Evaluation of routine proximal bone analysis for microbiology and histopathology in diabetes-related foot infections and osteomyelitis.

PURPOSE: The value of proximal bone analysis for surgical clearance of infection remains debated. Real-world practice traditionally utilized proximal bone microbiology rather than histopathology to diagnose residual diabetes-related osteomyelitis of the foot (DFO) post-amputation. We assessed the concordance between proximal bone microbiology and histopathology in determining residual infection and their predictability for revision operation in DFO and diabetes-related foot infection (DFI). METHODOLOGY: A single-centre retrospective study was conducted between June and December 2020 at a tertiary institution. We recruited patients with diabetes mellitus who had minor amputations for DFO and DFI and analyzed their proximal bone microbiology, histopathology and outcomes at 6 months. RESULTS: Eighty-four patients were recruited; 64 (76.2%) were male. The mean age was 69.3 years. The mean HbA1c was 8.6%. Seventy-seven operations were performed for DFO and 17 for DFI. Negative microbiology showed complete concordance with histopathology; and none had revision operation (P = 0.99). Positive microbiology had 9.8% concordance with histopathology (P = 0.99). Positive histopathology was associated with a higher rate of revision operation (80% vs. 12.5%; P = 0.01). High preoperative C-reactive protein was associated with residual DFO (P = 0.02) and revision operation (P = 0.01). CONCLUSION: Positive histopathology was more reliable for determining significant residual DFO and predicting revision operation. Positive microbiology was valuable for guiding antibiotic selection. We suggest routine proximal bone analysis for both histopathology and microbiology to optimize the treatment of DFO and DFI.

When you hear hoofbeats, think horses before zebras - a case of recurrent small bowel obstructions with a twist.

Mechanical small bowel obstructions (SBOs) account for a considerable proportion of hospital admissions for acute abdominal pain. SBOs are most frequently caused by adhesions; and very few SBOs are associated with intraperitoneal devices. An 84-year-old man was admitted to our tertiary institution with recurrent SBOs that were initially believed to be caused by his implantable cardioverter defibrillator which had undergone intraperitoneal migration. However, this was later found to be a misguided 'zebra'; as the cause was revealed to be a common 'horse' - adhesions. This article shares our key learnings from this diagnostic dilemma.

A multiphoton transition activated iron based metal organic framework for synergistic therapy of photodynamic therapy/chemodynamic therapy/chemotherapy for orthotopic gliomas.

Although photodynamic therapy (PDT) has exhibited good potential in therapy of gliomas, the limited penetration depth of light and the obstacle of the blood-brain barrier (BBB) lead to unsatisfactory treatment effects. Herein, a multifunctional nanodrug (UMD) was constructed with up-conversion nanoparticles (NaGdF4:Yb,Tm@NaYF4:Yb,Nd@NaYF4, UCNPs) as the core, the photosensitizer NH2-MIL-53 (Fe) as the shell and a carrier for loading chemotherapy drug doxorubicin hydrochloride (Dox) for synergistic therapy of gliomas. Lactoferrin (LF) was finally modified on the surface of the UMD to endow it with the ability to traverse the BBB and target cells (UMDL). The UCNP core can convert 808 nm near-infrared (NIR) light to ultraviolet light (UV light) for exciting NH2-MIL-53 (Fe), achieving NIR-mediated PDT. In addition, Fe3+ on the surface of the NH2-MIL-53 (Fe) shell could be reduced to Fe2+ in a tumor microenvironment (TME), and then reacted with over-expressed H2O2 in the TME to generate hydroxyl radicals (˙OH) for chemodynamic therapy (CDT). The Dox drug could be released in response to acidic conditions in the TME, inhibiting the growth of gliomas with low side effects. The synergistic effect of PDT/CDT/chemotherapy leads to effective suppression of orthotopic gliomas.

Modulating Nanozyme-Based Nanomachines via Microenvironmental Feedback for Differential Photothermal Therapy of Orthotopic Gliomas.

Gliomas are common and refractory primary tumors closely associated with the fine structures of the brain. Photothermal therapy (PTT) has recently shown promise as an effective treatment for gliomas. However, nonspecific accumulation of photothermal agents may affect adjacent normal brain structures, and the inflammatory response induced during PTT may result in an increased risk of brain tumor recurrence or metastasis. Here, the design and fabrication of an intelligent nanomachine is reported based on Gd2 O3 @Ir/TMB-RVG29 (G@IT-R) hybrid nanomaterials. These nanomaterials enable tumor-specific PTT and eliminate inflammation to protect normal brain tissue. The mechanism involves the rabies virus glycopeptide-29 peptide (RVG29) passing through the blood-brain barrier (BBB) and targeting gliomas. In the tumor microenvironment, Ir nanozymes can act as logic control systems to trigger chromogenic reaction amplification of 3,3',5,5'-tetramethylbenzidine (TMB) for tumor-specific PTT, whereas in normal brain tissues, they scavenge reactive oxygen species (ROS) generated by poor therapy and function as protective agents. Autophagy inhibition of Gd2 O3 enables excellent photothermal therapeutic effects on orthotopic gliomas and protection against inflammation in normal cells. The results of this study may prove useful in developing highly efficient nanomedicines for glioma treatment.

Blood-brain Barrier Permeable and Multi-stimuli Responsive Nanoplatform for Orthotopic Glioma Inhibition by Synergistic Enhanced Chemo-/Chemodynamic/Photothermal/Starvation Therapy.

Glioblastoma (GBM) is a common malignant tumor in brain, and the treatment is still a challenge owing to the high invasiveness and the existence of blood-brain barrier (BBB). Although temozolomide (TMZ) is the first line medication, its efficacy is not ideal, which is related to the defect of dose distribution and drug resistance. It is urgent to develop a novel BBB-permeable nanoagent with multiple therapeutic modalities for improving the treatment effect of GBM. In this work, we constructed an intelligent BBB-permeable nanoplatform (CTHG-Lf NPs) with hollow mesoporous copper sulfide nanoparticles (HM-CuS NPs) as temozolomide (TMZ) carrier and hyaluronic acid (HA) as gatekeeper, as well as further modification with glucose oxidase (GOx) and lactoferrin (Lf) for highly efficient synergistic therapy of orthotopic GBM. The modification of Lf endows CTHG-Lf NPs with good target and BBB-permeable ability. HA not only prevents the TMZ leakage during circulation, but also achieves responsive drug release at tumor site for effective chemotherapy (CT). GOx provides high hydrogen peroxide (H2O2) and gluconic acid for improving the treatment effect of chemodynamic therapy (CDT), and realizes the starvation therapy (ST) by consuming glucose. The good photothermal effect of CTHG-Lf NPs achieves the "mild" photothermal therapy (PTT), while enhancing the efficiency of Fenton-like reaction. The synergistic strategy with CT/CDT/PTT/ST can not only promote brain drug delivery, but also realize the combination of multiple mechanisms for effective tumor growth suppression in vivo.

A Novel Biodegradable Nanoplatform for Tumor Microenvironments Responsive Bimodal Magnetic Resonance Imaging and Sonodynamic/Ion Interference Cascade Therapy.

The unsatisfactory therapeutic effect and long-term adverse effect markedly prevent inorganic nanomaterials from clinical transformation. In light of this, we developed a novel biodegradable theranostic agent (MnCO3:Ho3+@DOX/Ca3(PO4)2@BSA, HMCDB) based on the sonosensitizer manganese carbonate (MnCO3) coating with calcium phosphate (Ca3(PO4)2) and simultaneously loaded it with the chemotherapeutic drug doxorubicin (DOX). Due to the mild acidity of the tumor microenvironment (TME), the Ca3(PO4)2 shell degraded first, releasing substantial quantities of calcium ions (Ca2+) and DOX. Meanwhile, with the ultrasound (US) irradiation, MnCO3 produced enough reactive oxygen species (ROS) to cause oxidative stress in the cells, resulting in accumulation of Ca2+. Consequently, the cascade effect significantly amplified the therapeutic effect. Importantly, the nanocomposite can be completely degraded and cleared from the body, demonstrating that it was a promising theranostic agent for tumor therapy. Furthermore, the doped holmium ions (Ho3+) and in situ generation of manganese ions (Mn2+) in TME endow the nanoagent with the ability for tumor-specific bimodality T1/T2-weighted magnetic resonance imaging (MRI). This novel nanoplatform with low toxicity and biodegradability holds great potential for cancer diagnosis and treatment.

Evaluation of 20(S)-ginsenoside Rg3 loaded hydrogel for the treatment of perianal ulcer in a rat model.

Background: As a kind of common complication of the surgery of perianal diseases, perianal ulcer is known as a nuisance. This study aims to develop a kind of 20(S)-ginsenoside Rg3 (Rg3)-loaded hydrogel to treat perianal ulcers in a rat model. Methods: The copolymers PLGA1600-PEG1000-PLGA1600 were synthesized by ring-opening polymerization process and Rg3-loaded hydrogel was then developed. The perianal ulcer rat model was established to analyze the treatment efficacy of Rg3-loaded hydrogel for ulceration healing for 15 days. The animals were divided into control group, hydrogel group, free Rg3 group, Rg3-loaded hydrogel group, and Lidocaine Gel® group. The residual wound area rate was calculated and the blood concentrations of interleukin-1 (IL-1), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) were recorded. Hematoxylin and eosin (H&E) staining, Masson's Trichrome (MT) staining, and tumor necrosis factor α (TNF-α), Ki-67, CD31, ERK1/2, and NF-κB immunohistochemical staining were performed. Results: The biodegradable and biocompatible hydrogel carries a homogenous interactive porous structure with 10 µm pore size and five weeks in vivo degradation time. The loaded Rg3 can be released sustainably. The in vitro cytotoxicity study showed that the hydrogel had no effect on survival rate of murine skin fibroblasts L929. The Rg3-loaded hydrogel can facilitate perianal ulcer healing by inhibiting local and systematic inflammatory responses, swelling the proliferation of nuclear cells, collagen deposition, and vascularization, and activating ERK signal pathway. Conclusion: The Rg3-loaded hydrogel shows the best treatment efficacy of perianal ulcer and may be a candidate for perianal ulcer treatment.

Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer.

Colorectal cancer is considered one of the major malignancies that threaten the lives and health of people around the world. Patients with CRC are prone to post-operative local recurrence or metastasis, and some patients are advanced at the time of diagnosis and have no chance for complete surgical resection. These factors make chemotherapy an indispensable and important tool in treating CRC. However, the complex composition of the tumor microenvironment and the interaction of cellular and interstitial components constitute a tumor tissue with high cell density, dense extracellular matrix, and high osmotic pressure, inevitably preventing chemotherapeutic drugs from entering and acting on tumor cells. As a result, a novel drug carrier system with targeted nanoparticles has been applied to tumor therapy. It can change the physicochemical properties of drugs, facilitate the crossing of drug molecules through physiological and pathological tissue barriers, and increase the local concentration of nanomedicines at lesion sites. In addition to improving drug efficacy, targeted nanoparticles also reduce side effects, enabling safer and more effective disease diagnosis and treatment and improving bioavailability. In this review, we discuss the mechanisms by which infiltrating cells and other stromal components of the tumor microenvironment comprise barriers to chemotherapy in colorectal cancer. The research and application of targeted nanoparticles in CRC treatment are also classified.

A Cu-based nanoplatform for near-infrared light amplified multi-mode prostate cancer specific therapy.

Chemodynamic therapy (CDT), as a new method for oncotherapy, can convert less reactive hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (˙OH) in the tumor microenvironment (TME) to kill tumor cells and inhibit tumor growth. However, the TME usually presents a low content of endogenous H2O2 and weak acidity, which weakens the therapeutic effect of CDT to a certain extent. Here, we developed a multifunctional nanoplatform based on Cu-doped mesoporous carbon nanospheres loaded with free radical generator 2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) and polyacrylic acid (Cu-MNCS-AIPH@PAA). Cu-MNCS-AIPH@PAA exhibited high photothermal conversion efficiency, and could not only act as a good photothermal agent for photothermal therapy (PTT) but also trigger AIPH to produce alkyl radicals. In response to the specificity of the TME, Cu-MNCS-AIPH@PAA could generate ˙OH through a Fenton-like reaction for CDT and enhance the efficacy of CDT by a photothermal effect. The excellent anticancer efficiency by the synergistic effect of CDT, PTT and free radicals, high biocompatibility and low adverse effects of Cu-MNCS-AIPH@PAA make it an ideal nanoplatform for tumor therapy.

Recent Advances in Nanotheranostic Agents for Tumor Microenvironment-Responsive Magnetic Resonance Imaging.

Nanomaterials integrating a variety of excellent properties (such as controllable/suitable size, surface modifier, and multifunctionality) have attracted increasing attention in the biomedical field and have been considered a new generation of magnetic resonance imaging (MRI) contrast agents (CAs). In recent years, stimuli-responsive nanomaterials with specifically responsive ability have been synthesized as MRI CAs, which can significantly improve the diagnostic sensitivity and accuracy depending on their outstanding performance. Furthermore, the inherent tumor microenvironment (TME) of malignant tumor is considered to possess several unique features, such as low extracellular pH, redox condition, hypoxia, and high interstitial pressure, that are significantly different from healthy tissues. Hence, constructing nanomaterials for TME-responsive MRI as an emerging strategy is expected to overcome the current obstacles to precise diagnosis. This review focuses on recent advances of nanomaterials in their application of TME-responsive MRI that trigger the diagnostic function in response to various endogenous stimulations, including pH, redox, enzyme, and hypoxia. Moreover, the future challenges and trends in the development of nanomaterials serving as TME-responsive MRI CAs are discussed.

Novel YOF-Based Theranostic Agents with a Cascade Effect for NIR-II Fluorescence Imaging and Synergistic Starvation/Photodynamic Therapy of Orthotopic Gliomas.

Accurate diagnosis and highly effective treatment of glioblastoma are still challenges in clinic. Near-infrared (NIR) light triggered fluorescence imaging and photodynamic therapy (PDT) showed the potential for theranostics of glioblastoma, but the presence of blood-brain barrier (BBB) and hypoxia limited treatment effect. Herein, the novel theranostic nanoagents with YOF:Nd3+ as core, MnO2 as shell, and further loading photosensitizer (indocyanine green, ICG) and glucose oxidase (GOx) were successfully constructed, and further modified with lactoferrin to endow them with BBB penetration and target abilities (YOF:Nd3+@MnO2-ICG-GOx-LF, YMIGL). The YOF:Nd3+ core with good fluorescence performances makes YMIGL act as promising probes for fluorescence imaging in the second biowindow (NIR-II FL). The combination of GOx and MnO2 shell significantly increased the O2 generation from the cascade reactions and consumed glucose, improving the treatment effect of PDT and achieving starvation treatment (ST). These theranostic nanoagents exhibit a highly efficient inhibition effect on orthotopic gliomas by cascade reactions, which improved PDT and ST.

A nanotheranostic agent based on Nd3+-doped YVO4 with blood-brain-barrier permeability for NIR-II fluorescence imaging/magnetic resonance imaging and boosted sonodynamic therapy of orthotopic glioma.

The specific diagnosis and treatment of gliomas is a primary challenge in clinic due to their high invasiveness and blood-brain barrier (BBB) obstruction. It is highly desirable to find a multifunctional agent with good BBB penetration for precise theranostics. Herein, we design and construct a core-shell structured nanotheranostic agent (YVO4:Nd3+-HMME@MnO2-LF, marked as YHM) with YVO4:Nd3+ particles as the core and MnO2 nanosheets as the shell. Sonosensitizer hematoporphyrinmonomethyl ether (HMME) and lactoferrin (LF) were further loaded and modified on the surface, giving it a good ability to cross the BBB, near-infrared fluorescence imaging in the second window (NIR-II)/magnetic resonance imaging (MRI) bimodality, and highly efficient sonodynamic therapy (SDT) of orthotopic gliomas. The YVO4:Nd3+ (25%) core exhibited good NIR-II fluorescence properties, enabling YHM to act as promising probes for NIR-II fluorescence imaging of vessels and orthotopic gliomas. MnO2 shell can not only provide O2 in the tumor microenvironments (TME) to significantly improve the healing efficacy of SDT, but also release Mn2+ ions to achieve T1-weight MRI in situ. Non-invasive SDT can effectively restrain tumor growth. This work not only demonstrates that multifunctional YHM is promising for diagnosis and treatment of orthotopic glioma, but also provides insights into exploring the theranostic agents based on rare earth-doped yttrium vanadate nanoparticles.

Correction: Rational design of Fe3O4@C nanoparticles for simultaneous bimodal imaging and chemo-photothermal therapy in vitro and in vivo.

Correction for 'Rational design of Fe3O4@C nanoparticles for simultaneous bimodal imaging and chemo-photothermal therapy in vitro and in vivo' by Qinghe Han et al., J. Mater. Chem. B, 2018, 6, 5443-5450, DOI: 10.1039/C8TB01184B.

Correction: Rapidly clearable MnCo2O4@PAA as novel nanotheranostic agents for T1/T2 bimodal MRI imaging-guided photothermal therapy.

Correction for 'Rapidly clearable MnCo2O4@PAA as novel nanotheranostic agents for T1/T2 bimodal MRI imaging-guided photothermal therapy' by Ying Zhao et al., Nanoscale, 2021, 13, 16251-16257, DOI: 10.1039/D1NR04067G.

A Tumor Microenvironment-Responsive Theranostic Agent for Synergetic Therapy of Disulfiram-Based Chemotherapy and Chemodynamic Therapy.

Despite the fact that chemotherapy has been widely used in the clinical treatment of breast cancer, the toxicity of chemotherapeutics to normal tissues cannot be ignored due to the low specificity. Therefore, due to the non-negligible toxicity of chemotherapeutic agents to normal tissues, tumor microenvironment (TME)-responsive cancer therapy has attracted a great deal of attention. Here, we report a TME-responsive theranostic nanoagent MnOx@PAA@HKUST-1-DSF@BSA fabricated via a layer-by-layer synthesis method. Once endocytosed by tumor cells, the nanoagent can be degraded into Mn2+ for magnetic resonance imaging and Cu2+ for Fenton-like reaction and chelating with released disulfiram in situ, achieving enhanced chemotherapy. Both in vitro and in vivo experiments demonstrate that the TME-targeted nanoagent can efficiently kill tumor cells. This work provides an alternative option for effective imaging and treatment of breast cancer without collateral damage to normal tissues.

Rapidly clearable MnCo2O4@PAA as novel nanotheranostic agents for T1/T2 bimodal MRI imaging-guided photothermal therapy.

Integrating multi-modal imaging and therapy functions into a nanoplatform has been recognized as a promising strategy for cancer theranostics with high accuracy and efficiency. However, there are still some challenges, such as the complicated synthesis process and instability. Herein, we successfully prepared clearable MnCo2O4 nanodots modified with polyacrylic acid (MnCo2O4@PAA) as nanoagents for T1/T2 bimodal MRI imaging-guided PTT. Owing to their intrinsic magnetic properties, single MnCo2O4@PAA nanomaterials can serve as contrasts for T1/T2 bimodal MRI, providing precise diagnotic information. Moreover, excellent absorption in the NIR biowindow endows MnCo2O4@PAA with good photothermal performance, and the ultrasmall size of MnCo2O4@PAA allows them to penetrate deeply into tumors, resulting in a good anticancer effect in vitro and in vivo. What is more, MnCo2O4@PAA can almost be completely cleared from mice at 7 d postinjection, implying their negligible long-term toxicity. These findings demonstrate that MnCo2O4@PAA are promising nanoagents for cancer diagnosis and treatment, which have great potential for clinical applications.

Delayed diagnosis of dorsal scapular artery pseudoaneurysm following blunt chest trauma.

Pseudoaneurysm is a well-recognised form of vascular injury following blunt trauma. Its diagnosis is often delayed due to late manifestation of signs and symptoms. Nonetheless, complications of pseudoaneurysm can be severe and even fatal. A 60-year-old man presented to our tertiary trauma centre with blunt chest trauma. His treatment was initially focused on the left clavicular fracture. He was eventually diagnosed with a dorsal scapular artery pseudoaneurysm and a large chest wall haematoma on computed tomography on his third hospital admission in two weeks. This pseudoaneurysm was treated with endovascular embolisation. This article highlights the value of meticulous clinical examination as well as judicious use of biochemistry and imaging in trauma management.

Carambola-like Bi2Te3 superstructures with enhanced photoabsorption for highly efficient photothermal therapy in the second near-infrared biowindow.

Photothermal therapy (PTT) stimulated by light in the second near-infrared (NIR-II) biowindow shows great superiorities in the penetration ability of tissue and maximum permissible exposure (MPE). Exploring new photothermal agents with good optical absorbance in the NIR-II region is highly desirable for efficient cancer therapy. Herein, we successfully prepare carambola-like bismuth telluride (Bi2Te3) superstructures modified with PEGylated phospholipid (Bi2Te3@PEG) for CT imaging-guided PTT in the NIR-II biowindow. Attributing to their superstructures, Bi2Te3@PEG exhibited enhanced photoabsorption with higher photothermal conversion efficiency (55.3% for 1064 nm) compared with that of Bi2Te3 nanoparticles. Furthermore, the good X-ray attenuation capacity of Bi endows Bi2Te3@PEG with an outstanding performance as computed tomography (CT) contrast agents. Bi2Te3@PEG superstructures have been confirmed to effectively eliminate tumor in vitro and in vivo with negligible long-term toxicities, offering them great potential to act as theranostic platforms for cancer diagnosis and treatment.

Bouveret syndrome-a rare form of gastric outlet obstruction.

Bouveret syndrome is a rare form of gastric outlet obstruction. It is typically diagnosed in frail elderly patients with protracted biliary disease. Thus, it has disproportionally high rates of morbidity and mortality. A 90-year-old man presented to our tertiary hospital with acute abdominal pain and symptoms of bowel obstruction. He was diagnosed with Bouveret syndrome on abdominal computed tomography and required judicious resuscitation and an emergency laparotomy. This article highlights the key features of Bouveret syndrome, and reviews the current diagnostic modalities as well as the contemporary treatment paradigm.

Boosting Chemodynamic Therapy by the Synergistic Effect of Co-Catalyze and Photothermal Effect Triggered by the Second Near-Infrared Light.

In spite of the tumor microenvironments responsive cancer therapy based on Fenton reaction (i.e., chemodynamic therapy, CDT) has been attracted more attentions in recent years, the limited Fenton reaction efficiency is the important obstacle to further application in clinic. Herein, we synthesized novel FeO/MoS2 nanocomposites modified by bovine serum albumin (FeO/MoS2-BSA) with boosted Fenton reaction efficiency by the synergistic effect of co-catalyze and photothermal effect of MoS2 nanosheets triggered by the second near-infrared (NIR II) light. In the tumor microenvironments, the MoS2 nanosheets not only can accelerate the conversion of Fe3+ ions to Fe2+ ions by Mo4+ ions on their surface to improve Fenton reaction efficiency, but also endow FeO/MoS2-BSA with good photothermal performances for photothermal-enhanced CDT and photothermal therapy (PTT). Consequently, benefiting from the synergetic-enhanced CDT/PTT, the tumors are eradicated completely in vivo. This work provides innovative synergistic strategy for constructing nanocomposites for highly efficient CDT.