Deep Tissue Infection Research Articles

Interface Polarization Strengthened Microwave Catalysis of MoS2/FeS/Rhein for the Therapy of Bacteria‐Infected Osteomyelitis

AbstractStaphylococcus aureus (S. aureus)‐induced osteomyelitis is fatal to patients, even leading to death without timely debridement processing, which is difficult to be treated by antibiotics or phototherapy due to deep infections. Herein, a microwave (MW) assisted bacteria‐killing strategy for treating S. aureus‐induced osteomyelitis by using MW‐responsive molybdenum disulfide (MoS2)/ferrous sulfide (FeS) heterojunction with anti‐inflammatory herb of rhein (Rhe) is reported. Under medical MW irradiation, MoS2/FeS/Rhe effectively eradicates S. aureus‐infected rat tibial osteomyelitis. The robust therapeutic effects of MoS2/FeS/Rhe are ascribed to the anti‐inflammatory effect of Rhe, the enhanced MW thermal and dynamic effects of MoS2/FeS. MoS2/FeS is composed of S‐Mo‐S‐Fe‐S stacked layers sandwiched in between by weak Van Der Waals interactions, which means that ions or molecules can be retained in the space between the layers. Under MW irradiation, dipoles or ions are aligned in an oscillating electric field, which cause dipolar polarization and ionic conduction, leading to molecular friction and dielectric loss to generate MW heat. In addition, the dipole orientation polarization caused by the interfacial polarization of MoS2/FeS is the main factor for microwave catalysis. This kind of MW responsive nanocomposite comprising inorganics and herbs may solve the challenge of how to effectively treat deep tissue infections.

Transdermal Delivery of High Molecular Weight Antibiotics to Deep Tissue Infections via Droplette Micromist Technology Device (DMTD).

Wound infection by multidrug-resistant (MDR) bacteria is a major disease burden. Systemic administration of broad-spectrum antibiotics colistin methanesulfonate (CMS) and vancomycin are the last lines of defense against deep wound infections by MDR bacteria. However, systemic administration of CMS and vancomycin are linked to life-threatening vital organ damage. Currently there are no effective topical application strategies to deliver these high molecular weight antibiotics across the stratum corneum. To overcome this difficulty, we tested if high molecular weight antibiotics delivered by Droplette micromist technology device (DMTD), a transdermal delivery device that generates a micromist capable of packaging large molecules, could attenuate deep skin tissue infections. Using green fluorescent protein-tagged E. coli and live tissue imaging, we show that (1) the extent of attenuation of deep-skin E. coli infection was similar when treated with topical DMTD- or systemic IP (intraperitoneal)-delivered CMS; (2) DMTD-delivered micromist did not spread the infection deeper; (3) topical DMTD delivery and IP delivery resulted in similar levels of vancomycin in the skin after a 2 h washout period; and (4) IP-delivered vancomycin was about 1000-fold higher in kidney and plasma than DMTD-delivered vancomycin indicating systemic toxicity. Thus, topical DMTD delivery of these antibiotics is a safe treatment for the difficult-to-treat deep skin tissue infections by MDR bacteria.

Prophylaxis of occipital pressure sores in patients after elective spinal surgery in a pandemic condition.

BackgroundOccipital pressure sores (OPS) are complications of the use of cervical collars. Prophylaxis of OPS in patients after cervical spinal surgery (CCS) appears to be neglected.Material and methodsCochrane Central, EMBASE, PubMed, SCOPUS, and Web of Science databases were searched for studies on OPS after CCS.ResultsWe present the case of a patient with rheumatic arthritis who was secured with a hard collar after revision CCS and was not seen by a health professional due to the COVID-19 outbreak. The result was an OPS leading to deep tissue infection. The patient required a prolonged hospital stay and long-term antibiotic therapy. We found a lack of literature on OPS prevention in patients after CCS.ConclusionsPatients with rheumatoid arthritis using collars after CCS are at risk of OPS. Protocols of prevention of OPS should be reviewed with respect to challenges resulting from epidemiological restrictions and accessibility of telemedical technologies.

Reversing Multidrug‐Resistant Escherichia coli by Compromising Its BAM Biogenesis and Enzymatic Catalysis through Microwave Hyperthermia Therapy

AbstractMultidrug‐resistant (MDR) bacteria are emerging and disseminating rapidly, undoubtedly posing an urgent threat to global public health. One particular concern is that MDR Gram‐negative bacteria are immunized to available antibiotics owing to a series of biogenetic effects, including the β‐barrel assembly machine (BAM complex) in the outer membrane, MDR efflux pumps, and enzymatic degradation/modification, which are known to induce antibiotic resistance (AbR). Here, this work identifies that the AbR mechanisms of MDR Escherichia coli become compromised and sensitive again to conventional antibiotics, when the temperature of infected tissues is elevated to ≈50 °C in situ. This thought is realized by the microwave‐driven poly(lactic‐co‐glycolic acid) microparticles that may effectively convert electromagnetic radiation to thermal energy. The microwave hyperthermia (MWH) therapy not only interrupts the essential surface‐exposed BamA protein of the BAM complex, but also enhances the permeability of the outer membrane and inhibits the action of MDR efflux pumps. MWH also impairs the hydrogen bond interaction between the catalytic residues of bacterial enzymes and functional groups of antibiotic molecules. Lastly, this work demonstrates these combined inhibitors can revitalize the bactericidal effects of conventional antibiotics in MDR Escherichia coli‐associated deep tissue infections.

Cook Cervical Ripening Balloon for placenta accreta spectrum disorders with placenta previa: a novel approach to uterus preserving.

To evaluate the efficacy of intrauterine inflated Cook Cervical Ripening Balloon (ICRB) in postpartum hemorrhage (PPH) management and fertility preserving for placenta accreta spectrum disorders with placenta previa (previa PAS). At a tertiary referral center, 74 patients suffering with previa PAS were entered into this retrospective cohort study from January, 2016 to December, 2020, and were confirmed intraoperatively that abnormal invasive placenta reaches the cervical internal ostium and the upper part of the cervical canal. In control group (n = 39), the combination of infrarenal abdominal aorta balloon occlusion (IAABO) and longitudinal parallel compression suture to lower uterine segment were performed. In study group (n = 35), in addition to the aforementioned surgical techniques, ICRB was implemented at the cervical internal ostium and the outside of the cervix simultaneously. Use of ICRB significantly reduced the rate of peripartum hysterectomy (2.9% vs 30.4%, p = 0.001), and associated with a reduction in surgical time and duration of IAABO (mean 172.7min vs 206.6min, p = 0.017; median 30min vs 40min, p < 0.001). Use of ICRB significantly reduced the estimated amount of blood loss (median 2500ml vs 4000ml, p < 0.001), amounts of packed red blood cells and fresh-frozen plasma transfusion (median 6 U vs 13.5 U, p < 0.001; median 450ml vs 1200ml, p < 0.001), postoperative hospital stay and the incidence of oligomenorrhea postoperatively (median 5days vs 6days, p = 0.009; 13.8% vs 61.1% p = 0.001). No significant difference was observed between both the groups regarding the use of cryo and PLT, injury of urinary system, relaparotomy, admission to the ICU, postpartum hematocele in uterine cavity, and postoperative complications (including incidence rate of DVT, incidence rate of femoral thrombosis, puerperal morbidity, intrauterine infection, surgical site infection, and deep tissue infection). ICRB was a simple, effective procedure for PPH management and fertility preserving in some previa PAS cases in which abnormal invasive placenta reaches the cervical internal ostium and the upper part of the cervical canal, in tandem with IAABO and compression suture.

Evaluation of the anticandidal activity of clotrimazole using Lactobacillus caseie ghosts as biological drug carrier.

Candida albicans cause oral and vaginal mucosa infections as well as bloodstream and deep-tissue infections. Commonly, clotrimazole as a broad-spectrum antimitotic drug applied for treatment of Candida albicans infections. Bacterial ghosts are dead cells that have the broad potential to target the various body tissues and cells as drug vector. We hope to conquest this resistance by using clotrimazole loaded on bacterial ghosts. Lactobacillus ghosts were produced by using tween 80 and lactic acid according to the protocol and the amount of the DNA and protein in supernatant was measured by Nano-drop spectrophotometry. Ghost's morphological characteristics were detected by using light microscopy, SEM and AFM. Antifungal activities of the synthesized ghosts were measured by plate methods. Three independent vertical Franz cells were used to evaluate drug release profile. BG-clotrimazole was added into cream base and was examined for dispensability as well as uniformity of the formulation on the skin. Results of the Nano-drop analysis showed that protein and DNA was seen in supernatant of treatment compared to control groups. AFM results showed well-dispersed and rod-shaped L. casei ghost cells. Lysis pores formation in the L. casei ghosts was indicated by SEM micrographs. BGs represent an excellent drug delivery system because of the high loading capability. Nearly, 50% of clotrimazole was released from BGs during 90min. Highest anticandidal activity occurred using 100mg/l clotrimazole-BG, while toxic effects were also seen with 10mg/l clotrimazole. IC50 clotrimazole-BG was found at 0.001mg/l. Chemical stability results showed that about 90% of clotrimazole remained in the formulation. It could be concluded that the bacterial ghosts are very talented to high loading capability, keeping and releasing drug during six months, therefore these could act as an excellent drug delivery system.

Antibiofilm potential of a negative pressure wound therapy foam loaded with a first-in-class tri-alkyl norspermidine-biaryl antibiotic.

Negative-pressure wound therapy (NPWT) is commonly utilized to treat traumatic injuries sustained on the modern battlefield. However, NPWT has failed to decrease the incidence of deep tissue infections experienced by Wounded Warriors, despite attempts to integrate common antimicrobials, like Ag+ nanoparticles, into the wound dressing. The purpose of this study was to incorporate a unique antibiofilm compound (CZ-01179) into the polyurethane matrix of NPWT foam via lyophilized hydrogel scaffolding. Foam samples with 2.5%, 5.0%, and 10.0% w/w CZ-01179 were produced and antibiofilm efficacy was compared to the current standards of care: V.A.C.® GRANUFOAM SILVER™ and V.A.C.® GRANUFOAM™. Gravimetric analysis and elution kinetics testing confirmed that this loading technique was both repeatable and controllable. Furthermore, zone of inhibition and antibiofilm efficacy testing showed that foam loaded with CZ-01179 had significantly increased activity against planktonic and biofilm phenotypes of methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii compared to the clinical standards. These findings motivate additional ex vivo and in vivo work with NPWT foam loaded with CZ-01179 with the overall objective of reducing NPWT-associated infections that complicate battlefield-related and other wounds.

Deep tissue perineal candida glabrata infection, related to sodium-glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin

Fournier’s gangrene is a rare and serious event, primarily caused by bacteria. Candida species, mainly Candida albicans (C.al) are infrequently isolated, usually as a part of polymicrobial infection. Non-C.al Fournier’s gangrene was reported in immunocompromised and diabetic patients. We report a case of a 60-year-old man with diabetes mellitus, who recently initiated treatment with SGLT-2 inhibitor presenting with perineal soft-tissue infection. Tissue cultures yielded Candida Glabrata as the sole pathogen. The patient received antibacterial and appropriate antifungal therapy, concurrent with surgical debridement. Yeast infection should be considered in diabetes patients under SGLT-2 therapy presenting with a deep tissue infection.

Antimicrobial production by perifollicular dermal preadipocytes is essential to the pathophysiology of acne.

Innate immune defense against deep tissue infection by Staphylococcus aureus is orchestrated by fibroblasts that become antimicrobial when triggered to differentiate into adipocytes. However, the role of this process in noninfectious human diseases is unknown. To investigate the potential role of adipogenesis by dermal fibroblasts in acne, a disorder triggered by Cutibacterium acnes, single-cell RNA sequencing was performed on human acne lesions and mouse skin challenged by C. acnes. A transcriptome consistent with adipogenesis was observed within specific fibroblast subsets from human acne and mouse skin lesions infected with C. acnes. Perifollicular dermal preadipocytes in human acne and mouse skin lesions showed colocalization of PREF1, an early marker of adipogenesis, and cathelicidin (Camp), an antimicrobial peptide. This capacity of C. acnes to specifically trigger production of cathelicidin in preadipocytes was dependent on TLR2. Treatment of wild-type mice with retinoic acid (RA) suppressed the capacity of C. acnes to form acne-like lesions, inhibited adipogenesis, and enhanced cathelicidin expression in preadipocytes, but lesions were unresponsive in Camp-/- mice, despite the anti-adipogenic action of RA. Analysis of inflamed skin of acne patients after retinoid treatment also showed enhanced induction of cathelicidin, a previously unknown beneficial effect of retinoids in difficult-to-treat acne. Overall, these data provide evidence that adipogenic fibroblasts are a critical component of the pathogenesis of acne and represent a potential target for therapy.

Minimally invasive open reduction of greater tuberosity fractures by a modified suture bridge procedure.

BACKGROUNDMost greater tuberosity fractures can be treated without surgery but some have a poor prognosis. The surgical procedures for avulsion fractures of the humeral greater tuberosity include screw fixation, suture anchor fixation, and plate fixation, all of which have treatment-associated complications. To decrease surgical complications, we used a modified suture bridge procedure under direct vision and a minimally invasive small incision to fix fractures of the greater tuberosity of the humerus.AIMTo investigate the clinical efficacy and outcomes of minimally invasive modified suture bridge open reduction of greater tuberosity evulsion fractures.METHODSSixteen patients diagnosed between January 2016 and January 2019 with an avulsion-type greater tuberosity fracture of the proximal humerus and treated by minimally invasive open reduction and modified suture bridges with anchors were studied retrospectively. All were followed up by clinical examination and radiographs at 3 and 6 wk, 3, 6 and 12 mo after surgery, and thereafter every 6 mo. Outcomes were assessed preoperatively and postoperatively by a visual analog scale (VAS), the University of California Los Angeles (UCLA) shoulder score, the American Shoulder and Elbow Surgeon score (ASES), and range of motion (ROM) for shoulders.RESULTSSeven men and nine women, with an average age of 44.94 years, were evaluated. The time between injury and surgery was 1-2 d, with an average of 1.75 d. The mean operation time was 103.1 ± 7.23 min. All patients achieved bone union within 3 mo after surgery. VAS scores were significantly decreased (P = 0.002), and the mean degrees of forward elevation (P = 0.047), mean degrees of abduction (P = 0.035), ASES score (P = 0.092) were increased at 3 wk. The UCLA score was increased at 6 wk (P = 0.029) after surgery. The average degrees of external rotation and internal rotation both improved at 3 mo after surgery (P = 0.012 and P = 0.007, respectively). No procedure-related deaths or incision-related superficial or deep tissue infections occurred.CONCLUSIONModified suture bridge was effective for the treatment of greater tuberosity evulsion fractures, was easier to perform, and had fewer implants than other procedures.

Ulcerating Stasis Dermatitis of the Forearm Associated With Arteriovenous Graft and Central Vein Stenosis

Stasis dermatitis is a pathologic condition of the skin that most commonly occurs in the lower limb, where it is caused by chronic venous insufficiency. Stasis dermatitis of the upper limb is rare. A 45-year-old male, resident in Angola, presented to the emergency department with an ulcer encompassing the entire left forearm. Past medical history comprised arterial hypertension and end stage renal disease treated with hemodialysis. Dialysis access consisted of a left brachial-basilic AV graft obtained 4 years before. The patient also reported that a right internal jugular vein catheter was used previously during the maturation of the left brachial-basilic AV graft. Stenosis of the left brachiocephalic vein was documented at angiography. Angioplasty was performed, with complete resolution of the wound 2 months after admission. The differential diagnosis of extensive ulcer of the forearm must include neoplasms, cellulitis, and/or deep tissue infection with secondary ulceration, but it is also important to maintain suspicion for venous stasis syndrome as a rare but possible cause of these lesions.

Deep tissue infection in a girl with juvenile idiopathic arthritis.

Deep tissue infection in a girl with juvenile idiopathic arthritis.

Phototherapy and optical waveguides for the treatment of infection.

With rapid emergence of multi-drug resistant microbes, it is imperative to seek alternative means for infection control. Optical waveguides are an auspicious delivery method for precise administration of phototherapy. Studies have shown that phototherapy is promising in fighting against a myriad of infectious pathogens (i.e. viruses, bacteria, fungi, and protozoa) including biofilm-forming species and drug-resistant strains while evading treatment resistance. When administered via optical waveguides, phototherapy can treat both superficial and deep-tissue infections while minimizing off-site effects that afflict conventional phototherapy and pharmacotherapy. Despite great therapeutic potential, exact mechanisms, materials, and fabrication designs to optimize this promising treatment option are underexplored. This review outlines principles and applications of phototherapy and optical waveguides for infection control. Research advances, challenges, and outlook regarding this delivery system are rigorously discussed in a hope to inspire future developments of optical waveguide-mediated phototherapy for the management of infection and beyond.

10:35 am.

“Who else is left?” the attending wearily asks toward the end of our morning rounds.“Adena,” I respond, knowing no further summary is needed given her 2 months and counting with us.AdenaThirty-three years with multiple co-morbidities. On dialysis thanks to complex Type 1 diabetes. Left leg amputated thanks to a deep tissue infection. Now under our care for a nasty wound on her hand, a persistent infection that requires our strongest intravenous antibiotics. We can only guess at her cardiac state, too fragile for an angiogram after a recent myocardial infarction.Her medical notes are detailed. But the notes miss the identity of the beaming, dimpled patient before me.AdenaMother to 6- and 3-year-olds.AdenaDaughter. Sister. Wife.AdenaDreamer. Optimist. Fighter.We find her sitting upright, eager for good news.“I'm to be discharged today, then?”Her most recent swabs have come back negative. I unroll her bandage. The attending examines the area. By now we know the telltale signs of his satisfaction.She starts from the bed in excitement. She is gushing about calling her husband to share the news, make arrangements, to end this standstill she is in and return to her real life. As I turn away to continue with my day, she calls out to me.The expression on her face is unmistakable: pure joy. I find myself filled with a familiar mixture of melancholy and relief, experienced when well-liked long-stay patients are cleared to head home. I must have been showing it—her expression darkens, mirroring my pensive one.“Don't worry, nothing is wrong,” I assure her. She nods at me and replies that she knows.“There's something about being here, becoming one with the hospital furniture... well for 2 months anyway,” Adena says. “I am eager to get back,” she continues. “But I didn't expect to feel so much fear...”I inch myself toward her, making sure I keep my posture inviting and attentive, and let my silence encourage her to continue.“What worries me,” she starts, steely gaze transfixed on the wall ahead, “Is it is my duty to look after Rizqan and the kids…but what use is a weak wife and mother to them?” She meets my eyes, tears freely coursing down her face. I feel drawn into comfort, in spite of myself. Of course, they taught all the relevant communication techniques in medical school: displaying empathy, listening effectively, the kind of language to use. They trained us exactly for moments like this. Instead, in this moment I find my mind racing, scrambling for words that are appropriate. Precepts from medical school crash into residency reality. Do I provide encouragement that all will work out or advice to plan for eventual early decline? How much do I give away? What should I say versus what she needs to hear? Should I let the blows fall at once or by degrees?Slowly, I muster the courage to validate her worries and try to normalize them. She seems skeptical, but I sense a shift in her—she trusts me. Perhaps it is the white lab coat, the comforting sense of institutional knowledge I represent. Even as her mind senses that the words do not fully fit, her heart believes. She clasps my palms and rewards me with a warm look.I pat her hand and smile. The physiotherapist arrives, chattering in a way that drives overly caffeinated residents to distraction. I hurry away to prepare discharge documents, sign them, and move on.I clearly remember the time—9:46 am, a half hour had passed—when I hear the shouts. We rush forward, not knowing what this could be. Not expecting what this could be.AsystoleAdena. Lips blue. Body limp.AsystoleAdena. On the receiving end of chest compressions. The code team notified, on their way in. I jump in to volunteer CPR at the next switch.Asystole“Her husband. He's on the way over. Someone needs to call her husband.”The staff nurse abides by protocol. His phone rings audibly—he's already just outside.“How long has it been?” Forty minutes. No return of spontaneous circulation. We stop to assess the presence of a rhythm and pulse.Her husband glimpses through the curtain, standing tall. He's beaming, excited to take her home: Adena is finally leaving the hospital.Just not as we envisioned it.How does one deliver this news to him? How does one keep going through the fading of the smile, the confusion in the eyes, the desperation in his anguish? How does one watch a happy day turn into the darkest of all? The truncating of a life they had planned, and delayed, and delayed?I stand there. Feet glued. Stomach churning.10:35 am.

What Are the Potential Benefits and Risks of Using Magnetically Driven Antegrade Intramedullary Lengthening Nails for Femoral Lengthening to Treat Leg Length Discrepancy?

What Are the Potential Benefits and Risks of Using Magnetically Driven Antegrade Intramedullary Lengthening Nails for Femoral Lengthening to Treat Leg Length Discrepancy?

Skin and mucous membranes colonisation with Staphylococcus aureus or MRSA as a risk factor for surgical site infections in elective Caesarean Section

The purpose of this study was to determine if skin and mucous membrane colonisation with Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA) increases the incidence of surgical site infection (SSI) post-elective Caesarean Sections. A prospective study was conducted at a major centre in Jordan, involving 127 patients who underwent elective Caesarean Section surgeries during 2019. Participants were screened for skin and mucous membranes colonisation for S. aureus preoperatively and were followed for 90 days for any signs of SSI. The screening sites were on three parts of the patients’ bodies; nose, throat, and groyne. The total SSI incidence was 18.9%. Among participants with SSI; 66.7% had a superficial infection and 33.3% had deep tissue infection. Skin and mucous membrane colonisation was positive in 42 participants (33.1%) in one of the three screening sites. Participants with positive skin and mucous membrane colonisation were found to have SSI incidence 2.43 times more than the non-colonised participants (Fisher’s Exact test = 3.832, p = .05, CI: 0.098–6.02). Participants with S. aureus skin and mucous membranes colonisation were significantly 2.94 times with more SSI incidence than those who were not colonised (Fisher’s Exact test = 5.485, p = .02, CI: 1.164–7.439). Skin and mucous membrane colonisation was found to increase the incidence of SSI. More attention should be performed to screen for skin and mucous membranes colonisation and subsequent selective skin decolonisation to decrease SSI incidence. IMPACT STATEMENT What is already known on this subject? Surgical site infection (SSI) is a challenge that increases the costs of health care. Surgical site infection is associated with high costs mainly due to the increase in the length of hospital stay. Skin screening for S. aureus or MRSA colonisation was found to be important for selective skin decolonisation using appropriate antiseptic preparation and preoperative antibiotic prophylaxis. What do the results of this study add? The incidence of SSI in the colonised group was found to be 2.43 times higher than in the non-colonised group. What are the implications of these findings for clinical practice and/or further research? Screening for colonisation and subsequent selective skin decolonisation should be a part of SSI prevention policies.

Clostridium perfringensによるガス産生性肝膿瘍の1例(A case of gas–forming liver abscess caused by Clostridium perfringens)

要旨ガス産生性肝膿瘍は致死率の高い疾患である。起因菌はKlebsiella pneumoniaeが主体であるが, 稀にC. perfringensによるものがある。急性胆嚢炎に伴いC. perfringensによるガス産生性肝膿瘍を発症し, 敗血症となりDICを合併したが, 救命し得た1例を経験したので報告する。症例は83歳の男性で, 腹痛と発熱を主訴として受診した。来院時，白血球増多と肝逸脱酵素の上昇および黄疸を認めるとともに, 低酸素血症を認めた。線溶系も亢進しており，画像上は，胆嚢頚部に胆石嵌頓が疑われるとともに, 肝右葉に内部不均一なガスを伴う膿瘍形成を認め，門脈ガス血症も伴っていた。急性胆嚢炎に伴うガス産生性肝膿瘍と診断した。カルバペネム系の抗菌薬投与を含む全身的なケアを行い，第10病日に開腹下膿瘍ドレナージおよび胆嚢摘出術を施行した。術後は順調に経過し，第65病日に自宅退院となった。C. perfringensによるガス産生性肝膿瘍は, 高齢者に多くみられる非外傷性の深部組織の感染症で, しかも進行が早いことから救命が難しい病態である。しかし, 画像診断の活用が救急外来においてもさらに進むことにより, 早期に診断される例も増加すると考えられる。今後, 救命への手がかりが蓄積して系統的なアプローチが整備されることが期待される。

Microwave-triggered ionic liquid-based hydrogel dressing with excellent hyperthermia and transdermal drug delivery performance

Phototherapy still lacks effectiveness in treating tissue infections due to poor penetration depth of light and laser-induced non-specific thermal diffusion. Microwave thermal therapy (MWTT) is advantageous as characterized by strong tissue penetration, and higher heating rate. In addition, transdermal delivery of drugs helps in the treatment of tissue infections. Herein, we present an all-in-one MW-therapeutic hydrogel for eradicating bacterial infections with transdermal drug delivery. A microwave-responsive ionic liquid (IL), i.e., vinylbenzyl trimethylammonium chloride (VBTMACl), and a transdermal-enhancer IL, i.e., [2-(methacryloyloxy)ethyl] trimethylammonium chloride (ChMACl), are copolymerized with acrylic acid (AA) to form the hydrogel VACPHs. Polyvinylpyrrolidone (PVP) is incorporated with VACPHs to improve their mechanical stability. The model drug levofloxacin (LEVO) is subsequently loaded into the hydrogel, and the VACPHs-LEVO shows strong antibacterial effect. It is attributed to the efficient microwaveocaloric therapy of VBTMACl and enhanced transdermal antibiotic delivery by ChMACl. The drug delivery hydrogel developed in this research exhibits excellent performance for the treatment of deep tissue infections.

Modifying TIMER to generate a slow-folding DsRed derivative for optimal use in quickly-dividing bacteria.

It is now well appreciated that members of pathogenic bacterial populations exhibit heterogeneity in growth rates and metabolic activity, and it is known this can impact the ability to eliminate all members of the bacterial population during antibiotic treatment. It remains unclear which pathways promote slowed bacterial growth within host tissues, primarily because it has been difficult to identify and isolate slow growing bacteria from host tissues for downstream analyses. To overcome this limitation, we have developed a novel variant of TIMER, a slow-folding fluorescent protein, named DsRed42, to identify subsets of slowly dividing bacteria within host tissues. The original TIMER folds too slowly for fluorescence accumulation in quickly replicating bacterial species (Escherichia coli, Yersinia pseudotuberculosis), however DsRed42 accumulates red fluorescence in late stationary phase cultures of E. coli and Y. pseudotuberculosis. We show DsRed42 signal also accumulates during exposure to sources of nitric oxide (NO), suggesting DsRed42 signal detects growth-arrested bacterial cells. In a mouse model of Y. pseudotuberculosis deep tissue infection, DsRed42 signal was detected, and primarily accumulates in bacteria expressing markers of stationary phase growth. There was no significant overlap between DsRed42 signal and NO-exposed subpopulations of bacteria within host tissues, suggesting NO stress was transient, allowing bacteria to recover from this stress and resume replication. This novel DsRed42 variant represents a tool that will enable additional studies of slow-growing subpopulations of bacteria, specifically within bacterial species that quickly divide.

Hematopoietic Stem Cell Transplantation in 65 Patients with Leukocyte Adhesion Deficiency Type I and Type III — A Retrospective Multi-Center Study

Leukocyte adhesion deficiency (LAD) is an autosomal recessive, primary immunodeficiency disorder, characterized by lethal deep tissue infections, leukocytosis with impaired pus-formation, delayed wound healing and hyper-inflammation. Life expectancy of affected patients is severely shortened. LAD-I is caused by defective expression of beta-2 integrin on immune cells, resulting in impaired leukocyte adhesion and migration. LAD-II is a metabolic disease with syndromal features. LAD-III is caused by mutations in the FERMT3 gene resulting in activation defect of all beta-integrins. LAD-III is characterized by leukocyte adhesion/migration deficiency and an additional Glanzmann's thrombasthenia-like syndrome.In this retrospective multi-center study, data were collected from the European Group for Blood and Marrow Transplantation (EBMT) registry. This study included 65 children from 14 European and Asian centers with either LAD-I (n=60) or LAD-III (n=5), all receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT) from 2008 to 2015.Median age at diagnosis was 0.3 years (yrs); interval from diagnosis to alloHSCT was 8.1 months (median; range 0.6 to 134.5 months). An HLA-identical sibling or matched non-sibling family donor was available for 35 (54%) patients; 28 (43%) received the allograft from a matched unrelated donor and 2 (3%) patients were transplanted from an HLA-haplo-identical family donor. Stem cell source was bone marrow in 37 (58%) patients, peripheral blood in 17 (26%) and cord blood in 10 (16%) of the cohort. Reduced intensity conditioning (RIC) was used in 19 (29%) and myeloablative conditioning (MAC) in 46 (71%) patients. Half of the cohort (n=33) received a busulfan-based conditioning regimen; treosulfan was used in 18 (28%) patients. Serotherapy was applied to 71% of the cohort and consisted primarily of ATG (85%).The overall survival of the cohort was 80% (95%CI: 70-91%) at 24 months, and 77% (95%CI: 65-89%) at 60 months post alloHSCT. In total 12 patients died. The cause of death was GVHD (n=6) and infections (n=6).Primary or secondary graft failure occurred in 9 patients. The incidence of graft failure at 24 months was 11% (95% CI: 7-24%) in RIC and 14% (95% CI: 3-24%) in MAC group. A second alloHSCT was performed in 8 patients; it was successful in 7 cases.At 100 days, 10% (95% CI: 2-17%) and 16% (95% CI: 7-25%) of patients developed grade I-II and grade III+IV aGVHD, respectively . Extensive chronic GVHD was reported in 2 cases.AlloHSCT restored leukocyte function in LAD-I and both leukocyte and thrombocyte function in LAD-III leading to complete remission of symptoms with hematological and immunological reconstitution. Transplantation should be performed early in the course of the disease and prior to the occurrence of life-threatening infectious complications. DisclosuresBader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.