Publications by authors named "George Zhang"

69 Publications

Functional impact of cancer patient-associated Bcl-xL mutations.

MedComm (Beijing) 2020 Dec 29;1(3):328-337. Epub 2020 Oct 29.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.

Bcl-xL, an antiapoptotic protein, is frequently overexpressed in cancer to promote survival of tumor cells. However, we have previously shown that Bcl-xL promotes migration, invasion, and metastasis independent of its antiapoptotic function in mitochondria. The pro-metastatic function of Bcl-xL may require its translocation into the nucleus. Besides overexpression, patient-associated mutations of Bcl-xL have been identified in large-scale cancer genomics projects. Understanding the functions of these mutations will guide the development of precision medicine. Here, we selected four patient-associated Bcl-xL mutations, R132W, N136K, R165W, and A201T, to investigate their impacts on antiapoptosis, migration, and nuclear translocation. We found that all four mutation proteins could be detected in both the nucleus and cytosol. Although all four mutations disrupted the antiapoptosis function, one of these mutants, N136K, significantly improved the ability to promote cell migration. These data suggest the importance of developing novel Bcl-xL inhibitors to ablate both antiapoptotic and pro-metastatic functions of Bcl-xL in cancer.
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http://dx.doi.org/10.1002/mco2.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302207PMC
December 2020

History of depression is associated with worsened postoperative outcomes following colectomy.

Colorectal Dis 2021 Jun 24. Epub 2021 Jun 24.

Colorectal Research Unit, Ravitch Colorectal Division, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Aim: Depression is a prevalent disorder that is associated with adverse health outcomes, but an understanding of its effect in colorectal surgery remains limited. The purpose of this study was to examine the impact of history of depression among patients undergoing colectomy.

Method: United States patients from Marketscan (2010-2017) who underwent colectomy were included and stratified by whether they had a history of depression within the past year, defined as (1) a diagnosis of depression during the index admission, (2) a diagnosis of depression during any inpatient or (3) outpatient admission within the year, and/or (4) a pharmacy claim for an antidepressant within the year. The primary outcomes were length of stay (LOS) and inpatient hospital charge. Secondary outcomes included in-hospital mortality and postoperative complications. Logistic, negative binomial, and quantile regressions were performed.

Results: Among 88 981 patients, 21 878 (24.6%) had a history of depression. Compared to those without, patients with a history of depression had significantly longer LOS (IRR = 1.06, 95% CI [1.05, 1.07]), increased inpatient charge (β = 467, 95% CI [167, 767]), and increased odds of in-hospital mortality (OR = 1.37, 95% CI [1.08, 1.73]) after adjustment. History of depression was also independently associated with increased odds of respiratory complication, pneumonia, and delirium (all P < 0.05).

Conclusion: History of depression was prevalent among individuals undergoing colectomy, and associated with greater mortality and inpatient charge, longer LOS, and higher odds of postoperative complication. These findings highlight the impact of depression in colorectal surgery patients and suggest that proper identification and treatment may reduce postoperative morbidity.
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http://dx.doi.org/10.1111/codi.15790DOI Listing
June 2021

High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer.

Cancer Lett 2021 Aug 24;514:79-89. Epub 2021 May 24.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA. Electronic address:

Pancreatic cancer has the lowest survival rate out of all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages, hence an urgent need for a better therapeutic development of this devastating disease. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm mice. However, we found that Rhamm mice expressed a truncated HMMR protein at higher abundance levels than wild-type RHAMM. While HMMR did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRAS mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRAS mice with heterozygous p53 knockout. Kras PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of HMMR was not apparent in these short lifespan mice. In addition, HMMR shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, high levels of HMMR , which lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC), accelerated pancreatic cancer progression.
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http://dx.doi.org/10.1016/j.canlet.2021.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235875PMC
August 2021

The reduced risk of septic shock/sepsis with laparoscopic surgery among ulcerative colitis patients with preoperative chronic steroid use.

Surgery 2021 Apr 28. Epub 2021 Apr 28.

Colorectal Research Unit, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Preoperative steroid use has been associated with worse surgical outcomes. The purpose of this study was to determine whether laparoscopic surgery reduces the risk of septic shock/sepsis among ulcerative colitis patients with preoperative chronic steroid use.

Methods: Patients with ulcerative colitis undergoing a total abdominal colectomy were identified from the American College of Surgeons National Surgical Quality Improvement Program database (2005-2019). Patients were stratified based on preoperative chronic steroid use and operative approach (open versus laparoscopic). The primary outcome was septic shock/sepsis. Multivariable regression models were used to assess the association between laparoscopic surgery and rates of septic shock/sepsis among steroid users and non-steroid users in both the elective and emergent settings.

Results: Among 8,644 patients undergoing a total abdominal colectomy, 67.1% were steroid users and 32.9% were non-steroid users. Compared with an open approach, elective laparoscopic surgery was associated with lower rates of septic shock/sepsis, albeit with higher readmission rates for both steroid users (15.1% [laparoscopic] vs 12.0% [open], P = .005) and non-steroid users (12.6% [laparoscopic] vs 9.4% [open], P = .019). On adjusted analysis, ulcerative colitis patients with chronic steroid use undergoing an elective laparoscopic total abdominal colectomy demonstrated a reduced risk of septic shock/sepsis compared to open surgery (odds ratio 0.61, 95% confidence interval 0.49-0.76, P < .001). Similar findings were seen among chronic steroid users undergoing emergent laparoscopic procedures (odds ratio 0.54, 95% confidence interval 0.31-0.95, P = .031).

Conclusion: Laparoscopic surgery was associated with a reduced risk of septic shock/sepsis among ulcerative colitis patients with preoperative chronic steroid use, suggesting that minimally invasive surgery may be a promising option among this unique patient population.
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http://dx.doi.org/10.1016/j.surg.2021.03.058DOI Listing
April 2021

The Global Anatomic Staging System Does Not Predict Limb Based Patency of Tibial Endovascular Interventions.

Ann Vasc Surg 2021 Apr 24. Epub 2021 Apr 24.

Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD; Diabetic Foot and Wound Service, The Johns Hopkins Hospital, Baltimore, MD. Electronic address:

Objective: Anatomic grading systems have historically been poor predictors of patency after endovascular tibial interventions. The Global Vascular Guidelines proposed a new Global Anatomic Staging System (GLASS) to estimate one-year limb-based patency (LBP). The purpose of this study was to determine the association of GLASS with LBP following endovascular tibial interventions.

Methods: We included all patients presenting to our multidisciplinary diabetic limb preservation service between 01/2012 and 8/2020 who underwent first-time endovascular tibial revascularization for chronic limb-threatening ischemia. Diagnostic angiograms were reviewed to define the preferred target artery pathway and assign a GLASS stage to each treated limb. One-year LBP was calculated and compared across GLASS stages using Kaplan-Meier curves with log-rank tests and Cox proportional hazards models.

Results: We performed tibial revascularization in 96 limbs (5.2% rest pain, 56.3% ulcer, 37.5% gangrene), including isolated tibial interventions in 61.5% and tibial + femoropopliteal interventions in 38.5%. 15.6% of limbs were GLASS stage 1, 28.1% were GLASS stage 2, and 56.3% were GLASS stage 3. Overall, one-year LBP was 43.2 ± 6.3%, and did not differ significantly across GLASS stages (P = 0.42). The hazard ratio for failed LBP was 1.94 (95% CI 0.70-5.41) for GLASS stage 2 and 1.49 (95% CI 0.56-3.94) for GLASS stage 3 limbs (versus GLASS stage 1). When analyzed excluding the calcium modifier, LBP remained similar across GLASS stages (P = 0.72). Major amputation was uncommon, occurring in 9.3 ± 3.4% of limbs at one year, and did not significantly differ by GLASS stage (P = 0.98).

Conclusion: The Global Anatomic Staging System did not predict limb-based patency following tibial endovascular interventions. Given the low major amputation rates in this cohort, anatomic complexity should not preclude endovascular limb salvage efforts below the knee.
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http://dx.doi.org/10.1016/j.avsg.2021.04.007DOI Listing
April 2021

Geographical socioeconomic disadvantage is associated with adverse outcomes following major amputation in diabetic patients.

J Vasc Surg 2021 Apr 15. Epub 2021 Apr 15.

Johns Hopkins Surgery Center for Outcomes Research, Department of Surgery, The Johns Hopkins Hospital, Baltimore, Md; Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, The Johns Hopkins Hospital, Baltimore, Md. Electronic address:

Objective: Socioeconomic disadvantage is a known predictor of adverse outcomes and amputation in patients with diabetes. However, its association with outcomes after major amputation has not been described. Here, we aimed to determine the association of geographic socioeconomic disadvantage with 30-day readmission and 1-year reamputation rates among patients with diabetes undergoing major amputation.

Methods: Patients from the Maryland Health Services Cost Review Commission Database who underwent major lower extremity amputation with a concurrent diagnosis of diabetes mellitus between 2015 and 2017 were stratified by socioeconomic disadvantage as determined by the area deprivation index (ADI) (ADI1 [least deprived] to ADI4 [most deprived]). The primary outcomes were rates of 30-day readmission and 1-year reamputation, evaluated using multivariable logistic regression models and Kaplan-Meier survival analyses.

Results: A total of 910 patients were evaluated (66.0% male, 49.2% Black), including 30.9% ADI1 (least deprived), 28.6% ADI2, 19.1% ADI3, and 21.2% ADI4 (most deprived). After adjusting for differences in baseline demographic and clinical factors, the odds of 30-day readmission was similar among ADI groups (P > .05 for all). Independent predictors of 30-day readmission included female sex (odds ratio [OR], 1.45), Medicare insurance (vs private insurance; OR, 1.76), and peripheral artery disease (OR, 1.49) (P < .05 for all). The odds of 1-year reamputation was significantly greater among ADI4 (vs ADI1; OR, 1.74), those with a readmission for stump complication or infection/sepsis (OR, 2.65), and those with CHF (OR, 1.53) or PAD (OR, 1.59) (P < .05 for all).

Conclusions: Geographic socioeconomic disadvantage is independently associated with 1-year reamputation, but not 30-day readmission, among Maryland patients undergoing a major amputation for diabetes. A directed approach at improving postoperative management of chronic disease progression in socioeconomically deprived patients may be beneficial to reducing long-term morbidity in this high-risk group.
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http://dx.doi.org/10.1016/j.jvs.2021.03.033DOI Listing
April 2021

Knowledge and attitudes of U.S. medical students regarding the care of Asian American patients: a cross-sectional survey study.

BMC Med Educ 2021 Mar 6;21(1):148. Epub 2021 Mar 6.

Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, 733 N. Broadway, Miller Research Building 137, Baltimore, MD, 21205, USA.

Background: Asian Americans (AsAm) are a rapidly growing population in the U.S. With this growing population, U.S. healthcare providers must be equipped to provide culturally competent care for AsAm patients. This project surveyed U.S. medical students on their knowledge of and attitudes towards AsAm to assess predictors of readiness to care for AsAm patients.

Method: This cross-sectional study surveyed medical students who had completed at least one clinical rotation. The survey was distributed online to nine medical schools throughout the U.S. The survey measured self-rated knowledge of, comfort with, cultural competency (CC) towards, and explicit biases towards AsAm patients. The first three domains were analyzed in a multivariate regression model including sociodemographic characteristics and past clinical, curricular, and social experiences with AsAm. Explicit bias questions were reported descriptively.

Results: There were 688 respondents. Asian race, AsAm-prevalent hometown, AsAm-related extracurricular activities, Asian language knowledge, and having taken a population health course predicted increased AsAm knowledge. Social interactions with AsAm increased comfort with AsAm patients. Increasing year in medical school, more frequent exposure to AsAm patients on rotations, and prior travel to an Asian country were predictors of increased CC toward AsAm. Importantly, having completed a CC course was a significant predictor in all domains. In terms of explicit bias, students felt that AsAm patients were more compliant than Caucasian patients. Students also believed that Caucasian patients were generally more likely to receive self-perceived "preferred" versus "acceptable" care, but that in their own clinical experiences neither group received preferred care.

Conclusion: Experience with and exposure to AsAm prior to and during medical school and CC courses may increase medical student knowledge, comfort, and CC with AsAm patients. Standardized and longitudinal CC training, increased simulations with AsAm patients, diverse student recruitment, and support for students to engage in AsAm-related activities and interact with AsAm may improve CC of future physicians towards AsAm patients and possibly other minority populations.
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http://dx.doi.org/10.1186/s12909-021-02568-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937206PMC
March 2021

Impact of Treatment Coordination on Overall Survival in Rectal Cancer.

Clin Colorectal Cancer 2021 Jan 23. Epub 2021 Jan 23.

Colorectal Research Unit, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: Rectal cancer treatment is often multimodal, comprising of surgery, chemotherapy, and radiotherapy. However, the impact of coordination between these modalities is currently unknown. We aimed to assess whether delivery of nonsurgical therapy within same facility as surgery impacts survival in patients with rectal cancer.

Methods: A patient cohort with rectal cancer stages II to IV who received multimodal treatment between 2004 and 2016 from National Cancer Database was retrospectively analyzed. Patients were categorized into three groups: (A) surgery + chemotherapy + radiotherapy at same facility (surgery + 2); (B) surgery + chemotherapy or radiotherapy at same facility (surgery + 1); or (C) only surgery at reporting facility (chemotherapy + radiotherapy elsewhere; surgery + 0). The primary outcome was 5-year overall survival (OS), analyzed using Kaplan-Meier curves, log-rank tests, and Cox proportional-hazards models.

Results: A total of 44,716 patients (16,985 [37.98%] surgery + 2, 12,317 [27.54%] surgery + 1, and 15,414 [34.47%] surgery + 0) were included. In univariate analysis, we observed that surgery+2 patients had significantly greater 5-year OS compared to surgery + 1 or surgery + 0 patients (5-year OS: 63.46% vs 62.50% vs 61.41%, respectively; P= .002). We observed similar results in multivariable Cox proportional-hazards analysis, with surgery + 0 group demonstrating increased hazard of mortality when compared to surgery + 2 group (HR: 1.09; P< .001). These results held true after stratification by stage for stage II (HR 1.10; P= .022) and stage III (HR 1.12; P< .001) but not for stage IV (P= .474).

Conclusion: Greater degree of care coordination within the same facility is associated with greater OS in patients with stage II to III rectal cancer. This finding illustrates the importance of interdisciplinary collaboration in multimodal rectal cancer therapy.
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http://dx.doi.org/10.1016/j.clcc.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298589PMC
January 2021

Acupuncture for Cancer Related Pain: Protocol for a Pragmatic Randomised Wait-List Controlled Trial.

Integr Cancer Ther 2020 Jan-Dec;19:1534735420976579

Chinese Medicine Centre, Western Sydney University, NSW, Australia.

Background: Acupuncture has been proved effective for cancer related pain (CRP) in China, America and some other countries. However, there is relative lack of evidence to support the use of acupuncture for CRP in Australia.

Objectives: To assess the effectiveness and safety of acupuncture for management of CRP in a real-world setting and to understand cancer patients' experience of undergoing acupuncture for CRP.

Methods: A pragmatic randomised controlled trial will be conducted in South Western Sydney Local Health District (SWSLHD) in NSW, Australia. Adults with cancer related pain (n = 106) will be randomised in a 1:1 ratio to receive the acupuncture intervention up front versus after a wait list period of 4 weeks. Pain level (by Numerical Rating Scale), analgesic use, auricular acupressure frequency and adverse events will be assessed at baseline, mid-treatment and post-treatment. Expectancy on trial outcome (by Credibility and Expectancy questionnaire) will be assessed at baseline. The perspective of the participants (by an interview) will be recorded after the last intervention.

Expected Outcomes: We hypothesise that acupuncture will relieve cancer related pain at mid-treatment and post-treatment. We also hypothesise that few adverse events will be provoked by acupuncture.

Trial Registration: Australia New-Zealand Clinical Trial Registry (ACTRN12620000325909).
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http://dx.doi.org/10.1177/1534735420976579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734530PMC
December 2020

What Does a Diagnosis of Depression Mean for Patients Undergoing Colorectal Surgery?

J Surg Res 2021 Apr 1;260:454-461. Epub 2020 Dec 1.

Colorectal Research Unit, Ravitch Colorectal Division, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Background: Depression has been linked to increased morbidity and mortality in patients after surgery. The purpose of this study is to investigate the impact of documented depression diagnosis on in-hospital postoperative outcomes of patients undergoing colorectal surgery.

Materials And Methods: Patients from the National Inpatient Sample (2002-2017) who underwent proctectomies and colectomies were included. The outcomes measured included total hospital charge, length of stay, delirium, wound infection, urinary tract infection (UTI), pneumonia, deep vein thrombosis, pulmonary embolism, mortality, paralytic ileus, leak, and discharge trends. Multivariable logistic and Poisson regression analyses were performed.

Results: Of the 4,212,125 patients, depression diagnosis was present in 6.72% of patients who underwent colectomy and 6.54% of patients who underwent proctectomy. Regardless of procedure type, patients with depression had higher total hospital charges and greater rates of delirium, wound infection, UTI, leak, and nonroutine discharge, with no difference in length of stay. On adjusted analysis, patients with a depression diagnosis who underwent colectomies had increased risk of delirium (odds ratio (OR) 2.11, 95% confidence interval (CI) 1.93-2.32), wound infection (OR 1.08, 95% CI 1.03-1.12), UTI (OR 1.15, 95% CI 1.10-1.20), paralytic ileus (OR 1.06, 95% CI 1.03-1.09), and leak (OR 1.37, 95% CI 1.30-1.43). Patients who underwent proctectomy showed similar results, with the addition of significantly increased total hospital charges among the depression group. Depression diagnosis was independently associated with lower risk of in-hospital mortality (colectomy OR 0.58, 95% CI 0.53-0.62; proctectomy OR 0.72, 95% CI 0.55-0.94).

Conclusions: Patients with a diagnosis of depression suffer worse in-hospital outcomes but experience lower risk of in-hospital mortality after undergoing colorectal surgery. Further studies are needed to validate and fully understand the driving factors behind this.
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http://dx.doi.org/10.1016/j.jss.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959253PMC
April 2021

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Guidelines on Model Fitting and Recommendations on Time Course for In Vitro Cytochrome P450 Induction Studies Including Impact on Drug Interaction Risk Assessment.

Drug Metab Dispos 2021 Jan 2;49(1):94-110. Epub 2020 Nov 2.

Genentech, South San Francisco, California (S.G.W.); Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Janssen R&D, Spring House, Pennsylvania (S.D.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); Pfizer Global Research and Development, Groton, Connecticut (T.C.G.); Pfizer Global Research and Development, Cambridge, Massachusetts (P.D.Y.); Eisai, Cambridge, Massachusetts (Y.A.S.); Corning Life Sciences, Woburn, Massachusetts (G.Z.); Merck & Co., Inc., Kenilworth, New Jersey (D.T., J.P.); and AstraZeneca, Cambridge, Cambridgeshire, United Kingdom (B.J.).

Translational and ADME Sciences Leadership Group Induction Working Group (IWG) presents an analysis on the time course for cytochrome P450 induction in primary human hepatocytes. Induction of CYP1A2, CYP2B6, and CYP3A4 was evaluated by seven IWG laboratories after incubation with prototypical inducers (omeprazole, phenobarbital, rifampicin, or efavirenz) for 6-72 hours. The effect of incubation duration and model-fitting approaches on induction parameters (E and EC) and drug-drug interaction (DDI) risk assessment was determined. Despite variability in induction response across hepatocyte donors, the following recommendations are proposed: 1) 48 hours should be the primary time point for in vitro assessment of induction based on mRNA level or activity, with no further benefit from 72 hours; 2) when using mRNA, 24-hour incubations provide reliable assessment of induction and DDI risk; 3) if validated using prototypical inducers (>10-fold induction), 12-hour incubations may provide an estimate of induction potential, including characterization as negative if <2-fold induction of mRNA and no concentration dependence; 4) atypical dose-response ("bell-shaped") curves can be addressed by removing points outside an established confidence interval and %CV; 5) when maximum fold induction is well defined, the choice of nonlinear regression model has limited impact on estimated induction parameters; 6) when the maximum fold induction is not well defined, conservative DDI risk assessment can be obtained using sigmoidal three-parameter fit or constraining logistic three- or four-parameter fits to the maximum observed fold induction; 7) preliminary data suggest initial slope of the fold induction curve can be used to estimate E/EC and for induction risk assessment. SIGNIFICANCE STATEMENT: Regulatory agencies provide inconsistent guidance on the optimum length of time to evaluate cytochrome P450 induction in human hepatocytes, with EMA recommending 72 hours and FDA suggesting 48-72 hours. The Induction Working Group analyzed a large data set generated by seven member companies and determined that induction response and drug-drug risk assessment determined after 48-hour incubations were representative of 72-hour incubations. Additional recommendations are provided on model-fitting techniques for induction parameter estimation and addressing atypical concentration-response curves.
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http://dx.doi.org/10.1124/dmd.120.000055DOI Listing
January 2021

Impact of Geographic Socioeconomic Disadvantage on Minor Amputation Outcomes in Patients With Diabetes.

J Surg Res 2021 02 24;258:38-46. Epub 2020 Sep 24.

Johns Hopkins Surgery Center for Outcomes Research, Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland; Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland. Electronic address:

Background: Socioeconomic disadvantage is a known contributor to adverse events and higher admission rates in the diabetic population. However, its impact on outcomes after lower extremity amputation is unclear. We aimed to assess the association of geographic socioeconomic disadvantage with short- and long-term outcomes after minor amputation in patients with diabetes.

Materials And Methods: Geographic socioeconomic disadvantage was determined using the area deprivation index (ADI). All patients from the Maryland Health Services Cost Review Commission database (2012-2019) who underwent minor amputation with a concurrent diagnosis of diabetes were included and stratified by the ADI quartile. Associations of the ADI quartile with 30-day readmission and 1-year reamputation were evaluated using Kaplan-Meier survival analyses and multivariable logistic regression models adjusting for baseline differences.

Results: A total of 7415 patients with diabetes underwent minor amputation (70.1% male, 38.7% black race), including 28.1% ADI1 (least deprived), 42.8% ADI2, 22.9% ADI3, and 6.2% ADI4 (most deprived). After adjusting for demographic and clinical factors, the odds of 30-day readmission were greater in the intermediate ADI groups than those in the ADI1 group, but not among the most deprived. Adjusted odds of 1-year reamputation were greater among ADI4 than those among ADI1. Kaplan-Meier analysis confirmed a greater likelihood of reamputation with an increasing ADI quartile over a 1-year period (P < 0.001).

Conclusions: Geographic socioeconomic disadvantage is independently associated with both short- and long-term outcomes after minor diabetic amputations in Maryland. A targeted approach addressing the health care needs of deprived regions may be beneficial in optimizing postoperative care in this vulnerable population.
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http://dx.doi.org/10.1016/j.jss.2020.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736544PMC
February 2021

Temporal considerations in contact lens discomfort.

Cont Lens Anterior Eye 2021 Feb 29;44(1):14-17. Epub 2020 Aug 29.

School of Optometry & Vision Science, University of New South Wales, Sydney, Australia.

Purpose: To determine the relative contributions to perceived discomfort during contact lens wear of contact time with the lens and the time of day at which wear begins, using a wearing framework similar to that of regular users.

Methods: Twenty-three participants reported ocular discomfort using a 1-100 visual analogue rating scale, when prompted by email, during one day without contact lenses and on three other days while wearing soft contact lenses for twelve hours. Contact lens wear began at a different time on each day. The effect of start time on the change in discomfort during the wearing period was evaluated.

Results: The average (± 95 % CI) change in discomfort over 12 h without contact lenses was -0.3 ± 3.5. The corresponding values during contact lens wear were 23.5 ± 14.6 when starting wear before 8am, 16.8 ± 11.0 when starting between 8am & 10am and 22.7 ± 8.4 when starting after 10am. While the increased discomfort was significant irrespective of start time (p < 0.01), there were no statistically significant differences between start times (p = 0.98).

Conclusion: Discomfort during contact lens wear is associated with the length of time lenses are on-eye but not with the time of day when lenses are placed on-eye. This relationship is variable in the population and does not, of itself, explain why contact lenses become uncomfortable during wear. Active monitoring of participant compliance should be a consideration in all studies involving time critical responses.
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http://dx.doi.org/10.1016/j.clae.2020.08.007DOI Listing
February 2021

Do specific operative approaches and insurance status impact timely access to colorectal cancer care?

Surg Endosc 2021 Jul 19;35(7):3774-3786. Epub 2020 Aug 19.

Colorectal Research Unit, Ravitch Division of Colon and Rectal Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Blalock 618, Baltimore, MD, 21205, USA.

Introduction: The increased use of minimally invasive surgery in the management of colorectal cancer has led to a renewed focus on how certain factors, such as insurance status, impact the equitable distribution of both laparoscopic and robotic surgery. Our goal was to analyze surgical wait times between robotic, laparoscopic, and open approaches, and to determine whether insurance status impacts timely access to treatment.

Methods: After IRB approval, adult patients from the National Cancer Database with a diagnosis of colorectal cancer were identified (2010-2016). Patients who underwent radiation therapy, neoadjuvant chemotherapy, had wait times of 0 days from diagnosis to surgery, or had metastatic disease were excluded. Primary outcomes were days from cancer diagnosis to surgery and days from surgery to adjuvant chemotherapy. Multivariable Poisson regression analysis was performed.

Results: Among 324,784 patients, 5.9% underwent robotic, 47.5% laparoscopic, and 46.7% open surgery. Patients undergoing robotic surgery incurred the longest wait times from diagnosis to surgery (29.5 days [robotic] vs. 21.7 [laparoscopic] vs. 17.2 [open], p < 0.001), but the shortest wait times from surgery to adjuvant chemotherapy (48.9 days [robotic] vs. 49.9 [laparoscopic] vs. 54.8 [open], p < 0.001). On adjusted analysis, robotic surgery was associated with a 1.46 × longer wait time to surgery (IRR 1.462, 95% CI 1.458-1.467, p < 0.001), but decreased wait time to adjuvant chemotherapy (IRR 0.909, 95% CI 0.905-0.913, p < 0.001) compared to an open approach. Private insurance was associated with decreased wait times to surgery (IRR 0.966, 95% CI 0.962-0.969, p < 0.001) and adjuvant chemotherapy (IRR 0.862, 95% CI 0.858-0.865, p < 0.001) compared to Medicaid.

Conclusion: Though patients undergoing robotic surgery experienced delays from diagnosis to surgery, they tended to initiate adjuvant chemotherapy sooner compared to those undergoing open or laparoscopic approaches. Private insurance was independently associated not only with access to robotic surgery, but also shorter wait times during all stages of treatment.
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http://dx.doi.org/10.1007/s00464-020-07870-4DOI Listing
July 2021

Outcomes and Predictors of Wound Healing among Patients with Complex Diabetic Foot Wounds Treated with a Dermal Regeneration Template (Integra).

Plast Reconstr Surg 2020 10;146(4):893-902

From the Diabetic Foot and Wound Service, Division of Vascular Surgery and Endovascular Therapy and the Center for Surgical Trials and Outcomes Research, Department of Surgery, the Division of Endocrinology and Metabolism, Department of Medicine, and the Department of Plastic Surgery, The Johns Hopkins Hospital; and The Johns Hopkins University School of Medicine.

Background: The utility of dermal regeneration templates for treating high-risk diabetic foot wounds is unclear. The authors report wound healing and major amputation outcomes among a cohort of diabetic patients with complex diabetic foot wounds treated in a multidisciplinary setting.

Methods: All patients with complex diabetic foot wounds treated with a dermal regeneration template (March of 2013 to February of 2019) were captured in a prospective institutional database. Wound severity was classified according to the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system to determine limb salvage prognosis at baseline. Wound healing and major amputation rates were reported using Kaplan-Meier analyses. A stepwise Cox proportional hazards model was used to identify independent characteristics associated with wound healing.

Results: Eighty-five patients with 107 complex diabetic foot wounds were treated (mean age, 61.2 ± 3.3 years; 63.5 percent male and 61.2 percent African American). Most diabetic foot wounds were high-risk (wound, ischemia, and foot infection stage 3 or 4, 93.5 percent), corresponding to a predicted 25 to 50 percent risk of major amputation at 1 year. Dermal regeneration template use resulted in successful wound granulation in 66.7 percent of cases, with a mean time to complete wound healing of 198 ± 18 days. Twelve- and 18-month wound healing rates were 79.0 ± 5.0 percent and 93.0 ± 3.3 percent, respectively. Major amputation was required in 11.2 percent of patients. Independent predictors of poor wound healing included lack of bone involvement, higher WIfI stage, and prior dermal regeneration template failure.

Conclusion: Application of a dermal regeneration template to complex diabetic foot wounds at high risk for major amputation results in good wound healing and excellent limb salvage outcomes among diabetic patients treated in a multidisciplinary setting.

Clinical Question/level Of Evidence: Therapeutic, IV.
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http://dx.doi.org/10.1097/PRS.0000000000007166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718978PMC
October 2020

Anti-inflammatory effects of lenabasum, a cannabinoid receptor type 2 agonist, on macrophages from cystic fibrosis.

J Cyst Fibros 2020 09 6;19(5):823-829. Epub 2020 May 6.

Child Health Research Centre (CHRC), The University of Queensland, Brisbane, Australia.

Background: Lenabasum is an oral synthetic cannabinoid receptor type 2 agonist previously shown to reduce the production of key airway pro-inflammatory cytokines known to play a role in cystic fibrosis (CF). In a double-blinded, randomized, placebo-control phase 2 study, lenabasum lowered the rate of pulmonary exacerbation among patients with CF. The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum exhibits in CF macrophages.

Methods: We used monocyte-derived macrophages (MDMs) from healthy donors (n = 15), MDMs with CFTR inhibited with C-172 (n = 5) and MDMs from patients with CF (n = 4). Monocytes were differentiated to macrophages and polarized into classically activated (M1) macrophages by LPS or alternatively activated (M2) macrophages by IL-13 in presence or absence of lenabasum.

Results: Lenabasum had no effect on differentiation, polarization and function of macrophages from healthy individuals. However, in CF macrophages lenabasum downregulated macrophage polarization into the pro-inflammatory M1 phenotype and secretion of the pro-inflammatory cytokines IL-8 and TNF-α in a dose-dependent manner. An improvement in phagocytic activity was also observed following lenabasum treatment. Although lenabasum did not restore the impaired polarization of anti-inflammatory M2 macrophage, it reduced the levels of IL-13 and enhanced the endocytic function of CF MDMs. The effects of lenabasum on MDMs with CFTR inhibited by C-172 were not as obvious.

Conclusion: In CF macrophages lenabasum modulates macrophage polarization and function in vitro in a way that would reduce inflammation in vivo. Further studies are warranted to determine the link between activating the CBR2 receptor and CFTR.
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http://dx.doi.org/10.1016/j.jcf.2020.03.015DOI Listing
September 2020

High-Density Surface EMG-Based Gesture Recognition Using a 3D Convolutional Neural Network.

Sensors (Basel) 2020 Feb 21;20(4). Epub 2020 Feb 21.

Shenzhen Key Laboratory of Electromagnetic Control, Shenzhen University, Shenzhen 518060, China.

High-density surface electromyography (HD-sEMG) and deep learning technology are becoming increasingly used in gesture recognition. Based on electrode grid data, information can be extracted in the form of images that are generated with instant values of multi-channel sEMG signals. In previous studies, image-based, two-dimensional convolutional neural networks (2D CNNs) have been applied in order to recognize patterns in the electrical activity of muscles from an instantaneous image. However, 2D CNNs with 2D kernels are unable to handle a sequence of images that carry information concerning how the instantaneous image evolves with time. This paper presents a 3D CNN with 3D kernels to capture both spatial and temporal structures from sequential sEMG images and investigates its performance on HD-sEMG-based gesture recognition in comparison to the 2D CNN. Extensive experiments were carried out on two benchmark datasets (i.e., CapgMyo DB-a and CSL-HDEMG). The results show that, where the same network architecture is used, 3D CNN can achieve a better performance than 2D CNN, especially for CSL-HDEMG, which contains the dynamic part of finger movement. For CapgMyo DB-a, the accuracy of 3D CNN was 1% higher than 2D CNN when the recognition window length was equal to 40 ms, and was 1.5% higher when equal to 150 ms. For CSL-HDEMG, the accuracies of 3D CNN were 15.3% and 18.6% higher than 2D CNN when the window length was equal to 40 ms and 150 ms, respectively. Furthermore, 3D CNN achieves a competitive performance in comparison to the baseline methods.
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http://dx.doi.org/10.3390/s20041201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070985PMC
February 2020

Aggressive Multimodal Treatment and Metastatic Colorectal Cancer Survival.

J Am Coll Surg 2020 04 31;230(4):689-698. Epub 2020 Jan 31.

Colorectal Research Unit, Ravitch Colon and Rectal Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: We aimed to assess patient and demographic factors, treatment trends, and survival outcomes of patients with colorectal cancer with metastasis to the liver, lung, or both sites. Differences remain among national guidelines about the optimal management strategy.

Methods: Adults from the National Cancer Database (2010 to 2015) with a primary diagnosis of colorectal liver, lung, or liver and lung metastases were included and stratified by metastasis site. The primary end point was 5-year overall survival, analyzed using Kaplan-Meier survival curves, log-rank test, and the Cox proportional hazards model.

Results: Among 82,609 included patients, 70.42% had liver, 8.74% had lung, and 20.85% had simultaneous liver and lung metastases. Treatment with chemotherapy alone was used the most (21.11%), followed by chemotherapy with colorectal radical resection (CRRR) (19.4%), no treatment (14.35%), CRRR alone (9.03%), and chemotherapy with CRRR and liver/lung resection (8.22%). Patients with lung metastasis had significantly better 5-year overall survival rates than the other 2 metastatic groups (15.99%, 16.70%, and 5.51%; p < 0.001), even after stratifying by treatment type and adjusting for other factors. Chemotherapy with CRRR and liver/lung resection was associated with the greatest reduction in mortality risk for all sites in both unadjusted (35.15%, 44.52%, and 20.10%; p < 0.001) and adjusted analyses (hazard ratio 0.42; 95% CI, 0.38 to 0.47; p < 0.001; hazard ratio 0.31; 95% CI, 0.18 to 0.53; p < 0.001; and hazard ratio 0.79; 95% CI, 0.62 to 1.01; p = 0.064 for trend), and forgoing treatment or CRRR alone offered the worst overall survival.

Conclusions: Patients with metastasis to lung had increased overall survival compared with other sites of metastases, regardless of treatment modality. Combined resection of primary tumor, metastasectomy, and chemotherapy appears to offer the greatest chance of survival.
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http://dx.doi.org/10.1016/j.jamcollsurg.2019.12.024DOI Listing
April 2020

Clinical implications of incidental venous thromboembolism in cancer patients.

Eur Respir J 2020 02 6;55(2). Epub 2020 Feb 6.

Dept of Vascular Medicine, Amsterdam Cardiovascular Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: In cancer patients, current guidance suggests similar treatment for incidental and symptomatic venous thromboembolism (VTE), mainly based on retrospective data. We aimed to evaluate anticoagulant therapy in cancer patients with incidental and symptomatic VTE.

Methods: The Hokusai VTE Cancer Study was a randomised controlled trial comparing edoxaban with dalteparin for cancer-associated VTE. The primary outcome was the composite of first recurrent VTE or major bleeding. Secondary outcomes included major bleeding, recurrent VTE and mortality. Outcomes in patients with incidental and symptomatic VTE were evaluated during the 12-month study period.

Results: 331 patients with incidental VTE and 679 patients with symptomatic VTE were enrolled, of whom the index event was confirmed by an independent radiologist. Median durations of anticoagulant treatment were 195 and 189 days, respectively. In patients with incidental VTE, the primary outcome occurred in 12.7% of patients, major bleeding in 6.6% of patients and recurrent VTE in 7.9% of patients. Out of the 26 VTE recurrences in patients with incidental VTE, five (31%) were incidental, seven (44%) were symptomatic and four (25%) were deaths for which pulmonary embolism could not be ruled out. In patients with symptomatic VTE, the primary outcome occurred in 13.8% of patients, major bleeding in 4.9% of patients and recurrent VTE in 10.9% of patients. All-cause mortality was similar in both groups.

Conclusion: Clinical adverse outcomes are substantial in both cancer patients with incidental and symptomatic VTE, supporting current guideline recommendations that suggest treating incidental VTE in the same manner as symptomatic VTE.
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http://dx.doi.org/10.1183/13993003.01697-2019DOI Listing
February 2020

(-)-Oleocanthal and (-)-oleocanthal-rich olive oils induce lysosomal membrane permeabilization in cancer cells.

PLoS One 2019 14;14(8):e0216024. Epub 2019 Aug 14.

Department of Biological Sciences, Hunter College of the City University of New York, New York, New York, United States of America.

(-)-Oleocanthal (oleocanthal) is a phenolic compound found in varying concentrations in extra virgin olive oil oleocanthal has been shown to be active physiologically, benefiting several diseased states by conferring anti-inflammatory and neuroprotective benefits. Recently, we and other groups have demonstrated its specific and selective toxicity toward cancer cells; however, the mechanism leading to cancer cell death is still disputed. The current study demonstrates that oleocanthal, as well as naturally oleocanthal-rich extra virgin olive oils, induced damage to cancer cells' lysosomes leading to cellular toxicity in vitro and in vivo. Lysosomal membrane permeabilization following oleocanthal treatment in various cell lines was assayed via three complementary methods. Additionally, we found oleocanthal treatment reduced tumor burden and extended lifespan of mice engineered to develop pancreatic neuroendocrine tumors. Finally, following-up on numerous correlative studies demonstrating consumption of olive oil reduces cancer incidence and morbidity, we observed that extra virgin olive oils naturally rich in oleocanthal sharply reduced cancer cell viability and induced lysosomal membrane permeabilization while oleocanthal-poor oils did not. Our results are especially encouraging since tumor cells often have larger and more numerous lysosomes, making them especially vulnerable to lysosomotropic agents such as oleocanthal.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216024PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693737PMC
March 2020

A Fully Integrated and Self-Powered Smartwatch for Continuous Sweat Glucose Monitoring.

ACS Sens 2019 07 4;4(7):1925-1933. Epub 2019 Jul 4.

Materials Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States.

Wearable devices for health monitoring and fitness management have foreseen a rapidly expanding market, especially those for noninvasive and continuous measurements with real-time display that provide practical convenience and eliminated safety/infection risks. Herein, a self-powered and fully integrated smartwatch that consists of flexible photovoltaic cells and rechargeable batteries in the forms of a "watch strap", electrochemical glucose sensors, customized circuits, and display units integrated into a "dial" platform is successfully fabricated for real-time and continuous monitoring of sweat glucose levels. The functionality of the smartwatch, including sweat glucose sensing, signal processing, and display, can be supported with the harvested/converted solar energy without external charging devices. The Zn-MnO batteries serve as intermediate energy storage units and the utilization of aqueous electrolytes eliminated safety concerns for batteries, which is critical for wearable devices. Such a wearable system in a smartwatch fashion realizes integration of energy modules with self-powered capability, electrochemical sensors for noninvasive glucose monitoring, and and real-time signal processing/display in a single platform for the first time. The as-fabricated fully integrated and self-powered smartwatch also provides a promising protocol for statistical study and clinical investigation to reveal correlations between sweat compositions and human body dynamics.
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http://dx.doi.org/10.1021/acssensors.9b00891DOI Listing
July 2019

Acupuncture for polycystic ovarian syndrome.

Cochrane Database Syst Rev 2019 07 2;7:CD007689. Epub 2019 Jul 2.

Faculty of Science, University of Technology Sydney, C/O Specialist Medical Services Group, 356 Homer Street, Earlwood, New South Wales, Australia, 2206.

Background: Polycystic ovarian syndrome (PCOS) is characterised by the clinical signs of oligo-amenorrhoea, infertility and hirsutism. Conventional treatment of PCOS includes a range of oral pharmacological agents, lifestyle changes and surgical modalities. Beta-endorphin is present in the follicular fluid of both normal and polycystic ovaries. It was demonstrated that the beta-endorphin levels in ovarian follicular fluid of otherwise healthy women who were undergoing ovulation were much higher than the levels measured in plasma. Given that acupuncture impacts on beta-endorphin production, which may affect gonadotropin-releasing hormone (GnRH) secretion, it is postulated that acupuncture may have a role in ovulation induction via increased beta-endorphin production effecting GnRH secretion. This is an update of our previous review published in 2016.

Objectives: To assess the effectiveness and safety of acupuncture treatment for oligo/anovulatory women with polycystic ovarian syndrome (PCOS) for both fertility and symptom control.

Search Methods: We identified relevant studies from databases including the Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CNKI, CBM and VIP. We also searched trial registries and reference lists from relevant papers. CENTRAL, MEDLINE, Embase, PsycINFO, CNKI and VIP searches are current to May 2018. CBM database search is to November 2015.

Selection Criteria: We included randomised controlled trials (RCTs) that studied the efficacy of acupuncture treatment for oligo/anovulatory women with PCOS. We excluded quasi- or pseudo-RCTs.

Data Collection And Analysis: Two review authors independently selected the studies, extracted data and assessed risk of bias. We calculated risk ratios (RR), mean difference (MD), standardised mean difference (SMD) and 95% confidence intervals (CIs). Primary outcomes were live birth rate, multiple pregnancy rate and ovulation rate, and secondary outcomes were clinical pregnancy rate, restored regular menstruation period, miscarriage rate and adverse events. We assessed the quality of the evidence using GRADE methods.

Main Results: We included eight RCTs with 1546 women. Five RCTs were included in our previous review and three new RCTs were added in this update of the review. They compared true acupuncture versus sham acupuncture (three RCTs), true acupuncture versus relaxation (one RCT), true acupuncture versus clomiphene (one RCT), low-frequency electroacupuncture versus physical exercise or no intervention (one RCT) and true acupuncture versus Diane-35 (two RCTs). Studies that compared true acupuncture versus Diane-35 did not measure fertility outcomes as they were focused on symptom control.Seven of the studies were at high risk of bias in at least one domain.For true acupuncture versus sham acupuncture, we could not exclude clinically relevant differences in live birth (RR 0.97, 95% CI 0.76 to 1.24; 1 RCT, 926 women; low-quality evidence); multiple pregnancy rate (RR 0.89, 95% CI 0.33 to 2.45; 1 RCT, 926 women; low-quality evidence); ovulation rate (SMD 0.02, 95% CI -0.15 to 0.19, I = 0%; 2 RCTs, 1010 women; low-quality evidence); clinical pregnancy rate (RR 1.03, 95% CI 0.82 to 1.29; I = 0%; 3 RCTs, 1117 women; low-quality evidence) and miscarriage rate (RR 1.10, 95% CI 0.77 to 1.56; 1 RCT, 926 women; low-quality evidence).Number of intermenstrual days may have improved in participants receiving true acupuncture compared to sham acupuncture (MD -312.09 days, 95% CI -344.59 to -279.59; 1 RCT, 141 women; low-quality evidence).True acupuncture probably worsens adverse events compared to sham acupuncture (RR 1.16, 95% CI 1.02 to 1.31; I = 0%; 3 RCTs, 1230 women; moderate-quality evidence).No studies reported data on live birth rate and multiple pregnancy rate for the other comparisons: physical exercise or no intervention, relaxation and clomiphene. Studies including Diane-35 did not measure fertility outcomes.We were uncertain whether acupuncture improved ovulation rate (measured by ultrasound three months post treatment) compared to relaxation (MD 0.35, 95% CI 0.14 to 0.56; 1 RCT, 28 women; very low-quality evidence) or Diane-35 (RR 1.45, 95% CI 0.87 to 2.42; 1 RCT, 58 women; very low-quality evidence).Overall evidence ranged from very low quality to moderate quality. The main limitations were failure to report important clinical outcomes and very serious imprecision.

Authors' Conclusions: For true acupuncture versus sham acupuncture we cannot exclude clinically relevant differences in live birth rate, multiple pregnancy rate, ovulation rate, clinical pregnancy rate or miscarriage. Number of intermenstrual days may improve in participants receiving true acupuncture compared to sham acupuncture. True acupuncture probably worsens adverse events compared to sham acupuncture.No studies reported data on live birth rate and multiple pregnancy rate for the other comparisons: physical exercise or no intervention, relaxation and clomiphene. Studies including Diane-35 did not measure fertility outcomes as the women in these trials did not seek fertility.We are uncertain whether acupuncture improves ovulation rate (measured by ultrasound three months post treatment) compared to relaxation or Diane-35. The other comparisons did not report on this outcome.Adverse events were recorded in the acupuncture group for the comparisons physical exercise or no intervention, clomiphene and Diane-35. These included dizziness, nausea and subcutaneous haematoma. Evidence was very low quality with very wide CIs and very low event rates.There are only a limited number of RCTs in this area, limiting our ability to determine effectiveness of acupuncture for PCOS.
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http://dx.doi.org/10.1002/14651858.CD007689.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603768PMC
July 2019

Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression.

Mol Cancer 2019 05 9;18(1):92. Epub 2019 May 9.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Box 69, New York, NY, 10065, USA.

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMM promoted liver metastasis. It was unknown whether RHAMM is upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms, RHAMM and RHAMM, by RNA-Seq analysis of primary PNETs and liver metastases. RHAMM, but not RHAMM, was significantly upregulated in liver metastases. RHAMM was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMM, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMM was substantially higher than RHAMM in pancreatic ductal adenocarcinoma (PDAC). RHAMM, but not RHAMM, correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMM-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMM, but not RHAMM, in promoting PNET metastasis in part through EGFR signaling. RHAMM can thus serve as a prognostic factor for pancreatic cancer.
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http://dx.doi.org/10.1186/s12943-019-1018-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506944PMC
May 2019

Determinants of the Quality of Warfarin Control after Venous Thromboembolism and Validation of the SAMe-TT2-R2 Score: An Analysis of Hokusai-VTE.

Thromb Haemost 2019 Apr 7;119(4):675-684. Epub 2019 Feb 7.

Thrombosis Research Unit, Division of Hematology, Department of Medicine I, University Hospital "Carl Gustav Carus," Dresden, Germany.

Background:  Time in therapeutic range (TTR) measures the quality of vitamin K antagonist (VKA) anticoagulation. In patients with atrial fibrillation, the dichotomized SAMe-TT2-R2 score (≥2 vs. < 2 points) can predict if adequate TTR is unlikely to be achieved.

Aims:  We validated the SAMe-TT2-R2 score in patients with venous thromboembolism (VTE) randomized to the warfarin arm of the Hokusai-VTE trial.

Patients And Methods:  A total of 3,874 patients were included in the primary analysis (day 31-180 from randomization). The efficacy and safety outcomes were symptomatic recurrent VTE and major or clinically relevant non-major bleeding.

Results:  The rates of recurrent VTE and bleeding events were higher in patients with a TTR below the median (< 66% vs. ≥66%) resulting in an absolute risk difference (ARD) of +0.5% (95% confidence interval: 0%, +1.1%) and +2.2% (0.9%, +3.5%), respectively. Patients with high SAMe-TT2-R2 score were 76% of total and had lower median TTR (64.7% vs. 70.7%). The SAMe-TT2-R2 score exhibited low negative (0.59) and positive (0.52) predictive value (TTR threshold 66%), and poor discrimination (c-statistic, 0.58). ARD between patients with high and low score was 0% (-0.6%, +0.7%) for recurrence and +1.3% (-0.1%, +2.7%) for bleeding. Results were confirmed in sensitivity analyses focusing on the whole study period (day 1-365).

Conclusion:  In VTE patients, the SAMe-TT2-R2 score showed unsatisfactory discrimination and predictive value for individual TTR and did not correlate well with clinical outcomes. The choice of starting a patient on VKA cannot be based on this parameter and its routine use after VTE may not translate into clinical usefulness.
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http://dx.doi.org/10.1055/s-0039-1678546DOI Listing
April 2019

Methylated Unsymmetric BODIPY Compounds: Synthesis, High Fluorescence Quantum Yield and Long Fluorescence Time.

J Fluoresc 2019 Mar 23;29(2):407-416. Epub 2019 Jan 23.

Institute of Applied Photochemistry, Hebei Normal University of Science and Technology, Qinhuangdao, 066004, Hebei Province, China.

We show that unsymmetric BODIPY compounds with one, two, and three methyl groups can be synthesized easily and efficiently by the unsymmetric reaction method. Their steady state and time-resolved fluorescence properties are examined in solvents of different polarity. These compounds show high fluorescence quantum yields (0.87 to 1.0), long fluorescence lifetimes (5.89 to 7.40 ns), and small Stokes shift (199 to 443 cm). The methyl substitution exhibits influence on the UV-Vis absorption and fluorescence properties, such as the blue shift in emission and absorption spectra. It is the number rather than the position of methyls that play major roles. Except for 3 M-BDP, the increase in the number of methyls on BODIPY core leads to the increase in both fluorescence quantum yield and radiative rate constant, but causes the decrease in fluorescence lifetime. H-bonding solvents increase both the fluorescence lifetime and quantum yields. The methylated BODIPYs show the ability to generate singlet oxygen (Δ) which is evidenced by near-IR luminescence and DPBF chemical trapping techniques. The formation quantum yield of singlet oxygen (Δ) for the compounds is up to 0.15 ± 0.05.
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http://dx.doi.org/10.1007/s10895-019-02349-5DOI Listing
March 2019

Orthotopic Pancreatic Tumor Mouse Models of Liver Metastasis.

Methods Mol Biol 2019 ;1882:309-320

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

The survival from pancreatic cancer is poor because most patients are diagnosed after the cancer has metastasized. Liver is the most common site of pancreatic cancer metastasis. Orthotopic mouse models of liver metastasis by intrasplenically injecting the pancreatic tumor cells are useful in studying the molecular mechanisms of metastasis and evaluating therapeutic regimens.
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http://dx.doi.org/10.1007/978-1-4939-8879-2_27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800204PMC
June 2019

Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation.

Cancer Gene Ther 2019 03 7;26(3-4):94-102. Epub 2018 Sep 7.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

We reported that inactivation of menin (the protein product of MEN1) increases activity of Dnmt1 and mediates DNA hypermethylation in the development of multiple endocrine neoplasia type 1 (MEN1) syndrome. We have developed a RCAS-TVA-based somatic gene transfer system that enables tissue-specific delivery of Dnmt1 to individual β-cells of the pancreas in a RIP-TVA mouse model. In the present study, we mediated Dnmt1 expression in islet β-cells in RIP-TVA mice by utilizing the RCAS-TVA system to test if the upregulation of Dnmt1 can promote β-cell proliferation. In vitro, we demonstrated that upregulation of Dnmt1 increased β-cell proliferation. In vivo, our results showed that the levels of serum insulin were increased in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Furthermore, we confirmed that mRNA and protein expression of Dnmt1 as well as Dnmt1 enzyme activity were upregulated in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Finally, we demonstrated that upregulation of Dnmt1 resulted in hyperplasia through β-cell proliferation. We conclude that the upregulation of Dnmt1 promotes islet β-cell proliferation and targeting Dnmt1 may be a promising therapy for patients suffering from pancreatic neuroendocrine tumors.
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http://dx.doi.org/10.1038/s41417-018-0046-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540611PMC
March 2019

Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study.

Thromb Haemost 2018 Aug 30;118(8):1439-1449. Epub 2018 Jul 30.

University of Oklahoma Health Sciences Center, College of Public Health, University of Oklahoma, Oklahoma City, Oklahoma, United States.

In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting.
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http://dx.doi.org/10.1055/s-0038-1667001DOI Listing
August 2018

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies: Focus on CYP3A4 mRNA In Vitro Response Thresholds, Variability, and Clinical Relevance.

Drug Metab Dispos 2018 Sep 29;46(9):1285-1303. Epub 2018 Jun 29.

Genentech, South San Francisco, California (J.R.K.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Sekisui-XenoTech LLC, Kansas City, Kansas (D.B.B.); Janssen R&D, Spring House, Pennsylvania (S.D.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); Amgen Inc., Cambridge, Massachusetts (J.G.D.); Sanofi, Waltham, Massachusetts (M.F.); Pfizer Global Research and Development, Groton, Connecticut (T.C.G.); Eisai, Andover, Massachusetts (Y.A.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.L.W.); Corning Life Sciences, Woburn, Massachusetts (G.Z.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.).

The Innovation and Quality Induction Working Group presents an assessment of best practice for data interpretation of in vitro induction, specifically, response thresholds, variability, application of controls, and translation to clinical risk assessment with focus on CYP3A4 mRNA. Single concentration control data and Emax/EC data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary. A large degree of variability was observed in both the clinical and in vitro induction responses; however, analysis confirmed in vitro data are able to predict clinical induction risk. Following extensive examination of this large data set, the following recommendations are proposed. a) Cytochrome P450 induction should continue to be evaluated in three separate human donors in vitro. b) In light of empirically divergent responses in rifampicin control and most test inducers, normalization of data to percent positive control appears to be of limited benefit. c) With concentration dependence, 2-fold induction is an acceptable threshold for positive identification of in vitro CYP3A4 mRNA induction. d) To reduce the risk of false positives, in the absence of a concentration-dependent response, induction ≥ 2-fold should be observed in more than one donor to classify a compound as an in vitro inducer. e) If qualifying a compound as negative for CYP3A4 mRNA induction, the magnitude of maximal rifampicin response in that donor should be ≥ 10-fold. f) Inclusion of a negative control adds no value beyond that of the vehicle control.
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http://dx.doi.org/10.1124/dmd.118.081927DOI Listing
September 2018

Solution-Synthesized High-Mobility Tellurium Nanoflakes for Short-Wave Infrared Photodetectors.

ACS Nano 2018 Jul 22;12(7):7253-7263. Epub 2018 Jun 22.

Electrical Engineering and Computer Sciences , University of California at Berkeley , Berkeley , California 94720 , United States.

Two-dimensional (2D) materials, particularly black phosphorus (bP), have demonstrated themselves to be excellent candidates for high-performance infrared photodetectors and transistors. However, high-quality bP can be obtained only via mechanical exfoliation from high-temperature- and high-pressure-grown bulk crystals and degrades rapidly when exposed to ambient conditions. Here, we report solution-synthesized and air-stable quasi-2D tellurium (Te) nanoflakes for short-wave infrared (SWIR) photodetectors. We perform comprehensive optical characterization via polarization-resolved transmission and reflection measurements and report the absorbance and complex refractive index of Te crystals. It is found that this material is an indirect semiconductor with a band gap of 0.31 eV. From temperature-dependent electrical measurements, we confirm this band-gap value and find that 12 nm thick Te nanoflakes show high hole mobilities of 450 and 1430 cm V s at 300 and 77 K, respectively. Finally, we demonstrate that despite its indirect band gap, Te can be utilized for high-performance SWIR photodetectors by employing optical cavity substrates consisting of Au/AlO to dramatically increase the absorption in the semiconductor. By changing the thickness of the AlO cavity, the peak responsivity of Te photoconductors can be tuned from 1.4 μm (13 A/W) to 2.4 μm (8 A/W) with a cutoff wavelength of 3.4 μm, fully capturing the SWIR band. An optimized room-temperature specific detectivity ( D*) of 2 × 10 cm Hz W is obtained at a wavelength of 1.7 μm.
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http://dx.doi.org/10.1021/acsnano.8b03424DOI Listing
July 2018
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