Peptidoglycan-Targeted [18F]3,3,3-Trifluoro-d-alanine Tracer for Imaging Bacterial Infection.

Imaging is increasingly used to detect and monitor bacterial infection. Both anatomic (X-rays, computed tomography, ultrasound, and MRI) and nuclear medicine ([111In]-WBC SPECT, [18F]FDG PET) techniques are used in clinical practice but lack specificity for the causative microorganisms themselves. To meet this challenge, many groups have developed imaging methods that target pathogen-specific metabolism, including PET tracers integrated into the bacterial cell wall. We have previously reported the d-amino acid derived PET radiotracers d-methyl-[11C]-methionine, d-[3-11C]-alanine, and d-[3-11C]-alanine-d-alanine, which showed robust bacterial accumulation in vitro and in vivo. Given the clinical importance of radionuclide half-life, in the current study, we developed [18F]3,3,3-trifluoro-d-alanine (d-[18F]-CF3-ala), a fluorine-18 labeled tracer. We tested the hypothesis that d-[18F]-CF3-ala would be incorporated into bacterial peptidoglycan given its structural similarity to d-alanine itself. NMR analysis showed that the fluorine-19 parent amino acid d-[19F]-CF3-ala was stable in human and mouse serum. d-[19F]-CF3-ala was also a poor substrate for d-amino acid oxidase, the enzyme largely responsible for mammalian d-amino acid metabolism and a likely contributor to background signals using d-amino acid derived PET tracers. In addition, d-[19F]-CF3-ala showed robust incorporation into Escherichia coli peptidoglycan, as detected by HPLC/mass spectrometry. Based on these promising results, we developed a radiosynthesis of d-[18F]-CF3-ala via displacement of a bromo-precursor with [18F]fluoride followed by chiral stationary phase HPLC. Unexpectedly, the accumulation of d-[18F]-CF3-ala by bacteria in vitro was highest for Gram-negative pathogens in particular E. coli. In a murine model of acute bacterial infection, d-[18F]-CF3-ala could distinguish live from heat-killed E. coli, with low background signals. These results indicate the viability of [18F]-modified d-amino acids for infection imaging and indicate that improved specificity for bacterial metabolism can improve tracer performance.

Evaluating the Performance of Pathogen-Targeted Positron Emission Tomography Radiotracers in a Rat Model of Vertebral Discitis-Osteomyelitis.

BACKGROUND: Vertebral discitis-osteomyelitis (VDO) is a devastating infection of the spine that is challenging to distinguish from noninfectious mimics using computed tomography and magnetic resonance imaging. We and others have developed novel metabolism-targeted positron emission tomography (PET) radiotracers for detecting living Staphylococcus aureus and other bacteria in vivo, but their head-to-head performance in a well-validated VDO animal model has not been reported. METHODS: We compared the performance of several PET radiotracers in a rat model of VDO. [11C]PABA and [18F]FDS were assessed for their ability to distinguish S aureus, the most common non-tuberculous pathogen VDO, from Escherichia coli. RESULTS: In the rat S aureus VDO model, [11C]PABA could detect as few as 103 bacteria and exhibited the highest signal-to-background ratio, with a 20-fold increased signal in VDO compared to uninfected tissues. In a proof-of-concept experiment, detection of bacterial infection and discrimination between S aureus and E coli was possible using a combination of [11C]PABA and [18F]FDS. CONCLUSIONS: Our work reveals that several bacteria-targeted PET radiotracers had sufficient signal to background in a rat model of S aureus VDO to be potentially clinically useful. [11C]PABA was the most promising tracer investigated and warrants further investigation in human VDO.

Chemoenzymatic Syntheses of Fluorine-18-Labeled Disaccharides from [18F] FDG Yield Potent Sensors of Living Bacteria In Vivo.

Chemoenzymatic techniques have been applied extensively to pharmaceutical development, most effectively when routine synthetic methods fail. The regioselective and stereoselective construction of structurally complex glycans is an elegant application of this approach that is seldom applied to positron emission tomography (PET) tracers. We sought a method to dimerize 2-deoxy-[18F]-fluoro-d-glucose ([18F]FDG), the most common tracer used in clinical imaging, to form [18F]-labeled disaccharides for detecting microorganisms in vivo based on their bacteria-specific glycan incorporation. When [18F]FDG was reacted with ß-d-glucose-1-phosphate in the presence of maltose phosphorylase, the α-1,4- and α-1,3-linked products 2-deoxy-[18F]-fluoro-maltose ([18F]FDM) and 2-deoxy-2-[18F]-fluoro-sakebiose ([18F]FSK) were obtained. This method was further extended with the use of trehalose (α,α-1,1), laminaribiose (ß-1,3), and cellobiose (ß-1,4) phosphorylases to synthesize 2-deoxy-2-[18F]fluoro-trehalose ([18F]FDT), 2-deoxy-2-[18F]fluoro-laminaribiose ([18F]FDL), and 2-deoxy-2-[18F]fluoro-cellobiose ([18F]FDC). We subsequently tested [18F]FDM and [18F]FSK in vitro, showing accumulation by several clinically relevant pathogens including Staphylococcus aureus and Acinetobacter baumannii, and demonstrated their specific uptake in vivo. Both [18F]FDM and [18F]FSK were stable in human serum with high accumulation in preclinical infection models. The synthetic ease and high sensitivity of [18F]FDM and [18F]FSK to S. aureus including methicillin-resistant (MRSA) strains strongly justify clinical translation of these tracers to infected patients. Furthermore, this work suggests that chemoenzymatic radiosyntheses of complex [18F]FDG-derived oligomers will afford a wide array of PET radiotracers for infectious and oncologic applications.

Chemoenzymatic syntheses of fluorine-18-labeled disaccharides from [ 18 F]FDG yield potent sensors of living bacteria in vivo.

Chemoenzymatic techniques have been applied extensively to pharmaceutical development, most effectively when routine synthetic methods fail. The regioselective and stereoselective construction of structurally complex glycans is an elegant application of this approach, that is seldom applied to positron emission tomography (PET) tracers. We sought a method to dimerize 2-deoxy-[ 18 F]-fluoro-D-glucose ([ 18 F]FDG), the most common tracer used in clinical imaging, to form [ 18 F]-labeled disaccharides for detecting microorganisms in vivo based on their bacteria-specific glycan incorporation. When [ 18 F]FDG was reacted with ß-D-glucose-1-phosphate in the presence of maltose phosphorylase, both the α-1,4 and α-1,3-linked products 2-deoxy-[ 18 F]-fluoro-maltose ([ 18 F]FDM) and 2-deoxy-2-[ 18 F]-fluoro-sakebiose ([ 18 F]FSK) were obtained. This method was further extended with the use of trehalose (α,α-1,1), laminaribiose (ß-1,3), and cellobiose (ß-1,4) phosphorylases to synthesize 2-deoxy-2-[ 18 F]fluoro-trehalose ([ 18 F]FDT), 2-deoxy-2-[ 18 F]fluoro-laminaribiose ([ 18 F]FDL), and 2-deoxy-2-[ 18 F]fluoro-cellobiose ([ 18 F]FDC). We subsequently tested [ 18 F]FDM and [ 18 F]FSK in vitro, showing accumulation by several clinically relevant pathogens including Staphylococcus aureus and Acinetobacter baumannii, and demonstrated their specific uptake in vivo. The lead sakebiose-derived tracer [ 18 F]FSK was stable in human serum and showed high uptake in preclinical models of myositis and vertebral discitis-osteomyelitis. Both the synthetic ease, and high sensitivity of [ 18 F]FSK to S. aureus including methicillin-resistant (MRSA) strains strongly justify clinical translation of this tracer to infected patients. Furthermore, this work suggests that chemoenzymatic radiosyntheses of complex [ 18 F]FDG-derived oligomers will afford a wide array of PET radiotracers for infectious and oncologic applications.

Improving the Breast Surgeon's Ergonomic Workload for Nipple-Sparing Mastectomies Using Exercise and Operating Room Positioning Protocol.

BACKGROUND: The objective of this study was to examine whether an exercise program and standardized operating room positioning protocol (EOPP) would improve surgeon muscle workload and/or surgeon perception of mental/physical workload for nipple-sparing mastectomy (NSM). METHODS: This prospective study analyzed muscle workload by EMG of four surgeons performing NSM before and after an EOPP. Surveys were administered assessing surgeon perception of mental/physical workload. EMG data were analyzed using repeated-measures ANOVA, controlling for surgeon, first assistant, duration and difficulty of procedure, left or right side, and sequence of the procedure. RESULTS: A total of 56 NSM cases performed by 3 surgeons were analyzed. One surgeon was excluded because of muscle injury and undergoing active physical therapy during the study period. After implementation of the EOPP, the left (P = 0.005) and right (P = 0.020) upper trapezii muscles had a significant decrease in overall ergonomic workload but there was no significant change in overall ergonomic workload for the bilateral cervical erector spinae, anterior deltoid, and lumbar erector spinae muscle groups. When analyzing muscle group exertion by surgeon, there was significant variability in all muscles except the left cervical erector spinae. Following the EOPP, surgeons reported that the procedures were more physically (P = 0.01) and mentally (P = 0.002) demanding and visualization (P = 0.04) was worse. The breast laterality and sequence did not affect muscle exertion. CONCLUSIONS: An EOPP decreased the overall ergonomic workload of one muscle group for surgeons performing NSM but did not impact surgeon perception of mental/physical workload. Further investigation is needed to improve surgeon ergonomics.

An In-Visit Decision Aid for Surgeons to Address Decision Making for Bilateral Mastectomy for Newly Diagnosed Breast Cancer Patients.

BACKGROUND: Few decision aids for newly diagnosed breast cancer patients are used by surgeons during their consultations with patients. METHODS: From 2017 to 2019, an online interactive breast cancer in-visit decision aid (BIDA) was used on 63 patients and 57 patients underwent usual care (UC). We compared knowledge, decision involvement, anxiety and distress (HADS scale), quality of life (PROMIS), fear of recurrence, body image, and patient values between BIDA and UC before surgery. A knowledge score of ≥ 57% was considered "high knowledge." RESULTS: A total of 188 patients were enrolled of which 120 (63.8%) completed all study procedures. Patient demographic characteristics and anxiety and quality of life (QOL) at baseline were similar between patients in BIDA and UC cohorts. After seeing the surgeon, patients in the BIDA group had higher composite knowledge scores compared with UC patients [n = 55 (87.3%) vs. n = 39 (68.4%) respectively, p = 0.012]. Patients in the BIDA cohort reported being asked more often their surgical preference (p = 0.013) and discussing bilateral mastectomy (BM) as an option (p = 0.048). There was a trend of less patients in the BIDA cohort undergoing BM then in the UC cohort [10 (15.9%) vs. 14 (24.6%), p = 0.49]. Anxiety and distress, QOL, fear of recurrence, and body image were not significantly different between BIDA and UC cohorts. CONCLUSIONS: A decision aid used by surgeons during their consultation was associated with higher knowledge levels, patients reporting more discussion about BM, and a trend of lower BMs. A larger study with more patients is needed to confirm this finding.

Assessing Parental Attributions through an Implicit Measure: Development and Evaluation of the Noncompliance IAT.

OBJECTIVES: Assessing parental attributions can be challenging given the reticence of some caregivers to report information that may be considered controversial or pejorative. To address this issue, recent efforts have focused on expanding existing parenting assessment batteries to include implicit measures. One of the most common methods for implicit assessment, the Implicit Association Test (IAT), had not yet been adapted to assess parental attributions. Two studies evaluated the psychometric properties (including convergent, concurrent, incremental, and predictive validity) of the novel Noncompliance IAT (N-IAT). METHODS: Study 1 included a low-risk sample of mothers (N = 60) of preschoolers. Study 2 included a diverse and higher risk sample of mothers and fathers who were assessed at three time points: immediately before the birth of their first child (N = 202 women; N = 144 male partners) and then 6 and 18 months after the birth. RESULTS: Findings from both studies supported the utility of the N-IAT as a measure of implicit parental attributions. The N-IAT demonstrated evidence of convergent and concurrent validity (e.g., significant correlations with explicit attribution measures and with measures of parenting) in both studies. The longitudinal design of Study 2 allowed for the evaluation of incremental and predictive validity; N-IAT scores before childbirth predicted later N-IAT scores, with indications that the N-IAT could demonstrate incremental validity related to child abuse risk. Study 2 also demonstrated moderate test stability for mothers and fathers. CONCLUSIONS: These results suggest that the N-IAT may be a helpful adjunct to assessments of parental attribution.

The "Nipple Whipple"?! A Pilot Study to Assess the Ergonomic Effects of Nipple-Sparing Mastectomy.

BACKGROUND: Nipple-sparing mastectomies (NSMs) with reconstruction are believed to be more difficult to perform than skin-sparing mastectomies (SSMs), but there is little quantitative data to support this claim. METHODS: This prospective study analyzed four surgeons performing mastectomies. Electromyography (EMG) electrodes placed on selected muscle groups on each surgeon were used to capture muscle exertion intraoperatively and a percentage of maximum voluntary exertion was calculated (%MVE). Data regarding surgeon demographics, exercise habits, musculoskeletal problems, and surgery-specific workload was collected using a questionnaire. RESULTS: A total of 61 mastectomies were analyzed; 40 were NSM and 21 were SSM/total mastectomies. NSM were considered to be more mentally demanding and physically demanding than SSM (p < 0.001). When the surgeons' EMG data was analyzed as a group, there was a statistically significant difference in %MVE for NSM versus SSM at high muscle activity in bilateral anterior deltoid muscle groups and at average muscle activity for the left anterior deltoid muscle only. At low muscle activity, there was a statistically significant increase in activation for SSM versus NSM in bilateral cervical erector spinae. Repeated measures ANOVA was performed, which showed statistically significant differences at high muscle activity between NSM and SSM in the left cervical erector spinae and bilateral anterior deltoid muscles. CONCLUSIONS: Our pilot study shows that intraoperative EMGs can assess muscle activity for mastectomy operations and show a difference between NSM and SSM. This is the first study to provide quantitative data on muscle strain with NSM.

Clinical accuracy of preoperative breast MRI for breast cancer.

BACKGROUND: It is unclear if breast magnetic resonance imaging (MRI) is more accurate than mammography (MGM) and ultrasound (U/S) in aggregate for patients with invasive cancer. METHODS: We compared concordance of combined tumor size and tumor foci between MRI and MGM and U/S combined to pathological tumor size and foci as the gold standard from 2009 to 2015. Tumor size was nonconcordant if it differed from the pathologic size by ≥33% and tumor foci was nonconcordant if >1 foci were seen. If one or both of the MGM or U/S was nonconcordant and the MRI was concordant, MRI provided greater accuracy. RESULTS: Of 471 patients with MGM, US, and MRI, MRI was more accurate for 32.9% of patients for tumor size and for 21.9% for tumor foci. Patients for whom MRI had greater accuracy were compared to those who did not for clinical and tumor factors. The only significant factor was calcifications on mammography. Tumor size, stage, molecular subtype, histology, grade, patient BMI, age, mammographic density, and use of hormone replacement therapy were not significantly different. CONCLUSIONS: Breast MRI provides greater accuracy for a third of patients undergoing preoperative MGM and U/S. Mammographic calcifications were associated with MRI clinical accuracy for patients with invasive cancer.

Impact of an In-visit Decision Aid on Patient Knowledge about Contralateral Prophylactic Mastectomy: A Pilot Study.

BACKGROUND: Studies have reported that breast cancer patients have limited understanding about the oncologic outcomes following contralateral prophylactic mastectomy (CPM). We hypothesized that an in-visit decision aid (DA) would be associated with higher patient knowledge about the anticipated short and long term outcomes of CPM. METHODS: We piloted a DA which used the SCOPED: (Situation, Choices, Objectives, People, Evaluation and Decision) framework. Knowledge, dichotomized as "low" (≤3 correct) versus "high" (≥4 correct), was assessed immediately after the visit by a 5 item survey. There were 97 DA patients (response rate 62.2 %) and 114 usual care (UC) patients (response rate 71.3 %). RESULTS: Patient demographic factors were similar between the two groups. Twenty-one (21.7 %) patients in the DA group underwent CPM compared with 18 (15.8 %) in the UC group (p = 0.22). Mean and median knowledge levels were significantly higher in the DA group compared with the UC group for patients of all ages, tumor stage, race, family history, anxiety levels, worry about CBC, and surgery type. Eighty-six (78.9 %) of UC versus 35 (37.9 %) DA patients had low knowledge. Of patients who underwent CPM, 15 (83.3 %) in the UC cohort versus 5 (25.0 %) of DA patients had "low" knowledge. CONCLUSIONS: Knowledge was higher in the DA group. The UC group had approximately three times the number of patients of the DA group who were at risk for making a poorly informed decision to have CPM. Future studies should assess the impact of increased knowledge on overall CPM rates.

Reducing Therapist Contact in Parenting Programs: Evaluation of Internet-Based Treatments for Child Conduct Problems.

This study evaluated two Internet-based versions of Parent Management Training (PMT) and the effects of greatly reducing the contact required of a mental health professional on treatment of children referred for conduct problems. We were interested whether reduced contact with a therapist influenced treatment outcome, therapeutic alliance, parent adherence to treatment prescriptions, and parent reactions to and evaluations of the treatment procedures. Sixty children and their caregivers were assigned to receive either Full Contact PMT (with the amount of weekly contact similar to traditional PMT; approximately 50 minutes of direct therapist contact each week) or Reduced Contact PMT (with most information provided through recordings; approximately 10 minutes of therapist contact each week). Children in both groups showed significant and similar reductions in antisocial behaviors specifically, internalizing and externalizing symptoms more generally, and improvements in overall adaptive functioning. Therapeutic alliance also was similar across the two treatment groups. However, parents rated Full Contact treatment as more acceptable than the reduced version. Both treatments were similar in outcomes to in-person treatment as evaluated by a nonrandomized matched sample used as a benchmark in supplementary analyses. Overall, the findings indicate that therapist contact can be reduced while positive treatment outcomes are maintained but that interventions that reduce direct time with a therapist may be viewed less positively by clients.

Integrating socially assistive robotics into mental healthcare interventions: applications and recommendations for expanded use.

As a field, mental healthcare is faced with major challenges as it attempts to close the huge gap between those who need services and those who receive services. In recent decades, technological advances have provided exciting new resources in this battle. Socially assistive robotics (SAR) is a particularly promising area that has expanded into several exciting mental healthcare applications. Indeed, a growing literature highlights the variety of clinically relevant functions that these robots can serve, from companion to therapeutic play partner. This paper reviews the ways that SAR have already been used in mental health service and research and discusses ways that these applications can be expanded. We also outline the challenges and limitations associated with further integrating SAR into mental healthcare. SAR is not proposed as a replacement for specially trained and knowledgeable professionals nor is it seen as a panacea for all mental healthcare needs. Instead, robots can serve as clinical tools and assistants in a wide range of settings. Given the dramatic growth in this area, now is a critical moment for individuals in the mental healthcare community to become engaged in this research and steer it toward our field's most pressing clinical needs.

The effects of hormone replacement therapy on postmenopausal breast cancer biology and survival.

BACKGROUND: The goal of this study was to compare the characteristics of breast cancers and survival rates in HRT users versus nonusers. METHODS: Data were analyzed for 1055 patients > or = 50 years of age who had definitive therapy for breast cancer from 1994 through 2002. RESULTS: There were 471 (45%) HRT users. The median age at diagnosis was 61.0 years for HRT users and 68.0 years for HRT nonusers (P < .001). HRT users more often had tumors that were <1 cm (P = .007), node negative (P = .033), and grade I (P = .016). HRT users had a decreased risk of death versus nonusers (hazard ratio = .438, 95% confidence limit = .263 to .729, P = .002). CONCLUSIONS: HRT users developed breast cancer at a younger age than nonusers; HRT use was associated with the development of biologically more favorable cancers than those that developed in nonusers; and overall and disease-free survival rates were higher in HRT users than nonusers.

Survival rates for breast cancers detected in a community service screening mammogram program.

BACKGROUND: This single-institution long-term prospective study was performed in the setting of community service screening mammography to evaluate the association between the methods of breast cancer detection and survival rates. METHODS: From 1994 through 2001, data on 1237 patients with breast cancer were collected concurrent with definitive surgical treatment and entered into a comprehensive database. RESULTS: Mammography was the sole method of detection for 517 (44%) of 1179 Tis-T2 breast cancers. Fifty-seven percent of invasive cancers detectable by mammography alone were less than 1 cm in diameter. For 1049 patients with invasive cancers, the 5-year overall observed survival rates were 94% for 372 whose cancers were detectable by mammogram alone and 87% for 677 whose cancers were detectable by palpation (alone or in combination with mammography) (P = .0002). CONCLUSIONS: Most of the contribution to breast cancer mortality reduction is from the detection of small nonpalpable cancers, not from adjuvant therapy.

Effectiveness of collaborative problem solving in affectively dysregulated children with oppositional-defiant disorder: initial findings.

Oppositional-defiant disorder (ODD) refers to a recurrent pattern of negativistic, defiant, disobedient, and hostile behavior toward authority figures. Research has shown that children with ODD and comorbid mood disorders may be at particular risk for long-term adverse outcomes, including conduct disorder. In this study, the authors examined the effectiveness of a cognitive-behavioral model of intervention--called collaborative problem solving (CPS)--in comparison with parent training (PT) in 47 affectively dysregulated children with ODD. Results indicate that CPS produced significant improvements across multiple domains of functioning at posttreatment and at 4-month follow-up. These improvements were in all instances equivalent, and in many instances superior, to the improvements produced by PT. Implications of these findings for further research on and treatment selection in children with ODD are discussed.