Higher rates of all-cause mortality and resource utilization during episodes-of-care for diabetic foot ulceration.

AIMS: Our primary objective was to determine whether all-cause rates of mortality and resource utilization were higher during periods of diabetic foot ulceration. In support of this objective, a secondary objective was to develop and validate an episode-of-care model for diabetic foot ulceration. METHODS: We evaluated data from the Medicare Limited Data Set between 2013 and 2019. We defined episodes-of-care by clustering diabetic foot ulcer related claims such that the longest time interval between consecutive claims in any cluster did not exceed a duration which was adjusted to match two aspects of foot ulcer episodes that are well-established in the literature: healing rate at 12 weeks, and reulceration rate following healing. We compared rates of outcomes during periods of ulceration to rates immediately following healing to estimate incidence ratios. RESULTS: The episode-of-care model had a minimum mean relative error of 4.2% in the two validation criteria using a clustering duration of seven weeks. Compared to periods after healing, all-cause inpatient admissions were 2.8 times more likely during foot ulcer episodes and death was 1.5 times more likely. CONCLUSIONS: A newly-validated episode-of-care model for diabetic foot ulcers suggests an underappreciated association between foot ulcer episodes and all-cause resource utilization and mortality.

Lower resource utilization for patients with healed diabetic foot ulcers during participation in a prevention program with foot temperature monitoring.

INTRODUCTION: We assessed the impact of a diabetic foot ulcer prevention program incorporating once-daily foot temperature monitoring on hospitalizations, emergency department and outpatient visits, and rates of diabetic foot ulcer recurrence and lower extremity amputations for patients with recently healed foot ulcers. RESEARCH DESIGN AND METHODS: In this retrospective analysis of real-world data, we enrolled 80 participants with a healed diabetic foot ulcer in a year-long foot ulcer recurrence prevention program. Four outpatient centers within a large integrated healthcare system in the USA contributed to enrollment. We evaluated diabetic foot-related outcomes and associated resource utilization for participants during three periods: the 2 years before the program, the year during the program, and after the program ended. We reported unadjusted resource utilization rates during the program and the periods before and after it. We then adjusted rates of outcomes in each phase using an interrupted time series approach, explicitly controlling for overall trends in resource utilization and recurrence during the three periods. RESULTS: Our unadjusted data showed high initial rates of resource utilization and recurrence before enrollment in the program, followed by lower rates during the program, and higher rates of resource utilization and similar rates of recurrence in the period following the end of the program. The adjusted data showed lower rates of hospitalizations (relative risk reduction (RRR)=0.52; number needed to treat (NNT)=3.4), lower extremity amputations (RRR=0.71; NNT=6.4), and outpatient visits (RRR=0.26; absolute risk reduction (ARR)=3.5) during the program. We also found lower rates of foot ulcer recurrence during the program in the adjusted data, particularly for wounds with infection or greater than superficial depth (RRR=0.91; NNT=4.4). CONCLUSIONS: We observed lower rates of healthcare resource utilization for high-risk participants during enrollment in a diabetic foot prevention program incorporating once-daily foot temperature monitoring. TRIAL REGISTRATION NUMBER: NCT04345016.

Accuracy of a foot temperature monitoring mat for predicting diabetic foot ulcers in patients with recent wounds or partial foot amputation.

AIMS: To assess the accuracy of once-daily foot temperature monitoring for predicting foot ulceration in diabetic patients with recent wounds and partial foot amputation, complications previously perceived as challenging. METHODS: We completed a planned analysis of existing data from a recent study in 129 participants with a previously-healed diabetic foot ulcer. We considered four cohorts: all participants, participants with partial foot amputation, participants with a recent wound, and participants without partial foot amputation and without a recent wound. We reported the prediction specificity, lead time, and annualized alert frequency in each cohort at maximum sensitivity. We assessed the two potentially challenging cohorts for non-inferior accuracy relative to the control cohort using Delong's method. RESULTS: We report non-inferior predictive accuracy in each of the two potentially-challenging cohorts relative to the control cohort (⍺ < 0.05). The alert lead time was similar across these cohorts, ranging from 33 to 42 days. CONCLUSIONS: Once-daily foot temperature monitoring is no less accurate for predicting foot ulceration in those with recent wounds and partial foot amputations than in those without these complications. These results support expanded practice of once-daily foot temperature monitoring, which may result in improved patient outcomes and reduced healthcare resource utilization.

Ulcer metastasis? Anatomical locations of recurrence for patients in diabetic foot remission.

BACKGROUND: The "cancer analogy" is powerful for communicating risk to and organizing care for patients with diabetic foot syndrome. One potentially underappreciated similarity between cancer and foot ulcers is that both can recur at anatomical locations distinct from the primary occurrence, albeit with different physiological mechanisms. Few studies have characterized the location of diabetic foot ulcer recurrence, and these have been limited by considering only the first recurrent wound following a recent-healed wound. We therefore characterized the anatomical locations at which diabetic foot ulcers are likely to recur considering multiple wounds during follow-up and the locations of all prior wounds documented in the participant's history. METHODS: We completed a secondary analysis of existing data from a 129 participant multi-center study of participants in diabetic foot remission. The primary outcome was plantar foot ulceration, and each participant was followed for 34 weeks or until withdrawing consent, allowing characterization of all wounds occurring. We stratified the anatomical locations of wounds prior to the trial by the following outcome categories during the trial: no recurrence, recurrence to the same anatomical location, recurrence to a different anatomical location on the same foot, and recurrence to the contralateral foot. RESULTS: A large percentage (48%) of wounds recurred to the contralateral foot, and the proportion of subsequent foot ulcer to the contralateral limb was largely unaffected by the anatomical location of foot ulcer prior to the study. Only 17% of prior diabetic foot ulcers were followed by recurrence to the same anatomical location. Rates of recurrence remained high during treatment of a wound (0.41 foot ulcer/ulcer-year). Participants had documented wounds to 2.2 distinct anatomical locations on average, and more than 60% of participants had wounds to more than one plantar location by the end of the study. CONCLUSIONS: Given the significant morbidity, mortality, and resource utilization associated with foot ulcer recidivism, quality and evidenced-based preventive care is essential. Our results better characterize the burden of recurrence and to what anatomy recurrence is most likely. These insights may benefit providers and patients alike for the provision of high-quality preventive care thereby resulting in reduced morbidity, mortality, and cost. TRIAL REGISTRATION: The study providing the data for this secondary analysis was registered on ClinicalTrials.gov (NCT02647346) on January 6, 2016. The study was retrospectively registered.

Unilateral remote temperature monitoring to predict future ulceration for the diabetic foot in remission.

Objective: Daily remote foot temperature monitoring is an evidence-based preventive practice for patients at risk for diabetic foot complications. Unfortunately, the conventional approach requires comparison of temperatures between contralaterally matched anatomy, limiting practice in high-risk cohorts such as patients with a wound to one foot and those with proximal lower extremity amputation (LEA). We developed and assessed a novel approach for monitoring of a single foot for the prevention and early detection of diabetic foot complications. The purpose of this study was to assess the sensitivity, specificity, and lead time associated with unilateral diabetic foot temperature monitoring. Research design and methods: We used comparisons among ipsilateral foot temperatures and between foot temperatures and ambient temperature as a marker of inflammation. We analyzed data collected from a 129-participant longitudinal study to evaluate the predictive accuracy of our approach. To evaluate classification accuracy, we constructed a receiver operator characteristic curve and reported sensitivity, specificity, and lead time for four different monitoring settings. Results: Using this approach, monitoring a single foot was found to predict 91% of impending non-acute plantar foot ulcers on average 41 days before clinical presentation with a resultant mean 4.2 alerts per participant-year. By adjusting the threshold temperature setting, the specificity could be increased to 78% with corresponding reduced sensitivity of 53%, lead time of 33 days, and 2.2 alerts per participant-year. Conclusions: Given the high incidence of subsequent diabetic foot complications to the sound foot in patients with a history of proximal LEA and patients being treated for a wound, practice of daily temperature monitoring of a single foot has the potential to significantly improve outcomes and reduce resource utilization in this challenging high-risk population.

Feasibility and Efficacy of a Smart Mat Technology to Predict Development of Diabetic Plantar Ulcers.

OBJECTIVE: We conducted a multicenter evaluation of a novel remote foot-temperature monitoring system to characterize its accuracy for predicting impending diabetic foot ulcers (DFU) in a cohort of patients with diabetes with previously healed DFU. RESEARCH DESIGN AND METHODS: We enrolled 132 participants with diabetes and prior DFU in this 34-week cohort study to evaluate a remote foot-temperature monitoring system (ClinicalTrials.gov Identifier NCT02647346). The study device was a wireless daily-use thermometric foot mat to assess plantar temperature asymmetries. The primary outcome of interest was development of nonacute plantar DFU, and the primary efficacy analysis was the accuracy of the study device for predicting the occurrence of DFU over several temperature asymmetry thresholds. RESULTS: Of the 129 participants who contributed evaluable data to the study, a total of 37 (28.7%) presented with 53 DFU (0.62 DFU/participant/year). At an asymmetry of 2.22°C, the standard threshold used in previous studies, the system correctly identified 97% of observed DFU, with an average lead time of 37 days and a false-positive rate of 57%. Increasing the temperature threshold to 3.20°C decreased sensitivity to 70% but similarly reduced the false-positive rate to 32% with approximately the same lead time of 35 days. Approximately 86% of the cohort used the system at least 3 days a week on average over the study. CONCLUSIONS: Given the encouraging study results and the significant burden of DFU, use of this mat may result in significant reductions in morbidity, mortality, and resource utilization.

New insights into the effect of rapid transfusion of fresh frozen plasma on ionized calcium.

STUDY OBJECTIVES: 1) To develop an in vitro system to simulate the kinetics of ionized calcium in mixed venous blood during rapid transfusion of fresh frozen plasma (FFP) and 2) to use the in vitro data to estimate the effect of the transfusion rate relative to cardiac output (CO) on ionized calcium. DESIGN: Experimental study. SETTING: Research laboratory of an academic hospital. MEASUREMENTS: Citrated FFP was mixed with compatible heparinized whole blood at various volume ratios in vitro to simulate the mixed venous blood obtained at various flow ratios of FFP transfusion to the recipient's venous system in vivo. Ionized calcium was measured after each mixture. MAIN RESULTS: Mixing FFP and whole blood at volume ratios of 0:100, 5:95, 10:90, and 15:85 yielded ionized calcium levels (mean ± SD, mmol/L) of 1.23, 0.81 ± 0.02, 0.54 ± 0.08, and 0.34 ± 0.02, respectively. The 50% reduction in ionized calcium occurred at a volume ratio of 7:93. CONCLUSIONS: An instantaneous 50% reduction in ionized calcium occurs in vitro at a proportion equivalent to a transfusion rate of FFP representing 7% of CO.

Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model.

An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.

Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.

Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.

Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity.

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.

Restructuring within an academic health center to support quality and safety: the development of the Center for Quality and Safety at the Massachusetts General Hospital.

Recent focus on the need to improve the quality and safety of health care has created new challenges for academic health centers (AHCs). Whereas previously quality was largely assumed, today it is increasingly quantifiable and requires organized systems for improvement. Traditional structures and cultures within AHCs, although well suited to the tripartite missions of teaching, research, and clinical care, are not easily adaptable to the tasks of measuring, reporting, and improving quality. Here, the authors use a case study of Massachusetts General Hospital's efforts to restructure quality and safety to illustrate the value of beginning with a focus on organizational culture, using a systematic process of engaging clinical leadership, developing an organizational framework dependent on proven business principles, leveraging focus events, and maintaining executive dedication to execution of the initiative. The case provides a generalizable example for AHCs of how applying explicit management design can foster robust organizational change with relatively modest incremental financial resources.

Novel pyrazolopyrimidines as highly potent B-Raf inhibitors.

A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.

Thiourea inhibitors of herpesviruses. Part 3: Inhibitors of varicella zoster virus.

The preparation of alpha-methylbenzyl thioureas and their biological activity against varicella zoster virus is described. Several analogs demonstrated IC50s<0.1 microM and their SAR are discussed. These compounds represent a novel class of potent and selective nonnucleoside inhibitors of varicella zoster virus.

Thiourea inhibitors of herpes viruses. Part 2: N-Benzyl-N'-arylthiourea inhibitors of CMV.

A series of highly potent thiourea inhibitors of cytomegalovirus (CMV) with improved stability properties was prepared and evaluated. Compound 29 inhibited the virus in cultured HFF cells with IC50 of 0.2 nM.

Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule.

A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of screening a chemical library by using a whole-virus infected-cell assay. Synthetic chemistry efforts yielded the analog designated CFI02, a compound whose potency had been increased about 100-fold over an initial inhibitor. The inhibitory concentration of CFI02 in various assays is in the low nanomolar range. CFI02 is a selective and potent inhibitor of HCMV; it has no activity against other CMVs, alphaherpesviruses, or unrelated viruses. Mechanism-of-action studies indicate that CFI02 acts very early in the replication cycle, inhibiting virion envelope fusion with the cell plasma membrane. Mutants resistant to CFI02 have mutations in the abundant virion envelope glycoprotein B that are sufficient to confer resistance. Taken together, the data suggest that CFI02 inhibits glycoprotein B-mediated HCMV virion fusion. Furthermore, CFI02 inhibits the cell-cell spread of HCMV. This is the first study of a potent and selective small molecule inhibitor of CMV fusion and cell-cell spread.

Thiourea inhibitors of herpes viruses. Part 1: bis-(aryl)thiourea inhibitors of CMV.

Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in cultured HFF cells. Of these, the thiazole analogue 38 was investigated as a potential development candidate.

Pyrimido[1,2-b]-1,2,4,5-tetrazin-6-ones as HCMV protease inhibitors: a new class of heterocycles with flavin-like redox properties.

The synthesis and biological activity of pyrimidotetrazin-6-ones against HCMV protease is described. The mechanism of action for these inhibitors is the oxidation of several cysteine residues to generate cross-linked enzyme.

Identification of small molecule compounds that selectively inhibit varicella-zoster virus replication.

A series of nonnucleoside, N-alpha-methylbenzyl-N'-arylthiourea analogs were identified which demonstrated selective activity against varicella-zoster virus (VZV) but were inactive against other human herpesviruses, including herpes simplex virus. Representative compounds had potent activity against VZV early-passage clinical isolates and an acyclovir-resistant isolate. Resistant viruses generated against one inhibitor were also resistant to other compounds in the series, suggesting that this group of related small molecules was acting on the same virus-specific target. Sequencing of the VZV ORF54 gene from two independently derived resistant viruses revealed mutations in ORF54 compared to the parental VZV strain Ellen sequence. Recombinant VZV in which the wild-type ORF54 sequence was replaced with the ORF54 gene from either of the resistant viruses became resistant to the series of inhibitor compounds. Treatment of VZV-infected cells with the inhibitor impaired morphogenesis of capsids. Inhibitor-treated cells lacked DNA-containing dense-core capsids in the nucleus, and only incomplete virions were present on the cell surface. These data suggest that the VZV-specific thiourea inhibitor series block virus replication by interfering with the function of the ORF54 protein and/or other proteins that interact with the ORF54 protein.