Effect of bimatoprost sustained-release intracameral implant on intraocular pressure and medication burden in patients with prior glaucoma surgery.

The present retrospective study evaluated intraocular pressure (IOP) and medication burden after bimatoprost sustained-release (bimatoprost SR, Durysta, Allergan) implantation in patients with glaucoma. A secondary objective was to examine an effect of bimatoprost SR in a subset of patients with prior minimally invasive and incisional glaucoma surgery. A retrospective chart review of 122 eyes that received bimatoprost SR by 6 glaucoma specialists at Wills Eye Hospital between March 2020 and September 2021 was performed. One hundred and eighteen eyes from 84 patients had a reduction in IOP (18.5±5.7mmHg vs. 16.0±5.4mmHg, P<0.01) and required fewer glaucoma medications (2.1±1.4 vs. 1.2±1.2, P<0.01) after bimatoprost SR implantation. In 41 eyes from 31 patients who previously underwent glaucoma surgery (including iStent, goniotomy, trabeculectomy, Xen Gel Stent, or tube shunt surgery), medication burden was decreased after bimatoprost SR implantation (1.9±1.3 vs. 1.0±1.0, P<0.001). These data suggest that bimatoprost SR is an efficacious treatment modality for glaucoma, even in post-surgical patients.

Concomitant Ulnar Styloid Fractures in Distal Radius Osteosynthesis Does Not Impact Radiographic Outcomes, Ulnar Sided Symptoms and Patient Outcomes.

Introduction: Current literature reports varied significance of ulnar styloid fractures (USF) associated with distal radius fractures. Our study assesses the role of ulnar styloid fractures and fragment size in surgically managed distal radius fractures. Materials and methods: We reviewed patients who underwent surgical fixation of distal radius fractures between January 2004 to June 2006. Patients were divided into those with (Group 1) and without (Group 0) USFs. Post-operative radiographic parameters, clinical outcomes and overall wrist function were analysed. Outcomes included ulnar-sided wrist pain, extensor carpi ulnaris (ECU) tendinitis, triangular fibrocartilage complex (TFCC) grind test, distal radioulnar joint (DRUJ) instability and pain. Overall wrist function was assessed with range of motion and Disabilities of the Arm, Shoulder and Hand (DASH) score. Results: Our study cohort included 31 males and 23 females, and 38.9% of these patients had concomitant USFs. There was no difference in terms of demographic data and fracture configuration between groups. Radiographic parameters were similar, except for palmar tilt, which was significantly higher in Group 1 (4.6º vs 9.4º, p=0.047). At 24 months, there were no differences in clinical outcomes and overall wrist function. A sub-group analysis showed that mean USF fragment size was larger in patients with a positive TFCC grind test (3.9mm vs 7.3mm, p=0.033). Conclusion: The presence of USFs in surgically managed distal radius fractures does not compromise clinical and functional outcome. Similarly, the size of USFs does not impact clinical and functional outcome but is associated with the presence of a positive TFCC grind test.

First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial).

BACKGROUND: The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use. PATIENTS AND METHODS: We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors. RESULTS: The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids. CONCLUSIONS: This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.

Effectiveness of a childbirth massage programme for labour pain relief in nulliparous pregnant women at term: a randomised controlled trial.

INTRODUCTION: The effect of massage for pain relief during labour has been controversial. This study investigated the efficacy of a programme combining intrapartum massage, controlled breathing, and visualisation for non-pharmacological pain relief during labour. METHODS: This randomised controlled trial was conducted in two public hospitals in Hong Kong. Participants were healthy low-risk nulliparous Chinese women ≥18 years old whose partners were available to learn massage technique. Recruitment was performed at 32 to 36 weeks of gestation; women were randomised to attend a 2-hour childbirth massage class at 36 weeks of gestation or to receive usual care. The primary outcome variable was the intrapartum use of epidural analgesia or intramuscular pethidine injection. RESULTS: In total, 233 and 246 women were randomised to the massage and control groups, respectively. The use of epidural analgesia or pethidine did not differ between the massage and control groups (12.0% vs 15.9%; P=0.226). Linear-by-linear analysis demonstrated a trend whereby fewer women used strong pharmacological pain relief in the massage group, and a greater proportion of women had analgesic-free labour (29.2% vs 21.5%; P=0.041). Cervical dilatation at the time of pethidine/epidural analgesia request was significantly greater in the massage group (3.8 ± 1.7 cm vs 2.3 ± 1.0 cm; P<0.001). CONCLUSION: The use of a massage programme appeared to modulate pain perception in labouring women, such that fewer women requested epidural analgesia and a shift was observed towards the use of weaker pain relief modalities; in particular, more women in the massage group were analgesic-free during labour.

Early Clinical Outcomes of Short versus Long Proximal Femoral Nail Anti-rotation (PFNA) in the Treatment of Intertrochanteric Fractures.

INTRODUCTION: Both short and long PFNA are employed to treat intertrochanteric fractures. Controversy exists in the choice between the two nails as each implant has specific characteristics and theoretical advantages. This retrospective study seeks to examine the operative complication rates and clinical outcomes of short versus long (Proximal Femoral Nail Antirotation) PFNA in the treatment of intertrochanteric fractures. MATERIAL AND METHODS: Between July 2011 and February 2015, 155 patients underwent PFNA insertion. The decision on whether to use a short or long PFNA nail, locked or unlocked, was determined by the attending operating surgeon. Visual Analogue Pain Score (VAS) Harris Hip Scores (HHS), Short-form 36 Health Questionnaire (SF-36) and Parker Mobility Scores (PMS) were collected at six weeks, six months and one year post-operatively. RESULTS: A total of 137 (88.4%) patients were successfully followed-up. Forty-two (30.7%) patients received a short PFNA. The patients were similar in baseline characteristics of age, gender, and comorbidities. Operative time was significantly longer in the short PFNA group (62 ±17 mins) versus the long PFNA group (56±17). While the patients in both groups achieved improvement in all outcome measures, there was no significant difference between the groups in terms of HHS (61.0 ±16.0 vs 63.0 ±16.8, p=0.443), PMS (2.3±1.5 vs 2.7±2.1, p=0.545) and VAS (1.7±2.9 vs 1.8 ±2.2 p=0.454). There were 3 (7.1%) and 7 (7.4%) complications in the short versus long PFNA group, respectively. CONCLUSION: Both short and long PFNA had similar clinical outcomes and complication rates in the treatment of intertrochanteric fractures in an Asian population.

Changes of the intestinal microbiota along the gut of Japanese Eel (Anguilla japonica).

Fish intestine contains different types of microbiomes, and bacteria are the dominant microbiota in fishes. Studies have identified various core gut bacteria in fishes. However, little is known about the composition and their relative functions of gut microbial community along the intestine. To explore this, the current study investigated the microbial community distribution along the gut in Anguilla japonica. By 16S rRNA gene sequencing, we profiled the gut microbiota in eel along the three regions (anterior intestine (AI), the middle intestine (MI) and the posterior intestine (PI)). Results suggested that the three regions did not have significant differences on the observed species and diversities. The cluster tree analysis showed that the bacteria community in MI was closer to PI than the AI. The dominant bacteria in AI were the Proteobacteria, in which the majority was graduated replaced by Bacteroidetes along the gut to PI region. Through PICRUSt analysis, shifts in the bacterial community along the gut were found to affect the genetic information processing pathways. Higher levels of translation and transcriptional pathway activities were found in MI and PI than in AI. The dominant bacterial species were different among the regions and contributed to various biological functions along the gut.

Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIMSM registry.

BACKGROUND: Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy. METHODS: Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIMSM registry data base was assessed utilizing the International Metastatic RCC Database Consortium (IMDC) risk criteria. Median follow-up is 23.4 months (mo.) (range 0.2-124 mo.). Subgroup evaluations were performed by separating patients by prior or no prior therapy, IL-2 alone, or therapy subsequent to IL-2. Some patients were in two groups. We will focus on the 356 patients who received IL-2 alone, and evaluate outcome by risk factor categories. RESULTS: Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively. CONCLUSIONS: Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria. TRIAL REGISTRATION: PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011.

Kinesiology tape does not facilitate muscle performance: A deceptive controlled trial.

Kinesiology tape (KinTape) is a therapeutic tape without much understanding of its mechanism. KinTape claims to increase cutaneous stimulation, which facilitates motor unit firing, and consequently improves functional performance; however these, benefits could be due to placebo effects. This study investigated the true effects of KinTape by a deceptive, randomized, and controlled trial. Thirty healthy participants performed isokinetic testing of three taping conditions: true facilitative KinTape, sham KinTape, and no KinTape. The participants were blindfolded during the evaluation. Under the pretense of applying adhesive muscle sensors, KinTape was applied to their quadriceps in the first two conditions. Normalized peak torque, normalized total work, and time to peak torque were measured at two angular speeds (60°/s and 180°/s) and analyzed with one-way repeated measures ANOVA. Participants were successfully deceived and they were ignorant about KinTape. No significant differences were found between normalized peak torque, normalized total work, and time to peak torque at 60°/s or 180°/s (p = 0.31-0.99) between three taping conditions. The results showed that KinTape did not facilitate muscle performance in generating higher peak torque, yielding a greater total work, or inducing an earlier onset of peak torque. These findings suggest that previously reported muscle facilitatory effects using KinTape may be attributed to placebo effects.

Early outcomes of proximal humerus fracture fixation with locking plate and intramedullary fibular strut graft.

Proximal humerus fractures are commonly encountered in elderly patients. Surgical treatment demonstrates high complication rates, including varus construct collapse and screw cutout. In this study, the authors evaluate the clinical outcome of locking plate fixation with intramedullary fibular strut graft augmentation as a primary surgical treatment in the prevention of early collapse and screw cutout. A total of 9 patients were evaluated. Surgery was performed for displaced proximal humerus fractures between April and December 2011. Patients were either class 2, 3, or 4, according to Neer classification. Mean patient age was 75.4 years. Preoperative and immediate, 6-week, and 3-month postoperative radiographs were evaluated. Head-shaft angles were measured to assess for varus collapse and displacement. Range of motion, complication rates, and functional recovery were also evaluated. Patients underwent open reduction and internal fixation with placement of an intramedullary fibular strut graft. Fixation was achieved with a Philos plate (Synthes, Oberdorf, Switzerland). Reduction and fixation were evaluated with radiographs. Passive exercises and range of motion were allowed immediately postoperatively, and all patients achieved active abduction and forward flexion 6 weeks postoperatively. Shoulder radiographs taken 12 weeks postoperatively revealed no loss of reduction or screw cutout. The introduction of the locking plate has improved outcomes. The addition of an intramedullary strut graft has shown improved preliminary results. Maintained reduction was observed in all 9 patients in the early postoperative period, and good functional motion was achieved. No incidence of screw cutout was recorded.

FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway.

Ovarian cancer (OC) can be classified into five biologically distinct molecular subgroups: epithelial-A (Epi-A), Epi-B, mesenchymal (Mes), Stem-A and Stem-B. Among them, Stem-A expresses genes relating to stemness and is correlated with poor clinical prognosis. In this study, we show that frizzled family receptor 7 (FZD7), a receptor for Wnt signalling, is overexpressed in the Stem-A subgroup. To elucidate the functional roles of FZD7, we used an RNA interference gene knockdown approach in three Stem-A cell lines: CH1, PA1 and OV-17R. Si-FZD7 OC cells showed reduced cell proliferation with an increase in the G0/G1 sub-population, with no effect on apoptosis. The cells also displayed a distinctive morphologic change by colony compaction to become more epithelial-like and polarised with smaller internuclear distances and increased z-axis height. Immunofluorescence (IF) staining patterns of pan-cadherin and ß-catenin suggested an increase in cadherin-based cell-cell adhesion in si-FZD7 cells. We also observed a significant rearrangement in the actin cytoskeleton and an increase in tensile contractility in si-FZD7 OC cells, as evident by the loss of stress fibres and the redistribution of phospho-myosin light chain (pMLC) from the sites of cell-cell contacts to the periphery of cell colonies. Furthermore, there was reciprocal regulation of RhoA (Ras homolog family member A) and Rac1 (Ras-related C3 botulinum toxin substrate 1 (Rho family, small GTP-binding protein Rac1)) activities upon FZD7 knockdown, with a significant reduction in RhoA activity and a concomitant upregulation in Rac1 activity. These changes in pMLC and RhoA, as well as the increased TopFlash reporter activities in si-FZD7 cells, suggested involvement of the non-canonical Wnt/planar cell polarity (PCP) pathway. Selected PCP pathway genes (cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3), prickle homolog 4 (Drosophila) (PRICKLE4), dishevelled-associated activator of morphogenesis 1 (DAAM1), profilin 2 (PFN2), protocadherin 9 (PCDH9), protocadherin α1 (PCDHA1), protocadherin ß17 pseudogene (PCDHB17), protocadherin ß3 (PCDHB3), sprouty homolog 1 (SPRY1) and protein tyrosine kinase 7 (PTK7)) were found to be more highly expressed in Stem-A than non Stem-A subgroup of OC. Taken together, our results suggest that FZD7 might drive aggressiveness in Stem-A OC by regulating cell proliferation, cell cycle progression, maintenance of the Mes phenotype and cell migration via casein kinase 1ɛ-mediated non-canonical Wnt/PCP pathway.

An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530).

The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.

Metformin in prostate cancer: two for the price of one.

BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer treatment induces a metabolic syndrome, which may contribute to non-cancer-related morbidity and mortality. Metformin may abrogate these effects. Additionally, metformin has potential antineoplastic activity in various malignancies including prostate cancer. MATERIALS AND METHODS: A literature review using PubMed with the keywords: AMPK, androgen deprivation therapy, insulin resistance, metabolic syndrome, metformin and prostate cancer was undertaken. RESULTS: This overview will look at the current evidence linking ADT and metabolic syndrome while discussing ongoing clinical trials under way assessing the effectiveness of metformin in abrogating these effects. The potential antineoplastic activity of metformin, mediated by multiple proposed mechanisms based on evidence from preclinical and clinical studies, will also be elucidated in this review. CONCLUSIONS: Overall available data support the potential dual benefit of metformin on ADT-induced metabolic syndrome and in its antineoplastic activity in prostate cancer, justifying the need for ongoing clinical trials to confirm these effects as the evidence currently available for standard practice is lacking.

Effects of azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT--a randomized double-blinded placebo-controlled study.

Bronchiolitis obliterans syndrome (BOS) is an important complication after hematopoietic SCT (HSCT). Recent observations suggested that azithromycin might improve lung function in BOS after HSCT. We conducted a randomized double-blinded placebo-controlled study on azithromycin in patients with BOS after HSCT. The treatment group (n=10) received oral azithromycin 250 mg daily while the control group (n=12) received placebo daily for 12 weeks. Respiratory symptoms were assessed by the St George Respiratory Questionnaires and spirometry at baseline (drug commencement), 1, 2, 3 (drug cessation) and 4 months (1 month after drug cessation). There was no significant difference in the baseline demographic characteristics between the treatment and the control groups in age, gender, time from HSCT to BOS, time since diagnosis of BOS, chronic GVHD, baseline respiratory symptom scores and baseline forced expiratory volume in 1 s (FEV(1)). Throughout and after 3 months of treatment, there were no significant changes in respiratory symptom scores and FEV(1) measurements between the treatment and the control groups. In conclusion, there was no significant benefit of 3 months of oral azithromycin on the respiratory symptoms and lung function in patients with relatively late BOS after HSCT in this randomized placebo-controlled study.

The effects of a gluten and casein-free diet in children with autism: a case report.

A boy with autism, growth and developmental retardation was brought to our clinic. He was diagnosed with CHARGE syndrome. Subsequently, various therapies were introduced when he was 5 months old yet the developmental delays persisted. Gastrointestinal problems such as frequent post-prandial vomiting and severe constipation were noted as well. At the age of 42 months, the boy was subjected to a gluten and casein-free diet. Soybean milk and rice were substituted for cow's milk, bread and noodles. After 2.5 months, interpersonal relations including eye to eye contact and verbal communication improved. At 5.5 months the boy was capable of playing and sharing toys with his sibling and other children, behavior noted to be closer to that of an unaffected child. In addition, the decreased frequency of postprandial vomiting led to a significant increment in body weight, body height (from below the third percentile to the tenth percentile) and vitality after 11 months on the diet. In view of the lack of consensus on the benefits of dietary intervention in patients with autism, we are suggesting an adjuvant therapy that is simple, safe and economical. In addition, the therapy may be more feasible in Taiwan as opposed to western countries because of cultural factors such as dietary preference and product availability.

Comparison of detection of glucose-6-phosphate dehydrogenase deficiency using fluorescent spot test, enzyme assay and molecular method for prediction of severe neonatal hyperbilirubinaemia.

INTRODUCTION: This study aimed to compare the detection rates of glucose-6-phosphate dehydrogenase (G6PD) deficiency in neonates by fluorescent spot test (FST), enzyme assay and molecular methods, and to identify which method was a significant predictor of severe hyperbilirubinaemia. METHODS: 74 term infants of Chinese descent admitted with severe hyperbilirubinaemia (total serum bilirubin equal or greater than 300 micromol/L) and 125 healthy term infants born in the hospital without severe hyperbilirubinaemia were recruited into the study. Specimens of blood were collected from each infant for FST, G6PD enzyme assay and TaqMan minor groove binder single nucleotide polymorphism genotyping assay. RESULTS: 26 (13.1 percent) infants were diagnosed to have G6PD deficiency by FST. They had significantly lower median enzyme levels (0.8 IU/g Hb, interquartile range [IQR] 0.4-4.3) than those diagnosed to be normal (12.0 IU/g Hb, IQR 10.3-15.8) (p-value is less than 0.0001). Based on the enzyme assay, 39 (19.6 percent) infants had G6PD deficiency at an enzyme cut-off level of less than 8.5 IU/g Hb. G6PD mutation was detected in 27 (13.6 percent) infants. Logistic regression analysis showed that the only significant predictors of severe hyperbilirubinaemia were G6PD deficiency based on a cut-off level of less than 8.5 IU/g Hb (adjusted odds ratio [OR] 5.3, 95 percent confidence interval [CI] 2.4-11.4; p-value is less than 0.0001) and exclusive breast-feeding (adjusted OR 11.4, 95 percent CI 3.1-42.4; p-value is less than 0.0001). The gender and birth weight of infants, FST results, G6PD mutation and the actual G6PD enzyme levels were not significant predictors. CONCLUSION: A G6PD enzyme level of less than 8.5 IU/g Hb is a significant predictor of severe hyperbilirubinaemia.

Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution.

We carried out a retrospective review over ten months of patients who had presented with a low-energy subtrochanteric fracture. We identified 13 women of whom nine were on long-term alendronate therapy and four were not. The patients treated with alendronate were younger, with a mean age of 66.9 years (55 to 82) vs 80.3 years (64 to 92) and were more socially active. The fractures sustained by the patients in the alendronate group were mainly at the femoral metaphyseal-diaphyseal junction and many had occurred after minimal trauma. Five of these patients had prodromal pain in the affected hip in the months preceding the fall, and three demonstrated a stress reaction in the cortex in the contralateral femur. Our study suggests that prolonged suppression of bone remodelling with alendronate may be associated with a new form of insufficiency fracture of the femur. We believe that this finding is important and indicates the need for caution in the long-term use of alendronate in the treatment of osteoporosis.