotherapy and radiation. While it can be effective, it also has a high toxicity profile. Preferential delivery of chemotherapeutics to the tumor while avoiding normal tissue would improve efficacy and lower toxicity. While this is challenging with conventional drug delivery technologies, nanotechnology offers a unique opportunity. In this study, we have engineered nanoparticles that are loaded with combination chemotherapeutics and showed such nanotherapeutics are more effective and less toxic than free chemotherapeutics in chemoradiotherapy. Our work highlights the importance and potential of nanoformulations of combination chemotherapy in chemoradiotherapy and cancer treatment. This approach can be translated clinically and it can have a significant impact on cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AZW is cofounder of Capio Biosciences and Archimmune Therapeutics. Neither is relevant to this work., (Copyright © 2021. Published by Elsevier Ltd.)

Activation of the innate immune system and natural killer (NK) cells has been a key effort in cancer immunotherapy research. Here, we report a nanoparticle-based trispecific NK cell engager (nano-TriNKE) platform that can target epidermal growth factor receptor (EGFR)-overexpressing tumors and promote the recruitment and activation of NK cells to eradicate these cancer cells. Moreover, the nanoengagers can deliver cytotoxic chemotherapeutics to further improve their therapeutic efficacy. We have demonstrated that effective NK cell activation can be achieved by the spatiotemporal coactivation of CD16 and 4-1BB stimulatory molecules on NK cells with nanoengagers, and the nanoengagers are more effective than free antibodies. We also show that biological targeting, either through radiotherapy or EGFR, is critical to the therapeutic effects of nanoengagers. Last, EGFR-targeted nanoengagers can augment both NK-activating agents and chemotherapy (epirubicin) as highly effective anticancer agents, providing robust chemoimmunotherapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin's lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)-based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR-expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Non-Hodgkin lymphoma is one of the most common types of cancer. Relapsed and refractory diseases are still common and remain significant challenges as the majority of these patients eventually succumb to the disease. Herein, we report a translatable concurrent chemo-immuno-radiotherapy (CIRT) strategy that utilizes fully synthetic antibody mimic Selective High-Affinity Ligand (SHAL)-functionalized doxorubicin-encapsulated nanoparticles (Dox NPs) for the treatment of human leukocyte antigen-D related (HLA-DR) antigen-overexpressed tumors. We demonstrated that our tailor-made antibody mimic-functionalized NPs bound selectively to different HLA-DR-overexpressed human lymphoma cells, cross-linked the cell surface HLA-DR, and triggered the internalization of NPs. In addition to the direct cytotoxic effect by Dox, the internalized NPs then released the encapsulated Dox and upregulated the HLA-DR expression of the surviving cells, which further augmented immunogenic cell death (ICD). The released Dox not only promotes ICD but also sensitizes the cancer cells to irradiation by inducing cell cycle arrest and preventing the repair of DNA damage. In vivo biodistribution and toxicity studies confirm that the targeted NPs enhanced tumor uptake and reduced systemic toxicities of Dox. Our comprehensive in vivo anticancer efficacy studies using lymphoma xenograft tumor models show that the antibody-mimic functional NPs effectively inhibit tumor growth and sensitize the cancer cells for concurrent CIRT treatment without incurring significant side effects. With an appropriate treatment schedule, the SHAL-functionalized Dox NPs enhanced the cell killing efficiency of radiotherapy by more than 100% and eradicated more than 80% of the lymphoma tumors., Competing Interests: The authors declare the following competing financial interest(s): The University of North Carolina at Chapel Hill and SHAL Technologies, Inc. filed a patent to protect the IP for therapeutic applications of SHAL-functionalized nanoparticles.

Introduction: A point prevalence survey was conducted to study the epidemiology of and risk factors associated with multidrug-resistant organism carriage among residents in residential care homes for the elderly (RCHEs)., Methods: A total of 20 RCHEs in Hong Kong were selected by stratified single-stage cluster sampling. All consenting residents aged ≥65 years from the selected RCHEs were surveyed by collection of nasal swab, axillary swab, rectal swab or stool on one single day for each home. Specimens were cultured and analysed for methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Acinetobacter (MDRA, defined as concomitant resistant to fluoroquinolones, carbapenems, aminoglycosides, cephalosporins and beta-lactam with or without beta-lactamase inhibitors), vancomycin-resistant Enterococcus (VRE), and carbapenemase-producing Enterobacteriaceae (CPE). One third of the MRSA-positive samples were selected at random for molecular typing; all positive MDRA, VRE and CPE samples were tested for molecular typing. Demographic and health information of residents including medical history, history of hospitalisation, antimicrobial usage, and use of indwelling catheters were collected to determine any associated risk factors., Results: Samples of 1028 residents from 20 RCHEs were collected. Prevalence of MRSA was estimated as 30.1% (95% confidence interval [CI]=25.1%-35.6%) and MDRA 0.6% (95% CI=0.1%-4.1%). No residents carried VRE nor CPE. Residents living in privately run RCHEs were associated with MRSA carriage. Non-Chinese residents were associated with MRSA carriage with borderline significance., Conclusions: This survey provided information about multidrug-resistant organism carriage among RCHE residents. This information will enable us to formulate targeted surveillance and control strategies for multidrug-resistant organisms.

Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Non-Hodgkin lymphoma (NHL) is one of the most common types of hematologic malignancies. Pretargeted radioimmunotherapy (PRIT), the sequential administration of a bispecific antibody-based primary tumor-targeting component followed by a radionucleotide-labeled treatment effector, has been developed to improve the treatment efficacy and to reduce the side effects of conventional RIT. Despite the preclinical success of PRIT, clinical trials revealed that the immunogenicity of the bispecific antibody as well as the presence of competing endogenous effector molecules often compromised the treatment. One strategy to improve PRIT is to utilize bio-orthogonal ligation reactions to minimize immunogenicity and improve targeting. Herein, we report a translatable pretargeted nanoradioimmunotherapy strategy for the treatment of NHL. This pretargeting system is composed of a dibenzylcyclooctyne (DBCO)-functionalized anti-CD20 antibody (α-CD20) tumor-targeting component and an azide- and yttrium-90-( 90 Y) dual-functionalized dendrimer. The physicochemical properties of both pretargeting components have been extensively studied. We demonstrated that an optimized dual-functionalized dendrimer can undergo rapid strain-promoted azide-alkyne cycloaddition with the DBCO-functionalized α-CD20 at the physiological conditions. The treatment effector in our pretargeting system can not only selectively deliver radionucleotides to the target tumor cells but also increase the complement-dependent cytotoxicity of α-CD20 and thus enhance the antitumor effects, as justified by comprehensive in vitro and in vivo studies in mouse NHL xenograft and disseminated models.

Chemoradiotherapy (CRT) with paclitaxel (PTX) and cisplatin (CP) is part of the standard of care for patients with locally advanced non-small cell lung cancer (NSCLC). Despite the high treatment intensity, many patients still develop local recurrence after treatment. Thus, there is a strong need to further improve CRT for lung cancer. One strategy is to co-deliver cytotoxic chemotherapy agents using biocompatible nanoparticles (NPs) which can limit off-target tissue toxicity and improve therapeutic efficacy. Herein, we report the development of dual-drug loaded nanoformulations that improve the efficacy of CRT for NSCLC by co-encapsulation of cisplatin (CP) and PTX in PLGA-PEG NPs. Mice bearing NSCLC xenografts given the dual-drug loaded NPs during CRT showed greater inhibition of tumor growth than free drug combinations or combinations of single-drug loaded NPs. These results indicate that using a NP co-delivery strategy for this common CRT regimen may improve clinical responses in NSCLC patients.

Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of this novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80-85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Collagen IV-targeting peptide-conjugated basement membrane-targeting nanoparticles are successfully engineered to identify early-stage blood vessel injury induced by high-dose radiotherapy., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Combining molecularly targeted agents and chemotherapeutics is an emerging strategy in cancer treatment. We engineered sub-50 nm diameter diblock copolymer nanoparticles (NPs) that can sequentially release wortmannin (Wtmn, a cell signaling inhibitor) and docetaxel (Dtxl, genotoxic anticancer agent) to cancer cells. These NPs were studied in chemoradiotherapy, an important cancer treatment paradigm, in the preclinical setting. We demonstrated that Wtmn enhanced the therapeutic efficacy of Dtxl and increased the efficiency of radiotherapy (XRT) in H460 lung cancer and PC3 prostate cells in culture. Importantly, we showed that NPs containing both Wtmn and Dtxl release the drugs in a desirable sequential fashion to maximize therapeutic efficacy in comparison to administering each drug alone. An in vivo toxicity study in a murine model validated that NPs containing both Dtxl and Wtmn do not have a high toxicity profile. Lastly, we demonstrated that Dtxl/Wtmn-coencapsulated NPs are more efficient than each single-drug-loaded NPs or a combination of both single-drug-loaded NPs in chemoradiotherapy using xenograft models. Histopathological studies and correlative studies support that the improved therapeutic efficacy is through changes in signaling pathways and increased tumor cell apoptosis. Our findings suggest that our nanoparticle system led to a dynamic rewiring of cellular apoptotic pathways and thus improve the therapeutic efficiency., Competing Interests: The authors declare no competing financial interest.

Objective: To evaluate the effectiveness of ultrasound-guided phenol nerve block in the treatment of severe hip adductor spasticity in long-term care patients., Methods: Double-blind placebo-controlled trial with a 9-month follow-up period., Setting: A 250-bed long-term care hospital and the infirmary units of 5 regional hospitals., Participants: Twenty-six long-term care patients with bilateral severe chronic hip adductor spasticity affecting perineal hygiene and nursing care., Interventions: Patients were randomized to 2 groups that received ultrasound and electrical stimulator guided obturator nerve block using either 5% phenol in aqueous solution or saline., Main Outcome Measures: The primary outcome measure was the Modified Ashworth Scale, which reflected the severity of hip adductor spasticity. Secondary outcomes included Goal Attainment Scale (GAS), hygiene score, distances between the knees during fast and slow passive hip abductions; passive range of movement for hip extension and knee extension. Pain was assessed using the Pain Assessment in Advanced Dementia Scale., Results: Twenty-six patients (7 males; mean age = 77, standard deviation = 14) were recruited. At week 6 post-injection, 12/16 (75%) patients in the treatment group vs 1/10 (10%) patients in the control group had at least 1-point reduction of Modified Ashworth Scale (P = .001) on both hip adductors. There was also significant improvement in the GAS, as well as the hygiene score, resting position, and distances between the knees during fast and slow passive hip abductions in the treatment group, which persisted until week 36. No significant difference in the Pain Assessment in Advanced Dementia Scale was found between the 2 groups. No serious phenol nerve block related adverse effects were reported., Conclusions: Obturator neurolysis with 5% aqueous phenol as guided by both ultrasound and electrical stimulation can safely and effectively reduce hip adductor spasticity, thus, improving hygiene scores and patient-centered outcomes measured by the GAS in affected long-term care residents., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to promote quality end-of-life (EOL) care for nursing home residents, through the establishment of advance care plan (ACP) and introduction of a new care pathway. This pathway bypassed the emergency room (ER) and acute medical wards by facilitating direct clinical admission to an extended-care facility., Design: An audit on a new clinical initiative that entailed the Community Geriatrics Outreach Service, ER, acute medical wards, and an extended-care facility during winter months in Hong Kong., Methods: The participants were older nursing home residents enrolled in an EOL program. We monitored the ratio of clinical to emergency admissions, ACP compliance rate, average length of stay (ALOS) in both acute hospital and an extended-care facility, and mortality rates., Results: A total of 76 patients were hospitalized from January to March 2013. Of them, 30 (39%) were directly admitted to the extended-care facility, either through the liaison of Community Geriatrics Outreach Service (group A, 19/76, 25%) or transferred from the ER (group B, 11/76, 14%). The remaining 46 patients (group C, 61%) were admitted via the ER to acute medical wards following the usual pathway, followed by transfer to an extended-care facility if indicated. The ACP compliance rate was nearly 100%. In the extended-care unit, groups A and C had similar ALOS of 11.8 and 11.1 days, respectively, whereas group B had a shorter stay of 7.6 days. The ALOS of group C in acute medical wards was 3.5 days. The in-hospital mortality rates were comparable in groups A and C of 26% and 28%, respectively, whereas group B had a lower mortality rate of 18%., Conclusions: Nearly 40% of EOL patients could be managed entirely in an extended-care setting without compromising the quality of care and survival. A greater number of patients may benefit from the EOL program by improving the collaboration between community outreach services and ER; and extending hours for direct clinical admission to an extended-care facility., (Copyright © 2014 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: SSc is associated with an increased prevalence of atherosclerosis (ATS). This study assessed the prevalence of subclinical ATS as measured by carotid US and explored serum proteins to identify potential biomarkers of SSc-ATS., Methods: Forty-six SSc female patients and 46 age- and ethnicity-matched controls underwent carotid US to assess the presence of plaque and carotid intima media thickness (CIMT). Abstracted data included demographics, ATS risk factors and serum measurements [cholesterol, proinflammatory high-density lipoprotein (piHDL), CRP, lipoproteins]. Serum cytokines/proteins analyses included circulating type I IFN activity by quantifying IFN-inducible genes, soluble junctional adhesion molecule A (sJAM-A) and 100 serum proteins by using a microplate-based multiplex platform. Proteins significant at P < 0.05 on bivariate analyses for the presence of plaque were used to develop a composite measure., Results: Patients with SSc had more plaque (45.6% vs 19.5%, P = 0.01) but similar CIMT compared with controls. Multiplex analysis detected significant associations between serum proteins of inflammation, vasculopathy and fibrosis with ATS in SSc, including IL-2, IL-6, CRP, keratinocyte growth factor, intercellular adhesion molecule 1, endoglin, plasminogen activator inhibitor 1 and insulin-like growth factor binding protein 3 associated with carotid plaque. Myeloid progenitor inhibitory factor 1, serum amyloid A, thrombomodulin, N-terminal pro-brain natriuretic peptide (BNP), and Clara cell secretory protein 16 kD correlated with CIMT. The median composite score for the plaque group was 6 and for the no plaque group it was 2 (P < 0.0001)., Conclusion: Patients with SSc have a higher prevalence of carotid plaque than matched controls, and patients with SSc-plaque vs patients without plaque have elevated serum proteins implicated in both vasculopathy and fibrosis. Further studies are needed to evaluate the role of these proteins in SSc compared with healthy controls.

Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases.

We report the use of near-infrared (NIR) radiation to trigger the irreversible flocculation of poly(oligo(ethylene glycol) methacrylate)-stabilised polypyrrole nanoparticles in physiological buffer.

Optical coherence tomography (OCT) is a modern high resolution subsurface medical imaging technique. Herein we describe: (i) the synthesis of a thiophene-functionalized oligo(ethylene glycol) methacrylate (OEGMA)-based statistical copolymer, denoted poly(2TMOI-OEGMA); (ii) the preparation of sterically-stabilized polypyrrole (PPy) nanoparticles of approximately 60 nm diameter; (iii) the evaluation of these nanoparticles as a NIR-absorbing optical contrast agent for high-resolution OCT imaging. We show that poly(2TMOI-OEGMA)-stabilized PPy nanoparticles exhibit similar optical properties to poly(vinyl alcohol) (PVA)-stabilized PPy nanoparticles of comparable size prepared using commercially available PVA. Spectroscopic measurements and Mie calculations indicate that both types of PPy nanoparticles strongly absorb NIR radiation above 1000 nm, suggesting their potential use as OCT contrast agents. In vitro OCT studies indicate that both types of PPy nanoparticles reduce NIR backscattering within homogeneous intralipid tissue phantoms, offering almost identical contrast performance in this medium. However, PVA-stabilized PPy nanoparticles became colloidally unstable when dispersed in physiological buffer and immersed in a solid biotissue phantom and hence failed to generate a strong contrast effect. In contrast, the poly(2TMOI-OEGMA)-stabilized PPy nanoparticles remained well-dispersed and hence exhibited a strong rapid onset contrast effect within the biotissue phantom under identical physiological conditions. Ex vivo studies performed on excised chicken and porcine skin tissue demonstrated that topical administration of a low concentration of poly(2TMOI-OEGMA)-stabilized PPy nanoparticles rapidly enhances OCT image contrast in both cases, allowing key tissue features to be readily identified., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: A knowledge transfer program was carried out to improve knowledge in end-of-life care staff at all levels in residential care homes for the elderly, using a model similar to that developed for a non-acute care hospital setting., Methods: The program consisted of a series of seminars and on-site sharing sessions held in the hospital providing outreach support to residential care homes for the elderly (RCHEs), as well as case discussions in the RCHEs. Evaluation was carried out using a knowledge assessment questionnaire before and after the initiative, as well as recording RCHE staff feedback and in-depth interviews with selected residents and their family members., Results: Knowledge gaps among RCHE staff existed in the areas of mortality relating to chronic diseases, pain and use of analgesics, feeding tubes, dysphagia, sputum management, and attitudes towards end-of-life care issues, which improved after the program. From the qualitative study, RCHE staff highlighted knowledge and service gaps, issues relating to use of feeding tubes and refusal to eat, lack of confidence in managing the dying process, application of Advance Care Plan (ACP) in the RCHE setting, and the need for training in these areas. Residents and family members highlighted the preference for death over suffering, planning for death, misconceptions about life-sustaining treatments and the advance directive (AD) document, and service gaps in advance care planning., Conclusion: Considerable knowledge and service gaps exist among staff and residents of RCHEs, which can be improved by the hospital geriatric team providing services to RCHEs.

We report an uncommon mitochondrial variant in a baby girl with congenital hyperlactataemia and Leigh syndrome. The patient presented with a single episode of generalised clonic convulsion at day 19, and was found to have isolated and persistent hyperlactataemia ranging from 3.34 to 9.26 mmol/L. She had elevated serum lactate-to-pyruvate ratios of up to 35 and high plasma alanine concentration, indicative of a respiratory chain defect. At the age of 8 months, she developed evolving neurological and imaging features compatible with Leigh syndrome. Genetic testing for common mitochondrial DNA mutations, large mitochondrial DNA deletions, and selected nuclear genes was negative. Further analysis of lymphocyte mitochondrial DNA by sequencing revealed an uncommon heteroplasmic variant, NC&#95;012920.1(MT-ND5):m.13094T>C (p.Val253Ala), which was previously shown to reduce complex I activity. In patients in whom there was a high suspicion of mitochondrial disorder, entire mitochondrial DNA analysis may be warranted if initial screening of common mitochondrial DNA mutations is negative.

There is increasing interest in using serum albumin, the most abundant plasma protein, as a stabilizing agent in the context of nanomedicine. Using poly(vinyl amine)-stabilized polypyrrole nanoparticles as an example, we report a facile generic route to prepare serum albumin-nanoparticle conjugates via heterocoagulation. Time-resolved dynamic light scattering (DLS), disk centrifuge photosedimentometry (DCP), and circular dichroism (CD) spectroscopy studies confirm that bovine serum albumin (BSA) adsorbs rapidly onto the cationic poly(vinyl amine)-stabilized polypyrrole nanoparticles and suggest that the initial well-defined protein coronal is subsequently cross-linked via thiol-disulfide exchange. These BSA-nanoparticle conjugates were further characterized by X-ray photoelectron spectroscopy (XPS), aqueous electrophoresis, field emission scanning electron microscopy (FE SEM), and transmission electron microscopy (TEM). They exhibit excellent long-term colloidal stability under physiological conditions without further purification, suggesting strong irreversible adsorption by the BSA. Protein adsorption appears to be co-operative and both thermodynamic and mechanistic aspects were examined via aqueous electrophoresis, DCP, and DLS studies.

A near-infrared (NIR) absorbing contrast agent based on polypyrrole nanoparticles is described. Quantitative optical coherence tomography studies on tissue phantoms and Mie scattering calculations indicate their potential application for early-stage cancer diagnosis., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Kearns-Sayre syndrome is a rare disorder often caused by mitochondrial DNA rearrangement. The most commonly reported mitochondrial DNA deletion is 4977 bp in size spanning nucleotides 8469 and 13447. The clinical signs of Kearns-Sayre syndrome include chronic progressive external ophthalmoplegia, retinitis pigmentosa, heart block and cerebellar ataxia, as well as other heterogeneous manifestations including neuromuscular problems and endocrine disorders. Cardiac conduction defects can develop insidiously, leading to sudden death sometimes if not promptly recognised. This report focuses on the diagnosis of Kearns-Sayre syndrome in a Chinese girl who presented initially with short stature, delayed puberty, insidious onset of ptosis and later with typical features of Kearns-Sayre syndrome including complete heart block. Genetic analysis disclosed a novel 7.2 kilobases deletion in muscle tissue. Mitochondrial diseases have heterogeneous phenotypes and mutational analysis has proven to be an effective tool for confirming the diagnosis.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset hereditary condition caused by mutations in the Notch3 gene. A Chinese man was studied., Method: Electronic microscopy examination of skin biopsy. The Notch3 gene was screened for mutations by polymerase chain reaction and direct DNA sequencing., Results: Electronic microscopy showed the presence of deposits of granular osmiophilic material in dermal capillaries in the index patient. A novel heterozygous C271F in exon 6 was detected in the index patient. This heterozygous C271F mutation was also detected in the asymptomatic elder son but was not detected in the asymptomatic wife of the patient. Allele specific amplification showed that C271F was not detected in 100 normal subjects., Conclusion: We established the molecular basis of CADASIL in a Chinese man. Mutation detection assay provides a reliable method for confirming the diagnosis of CADASIL.

We report a sporadic large-scale mitochondrial deletion in a paediatric patient with Fanconi's syndrome. Renal biopsy disclosed chronic interstitial nephritis. Ultrastructural examination of the renal tissue showed many giant atypical mitochondria. Histochemical stains revealed markedly reduced cytochrome c oxidase (COX). Genetic analysis disclosed a novel mitochondrial deletion of 7.3 kb in both peripheral blood and renal tissue. Mitochondrial diseases have heterogeneous clinical phenotypes; mutation analysis has proved to be an effective tool in confirming the diagnosis.

Chronic osteomyelitis with subperiosteal new bone formation results from periosteal reaction to chronic inflammatory/infectious stimulation. In the maxillofacial region, it has traditionally been termed Garrè's osteomyelitis with proliferative periostitis and more recently periostitis ossificans. The term Garrè's osteomyelitis has been regarded as a misnomer by many authors in the recent literature. The term chronic osteomyelitis with proliferative periostitis, although cumbersome, is considered to be the most accurate description of the pathology. It usually affects the mandible of young patients secondary to dental infection. Management involves removal of the source of infection and antibiotic treatment. We present an unusual case of chronic osteomyelitis with proliferative periostitis affecting the mandible of a 12-year-old patient. The source of infection was related to the developing lower left third molar, which had apparently no communication with the oral cavity.

We report a 39-year-old woman with spinocerebellar ataxia type 6. She presented with ataxia and a 3-year history of progressive ataxia and recurrent falls. There was no relevant family history. Genetic tests revealed an expanded allele of 24 CAG repeats at the spinocerebellar ataxia type 6 locus. This appears to be the first case reported in Hong Kong. As genetic testing becomes more widely available and clinical awareness increases, more such patients are expected to be diagnosed.

Background: Butyrylcholinesterase (BCHE) deficiency is characterized by prolonged apnea after the use of certain muscle relaxants with the genetic defect lying in the BCHE gene., Methods: Two Chinese patients with no serum BCHE activity were studied. The BCHE genes were screened for mutations by polymerase chain reaction and direct DNA sequencing., Results: Of the four mutations detected, two novel mutations were identified in the two patients, i.e., F474L, and an insertion of an adenine between nucleotide positions 395 and 396. This information was used to screen the immediate families of the patients for carrier status., Conclusions: We established the molecular basis of butyrylcholinesterase deficiency in two Chinese patients. The developed mutation detection assay provides a reliable method for identifying mutant BCHE carriers.

Objective: To assess the frequency and clinical features of different types of hereditary spinocerebellar ataxia in Hong Kong., Design: Cross-sectional study using a questionnaire and clinical examination, with the majority of the information retrospectively collected., Setting: Three regional hospitals, Hong Kong., Participants: All patients with spinocerebellar ataxia that was confirmed by molecular genetic tests between January 2001 and October 2003., Main Outcome Measures: History, latest physical examination results, clinical investigation results, and genetic profiles., Results: A total of 16 Chinese patients had received diagnoses of spinocerebellar ataxia. These patients had spinocerebellar ataxia type 1 (n=3), spinocerebellar ataxia type 3 (Machado-Joseph disease; n=12), and dentatorubro-pallidoluysian atrophy (n=1). The most common manifestation was ataxia (15/16), followed by pyramidal signs (12/16). Other features such as bulbar dysfunction, ophthalmoplegia, neuropathy, and cognitive impairment were present but variable., Conclusions: The clinical manifestations of different types of spinocerebellar ataxia overlap, and genetic study is necessary to confirm the diagnosis. The frequency of spinocerebellar ataxia type 3 is greater than that of other types among these Chinese patients. The age of onset of this type may correlate inversely with the number of CAG repeats.

Background: Diagnosis of tuberculous pleuritis is difficult because of its nonspecific clinical presentation and insufficient efficiency of traditional diagnostic methods. We investigated the use of adenosine deaminase (ADA) activity in tuberculous pleuritis diagnosis., Methods: We optimized a kinetic assay and retrospectively analysed 210 patients with exudative pleural effusions. Using the ROC curve, we determined the optimal cutoff for TB pleurisy., Results: One hundred forty-seven exudative samples were nontuberculous (non-TB) and 63 were tuberculous (TB). There was statistically significant difference (p<0.0001) between the means of pleural fluid ADA levels among the TB and non-TB populations. The disease prevalence of TB pleurisy in the studied population was 30%. The cutoff value for diagnosing TB effusions was >55.8 U/L, with a sensitivity of 87.3% (95% CI: 76.5-94.3%) and specificity of 91.8% (95% CI: 86.2-95.7%). The positive predictive value (PPV) was 82.1% and the negative predictive value (NPV) was 94.4%. A pleural fluid ADA value <16.81 IU/L suggests that a tuberculous effusion is highly unlikely (100% sensitive with 100% NPV and 0% negative likelihood ratio for a pleural fluid ADA level>/=16.81 U/L). In addition, the area under the ROC curve was 0.933 (S.E.=0.0230, 95% CI: 0.890-0.963)., Conclusion: Pleural fluid total ADA assay is a sensitive and specific test suitable for rapid diagnosis of TB pleurisy.

Purpose: To investigate the immediate and midterm results of carotid stenting for severe radiation-induced extracranial carotid artery disease., Methods: Between April 1998 and May 2002, 16 patients (15 men; mean age 64 +/- 8 years, range 48-72) presented with 18 severe radiation-induced carotid stenoses in the internal carotid artery (n=3), common carotid artery (n=7), and both vessels (n=8). Thirteen (76%) patients were symptomatic; the mean degree of carotid stenosis was 85% +/- 10% (range 70%-95%). An independent neurological specialist assessed perioperative neurological complications before and after treatment. The patients were followed prospectively for at least 12 months by clinical examination and serial duplex ultrasound scanning. Restenosis was defined as a diameter reduction >50%., Results: Of 18 stent procedures attempted (2 staged), 1 was abandoned owing to failure to pass the guidewire across a tight lesion (94% technical success by intent to treat). In the 17 successfully completed procedures, 17 Wallstents and 4 SMART stents were deployed with satisfactory anatomical results. One postoperative stroke occurred as a result of thromboembolism to the ipsilateral middle cerebral artery and led to hospital death (5.9% combined stroke and death rate). One transient ischemic attack occurred (11.6% neurological event rate). With a median 30-month follow-up (range 5-55), 3 (17.6%) recurrent stenoses (>50%) were detected on duplex scan; 1 repeat angioplasty was performed. No new neurological event has been detected., Conclusions: Carotid stenting may be performed in patients with irradiation-induced carotid stenosis with acceptable risks and midterm durability.

A 4-year-old boy presented with multiple tuberous xanthomata and a fasting plasma sterol concentration of 18.3 mmol/L, consisting primarily of cholesterol. Two months after changing from an unrestricted diet to a cholesterol-lowering diet, the plasma sterol concentration decreased to 4 mmol/L. Fasting plasma cholesterol levels for his father and mother were 7.3 mmol/L and 6.0 mmol/L, respectively. The degree and rapidity of the child's response to dietary control, together with the fasting cholesterol results of both parents suggested a diagnosis of sitosterolaemia. Gas chromatography and mass spectrometry of the patient's plasma sterol levels showed that the percentage of beta-sitosterol was raised at 12.76%, as was campesterol (6.26%), and stigmasterol (0.71%), confirming the diagnosis of sitosterolaemia. The addition of cholestyramine 4 g/day to a low sterol diet maintained the plasma sterol concentration at 4 to 5 mmol/L, and gradual regression of the xanthoma was observed. These findings indicate that a diagnosis of sitosterolaemia, a treatable cause of premature atherosclerosis, should be considered in children with severe hypercholesterolaemia whose plasma cholesterol level is highly responsive to dietary manipulation.

Kennedy's disease is an X-linked, neurodegenerative disorder, characterised by lower motor neuron syndrome. This report gives the clinical details of six male patients with Kennedy's disease diagnosed at Princess Margaret Hospital. Three were initially diagnosed with other neurological diseases, with the diagnosis of Kennedy's disease made after genetic testing. This hereditary disease should be considered in male patients with muscle weakness, particularly those with a presentation suggesting atypical motor neuron disease.

Dihydropyrimidine dehydrogenase deficiency is an inborn error of pyrimidine metabolism characterised by thymine-uraciluria, convulsive disorders and developmental delay in paediatric patients, and an increased risk of toxicity from 5-fluorouracil treatment. This report is of the first patient with dihydropyrimidine dehydrogenase deficiency diagnosed in Hong Kong. The patient was a 2-day-old male neonate of Pakistani origin who presented with convulsions. Diagnosis was made by gas chromatographic-mass spectrometric detection of thymine-uraciluria and by molecular detection of a G to A point mutation in a 5'-splicing site leading to skipping of exon 14 in the DPYD gene of chromosome location 1q22. The results showed that the patient and his mother were homozygous and the father heterozygous for the splice site mutation. The mother also had thymine-uraciluria but was clinically asymptomatic.