TBS as a Tool to Differentiate the Impact of Antiresorptives onCortical and Trabecular Bone in Children With OsteogenesisImperfecta.

INTRODUCTION/BACKGROUND: Osteogenesis imperfecta is a hereditary connective tissue disorder, resulting in low bone mass and high bone fragility. Dual-energy X-ray absorptiometry (DXA) and in adulthood also the trabecular bone score (TBS) are well established to assess bone health and fracture risk. The purpose of this investigation was to assess the usefulness of TBS in respect to different treatment regimes in children with osteogenesis imperfecta. Changes of areal bone mineral density (aBMD) and TBS using DXA scans of children treated with antiresorptive therapies were evaluated. METHODOLOGY: DXA scans (aBMD, TBS) of 8 children with OI were evaluated. The scans were taken during a 1 yr period of treatment with bisphosphonates and during 1 yr pilot trial using denosumab. Changes of aBMD and TBS during both treatment regimens were compared. RESULTS: During bisphosphonate treatment aBMD increased about 6.2%, while TBS increased about 2.1%. The difference between aBMD and TBS before and after bisphosphonate treatment was not significant (p = 0.25). During denosumab treatment aBMD increased around 25.1%, while TBS increased 6.7%. The change of aBMD was significant (p = 0.007), as was the difference between aBMD and TBS (p < 0.001). CONCLUSIONS: Denosumab had a significant effect on both aBMD and TBS but was significantly more pronounced in aBMD. These results suggest a stronger effect of denosumab on cortical bone and the growth plate in comparison to bisphosphonates. Beside the lack of paediatric reference data and the small sample size, the results suggest TBS to be a useful tool for monitoring skeletal changes during development, growth, and antiresorptive therapy in children with OI.

Heat shock protein 70 and tumor-infiltrating NK cells as prognostic indicators for patients with squamous cell carcinoma of the head and neck after radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).

Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre-activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor-infiltrating CD56+ NK cells in formalin-fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin-based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3-4) showed significantly decreased overall survival (OS; p = 0.008), local progression-free survival (LPFS; p = 0.034) and distant metastases-free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0-2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16- (p = 0.001), p53- (p = 0.0003) and HPV16 DNA-negative (p = 0.001) tumors. The absence or low numbers of tumor-infiltrating CD56+ NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor-infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor-infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers.

Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis.

BACKGROUND: Chronic post-traumatic and postoperative osteomyelitis is a refractory disease which results in significant morbidity and mortality. The effect of combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded polymethyl methacrylate (PMMA) was unknown. METHODS: Fifty-one patients suffering from chronic post-traumatic or postoperative osteomyelitis of the lower extremities were included in the retrospective investigation. The patients were assigned to the study group of the combination therapy with antibiotic-loaded calcium sulfate and antibiotic-loaded PMMA or the control group of the antibiotic-loaded PMMA. Hematological parameters, eradication of infection, rate of infection recurrence and reoperation rate were evaluated during the follow-up. RESULTS: The cases were followed up for an average of 24 months (range, 15-48 months) after the first-stage surgical operation. In the study group, all the patients revealed complete calcium sulfate resorption at an average of 6 weeks (range, 30-60 days). In the study group, infection was primarily eradicated in 92.31% (24 of 26) of patients and re-operation rate of 7.69% (2 of 26) after the first-stage surgery. Two patients underwent further surgical operation in the study group. One case achieved infection eradication in the recurrent two cases, with a secondary infection eradication rate of 96.15% (25 of 26). There was no persistent infection in the study group. In the control group, infection was eradicated in 64.00% (16 of 25) of patients and re-operation rate was 36.00% (9 of 25) after the first-stage surgery. Nine patients in the control group underwent further surgical operation. Two case achieved infection eradication in these cases who suffered from persistent or recurrent infection, with a secondary infection eradication rate of 72.00% (18 of 25). There was more re-operation rate in the control group (PMMA group, 9 vs combination therapy group, 2; P = 0.034). CONCLUSION: The combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA possibly achieved more effective control of infection in the treatment of osteomyelitis through synergistic effect. The immediate structural stabilization and higher concentration of antibiotic at the local site of infection may be achieved through the combination of biodegradable and non-biodegradable devices in the treatment of chronic post-traumatic and postoperative osteomyelitis. The study was retrospectively registered at 11/16/2016 (TRN: NCT02968693).

Comparing the efficacy of anti-seizure medications using matched cohorts on a large insurance claims database.

Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.

Efficacy and Safety of Rivaroxaban for Extremely Aged Patients with Venous Thromboembolism: A Retrospective, Cross-Sectional Real-World Study.

Background: Rivaroxaban, a non-vitamin K antagonist oral anticoagulant, has become widely used for the management of venous thromboembolism (VTE) in adult patients. However, few trials have explored the efficacy and safety of rivaroxaban in VTE patients over 80 years of age. This necessitates further real-world studies of rivaroxaban across elderly populations. Methods: We performed a retrospective single center study involving extremely aged VTE sufferers treated with rivaroxaban. The sample comprised 121 patients newly initiated on rivaroxaban diagnosed between January 2018 and January 2020. Patients were followed up for no less than 2 years. The effectiveness outcome was the disappearance of thromboembolism. The safety outcome was the incidence of major bleeding events. Comorbidities and complications were recorded throughout the entire study. Results: The efficacy outcome occurred in 114 of 121 patients (94.21%) and the safety outcome occurred in 12 of 121 patients (9.91%). Increased hemorrhages were observed in patients with infection (15.15% vs 7.80%), but no significant difference was observed due to limited sample size (P=0.3053). Patients with an age-adjusted Charlson comorbidity index score higher than 6 points exhibited higher bleeding rates (14.08% vs 4.00%; P=0.0676) and lower thrombus cure rates (88.73% vs 100%; P=0.0203). Key conclusions: Patients with infection should be more careful of bleeding events during rivaroxaban therapy. An age-adjusted Charlson comorbidity index score higher than 6, which predicted poor survival, indicated inferior safety and efficacy of rivaroxaban. Aim: To investigate the efficacy and safety of Rivaroxaban in an aged venous thromboembolism patient population under real-world conditions.

Retrospective, Multi-center, Cohort Study Evaluating Clinical, Technical, Biological, and Esthetic Outcomes of Implant Supported Zirconia Single Crowns Cemented on Titanium-base Abutments: 7-year Mean Follow-up.

PURPOSE: To retrospectively evaluate the long-term clinical, technical, biological, and esthetic outcomes of implant supported single zirconia crowns (ISCs) intraorally cemented to Ti-base hybrid-abutments up to 16 years after placement. MATERIALS AND METHODS: A total of 63 ISCs (Xive S, Camlog Screw Line, Replace Select TC NP, Branemark MK II, and 3i Osseotite) were evaluated in 36 patients at two different centers. Original Ti-bases were selected and zirconia meso structures and zirconia crowns were designed using CAD/CAM software and then milled from partially stabilized zirconia blocks. After the meso structures were cemented extraorally onto the Ti-bases, the ceramic crowns were intraorally luted to the hybrid abutments. The Ti-base ISC restorations were followed up for up to 16 years, and their clinical, biological, and esthetic outcomes were recorded at distinct time points (T1; T2) at three-year intervals. RESULTS: 36 patients (18 men, 18 women) received 32 ISCs in the anterior region and 31 in the posterior region of the maxilla and mandible. The mean follow-up of the Ti-base ISCs was 6.93 ± 2.60 years. The mean follow-up of the implants amounted to 8.11 ± 3.26 years. No implants were lost during follow-up, resulting in a cumulative implant survival rate of 100%. Abutment screw loosening was observed in two ISCs after one year in service. The overall cumulative restorative survival rate of the Ti-base restorations reached thus 96.83%. At T2 follow-up 24% of the ISCs exhibited an increase in PD despite maintaining clinically healthy peri-implant tissue. An 11% increase in BOP and a 3.17% decrease in PI were recorded. Despite spectrophotometrically measured ΔE values indicating visible discoloration of some restorations and their peri-implant soft tissue, a low incidence of esthetic complications was observed with an average PES/WES score of ≥ 12. No correlation was found between PES (R = -0.25; p = 0.27) and WES (R = -0.18; p = 0.43) scores and digital shade determination. CONCLUSIONS: The results of the present retrospective, multicenter, cohort study indicate satisfactory clinical outcomes for intraorally cemented single zirconia crowns (ISCs) supported by Ti-base hybrid abutments. An overall esthetic superiority of Ti-base ISCs could not be confirmed.

The Effects of Hyperbaric Oxygen Treatment on Verbal Scores in Children With Autism Spectrum Disorder: A Retrospective Trial.

Introduction Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects millions worldwide. Suggested pathophysiology includes cerebral hypoperfusion, inflammation, mitochondrial and immune dysregulation, and oxidative stress. Debate exists concerning the benefit of hyperbaric oxygen therapy (HBOT) in treating ASD and its impacts on verbal behavior. The present study directly assesses the impacts of HBOT treatments on verbal behavior using a novel and unique manner.  Materials and methods A two-group quasi-experimental trial using a pretest and a posttest was designed to retrospectively assess (n = 65) any association between HBOT and change in verbal scores in children (n = 65) with ASD. All children completed two verbal tests six months apart, either the Verbal Behavior Milestones Assessment and Placement Program (VBMAPP) or the Assessment of Basic Language and Learning Skills (ABLLS), based on their developmental age. The control cohort received applied behavior analysis (ABA) without HBOT. The experimental cohort received ABA and a minimum of 40 HBOT treatments, breathing 100% oxygen at 2.0 atmosphere absolute (ATA) for 60 minutes. Results Sixty-five children were included, of which 32 received HBOT (mean (M) = 5.1, standard deviation (SD) = 2.93), with an age range of two to 17 years. More than 63% of the subjects had an autism severity level of three. The 23 children administered VBMAPP who received HBOT showed substantial mean differences with high effect sizes (ESs) (-0.743 to -1.65) and a total score (TS) ES equal to -1.23 as measured by Cohen's d. There was a statistically significant improvement (p < 0.05) in all VBMAPP milestone domains and TS. TS change from baseline versus those in the non-HBOT (Control-ABA) group (n=12) was 46.41 ± 20.14 vs 14.42 ± 6.99; p < 0.0001, ES = -1.23. The 30 children administered the ABLLS showed substantial mean difference (TS) change from baseline 268.89 ± 182.05 vs 190.81 ± 135.26 and exhibited small to medium (-.114 to -.773) ESs with a TS ES = -0.487. Due to the high within-group variability (low statistical power) within the ABLLS cohort, there was a non-significant mean difference between the control (ABA) and experimental (ABA + HBO2) groups' difference scores (p > 0.2024), despite the medium (TS) ES. Conclusions The child cohorts administered the VBMAPP and the ABLLS demonstrated substantial improvements between the non-HBOT (control-ABA) and HBOT (experimental-ABA + HBO2) groups as measured by the significant mean differences and small to large ESs. Simply put, the children in the experimental cohort acquired more verbal skills than their counterparts in the control group.

Network pharmacology-based and clinically relevant prediction of active ingredients and potential targets of Chinese herbs on stage IV lung adenocarcinoma patients.

AIM: This study is designed to ascertain the relative molecular targets of effective Chinese herbs in treating stage IV lung adenocarcinoma based on clinical data and network pharmacology. In addition, we showed that Chinese Herbal Medicine (CHM) treatment was associated with survival benefit for patients with stage IV lung adenocarcinoma and identified 18 herbs beneficial to survival through correlation analysis. BACKGROUND: Increasing evidence has shown that CHM has efficient therapeutic effects for advanced lung adenocarcinoma, while active ingredients and potential targets remain unclear. METHODS: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of CHM treatment, and correlation analysis was applied to identify the most effective components in the formulas. A network pharmacological approach was used to decipher the potential therapeutic mechanisms of CHM. RESULTS: CHM treatment was an independent protective factor. The hazard ratio (HR) was 0.487 (95% CI 0.293-0.807; P = 0.005). Patients in the CHM group had a longer median survival time (31 months) compared with the non-CHM group (19 months; P < 0.001). 18 out of the total 241 herbs were significantly correlated with favorable survival outcomes (P < 0.05), likely representing the most effective components in these formulas. Bioinformatics analysis suggested that the 18 herbs realize anti-lung-adenocarcinoma activity mainly through (1) inhibiting the activity of some growth factors' receptors, such as HGFR, EGFR, and IGFR. (2) Suppressing angiogenesis not only through VEGFR and PDGFR, but also through the function of neurotransmitters such as dopamine and serotonin. (3) Inhibiting the Ras signaling pathway directly through Ras as well as through ALK and FNTA/FNTB. CONCLUSIONS: We performed a network pharmacological method to decipher the underlying mechanisms, which provides a good foundation for herbal research based on clinical data.

Compression stockings limit the incidence of postoperative lymphocele in kidney transplantation.

BACKGROUND: Lymphoceles account for considerable morbidity rates after kidney transplantation. As yet, there is no therapeutic strategy to prevent the formation of lymphoceles. The lower limb provides a large reservoir for lymphatic tissue. Prophylactic compression therapy limits tissue volume and edema formation and may therefore reduce postoperative lymph flow. PATIENTS AND METHODS AND RESULTS: In a non-randomized prospective study using a historical control group prior to 2006 as comparison from our center (2004-2008: total n=126), we found that lymphoceles are significantly diminished on the ipsilateral lower limb of the operative side when patients wear class II compression stockings (n=69) for four weeks after transplantation compared to patients achieving standard antithrombotic therapy by compression class I stockings (n=57) for thrombosis prophylaxis until full mobilization (33% versus 15%, p-value<0.05). Furthermore, a significantly lower percentage of patients needed surgical treatment of the lymphoceles for obstructive complications after class II compression (4% versus 18%, p-value<0.01). These findings were independent of the recipients' demographics, the duration of the surgical procedure, and the operating surgeon. CONCLUSION: Further studies are needed to demonstrate the usefulness of compressing stockings for the reduction of lymphoceles after kidney transplantation. This approach would not only reduce post-transplantation morbidity, but also provide an easy and cost-effective treatment without side-effects.