"Breaking Bread" With Respondents: Strategies to Increase Response Rates and Create Long-Term Cooperation With Health Clinic Administrators.

BACKGROUND AND OBJECTIVES: To fully understand the impact of unintended pregnancy, as well as to evaluate the implementation and outcomes of programs targeted at reducing unintended pregnancy, it is critical that researchers be able to collect comprehensive data from health clinics that provide these services in vulnerable communities. METHODS: Our paper details recruitment and incentive strategies, as well as the theories that guided them, which allowed us to achieve a high survey response rate among health clinic administrators in public health clinics in 2 Southeastern states-South Carolina and Alabama-both of which have high rates of unintended pregnancy. RESULTS: Grounded in organizational theory, and utilizing the Tailored Design Method, we achieved a 68% response rate utilizing paper and web survey administration with multiple contact modes. Our incentive structure comprised both traditional cash-based and food-based incentives. CONCLUSIONS: Findings indicate high response rates are achievable despite high survey burden (ie, detailed information, length of survey). We found that sample screening was critical and that food-based incentives made an impression on respondents that positively impacted the researcher-respondent relationship. Providing detailed methodology and additional literature will assist researchers working with similar populations-a gap in the applied methodological literature that was problematic at the project's onset.

Preclinical characterization and IND-enabling safety studies for PNT001, an antibody that recognizes cis-pT231 tau.

BACKGROUND: The cis-conformer of tau phosphorylated at threonine-231 (cis-pT231 tau) is hypothesized to contribute to tauopathies. PNT001 is a humanized, monoclonal antibody that recognizes cis-pT231 tau. PNT001 was characterized to assess clinical development readiness. METHODS: Affinity and selectivity were assessed by surface plasmon resonance and enzyme-linked immunosorbent assay. Immunohistochemistry (IHC) was performed with brain sections from human tauopathy patients and controls. Real-time quaking-induced conversion (RT-QuIC) was used to assess whether PNT001 reduced tau seeds from Tg4510 transgenic mouse brain. Murine PNT001 was evaluated in vivo in the Tg4510 mouse. RESULTS: The affinity of PNT001 for a cis-pT231 peptide was 0.3 to 3 nM. IHC revealed neurofibrillary tangle-like structures in tauopathy patients with no detectable staining in controls. Incubation of Tg4510 brain homogenates with PNT001 lowered seeding in RT-QuIC. Multiple endpoints were improved in the Tg4510 mouse. No adverse findings attributable to PNT001 were detected in Good Laboratory Practice safety studies. DISCUSSION: The data support clinical development of PNT001 in human tauopathies.

"It's Took Over This Region": Patient Perspectives of Prescription Drug Abuse in Appalachia.

Background: Prescription drug abuse is a public health problem in the United States and the region of Appalachia, specifically. Primary care and addiction medicine-as possible points of access for prescription drugs with abuse potential and points of intervention for prescription drug abuse-are among the medical fields at its forefront. Little is known, however, about perceptions of prescription drug abuse across the two patient populations. Objectives: The objective of this qualitative analysis was to explore perceptions of the scale and context of prescription drug abuse among primary care and addiction medicine patients in Appalachia. Methods: As part of a mixed methods study, semi-structured interviews were conducted with 20 patients from primary care and addiction medicine in Central and South Central Appalachia from 2014 to 2015. The interviews were audio-recorded and transcribed verbatim. Thematic analysis was used to identify themes. Results: Three themes were identified: (1) pervasiveness of prescription drug abuse, describing perceptions of its high prevalence and negative consequences; (2) routes and routine practices for prescription drug acquisition and distribution, describing perceptions of routes of access to prescription drugs and behaviors exhibited to acquire and distribute prescription drugs; and (3) rationales for prescription drug acquisition and distribution, describing perceptions of the two underlying reasons for these processes-tolerance/addiction and revenue source. Conclusions/Importance: Perceptions of prescription drug abuse among primary care and addiction medicine patients in Appalachia are multifaceted, especially regarding prescription drug acquisition and distribution. Clinical practice implications for mitigating prescription drug abuse are discussed.

Communication Experiences of DATA-Waivered Physicians with Community Pharmacists: A Qualitative Study.

Background: Patients engaged in evidence-based opioid use disorder (OUD) treatment can obtain prescriptions for buprenorphine containing products from specially trained physicians that are subsequently dispensed by community pharmacists. Despite the involvement of physicians and community pharmacists in buprenorphine prescribing and dispensing, respectively, our understanding of their interactions in this context is limited. Objective: To qualitatively describe the communication and collaborative experiences between Drug Addiction Treatment Act 2000 (DATA)-waivered physicians and community pharmacists from the perspective of the physician. Methods: Ten key informant interviews were conducted with DATA-waivered physicians practicing in Northeast Tennessee. A semi-structured interview guide was used to explore communication and collaborative experiences between the physicians and community pharmacists. Interviews were audio recorded and transcribed verbatim. A coding frame was developed using concepts from the scientific literature and emerging codes from physician interviews. Interviews were coded using NVivo 11, with the data subsequently organized and evaluated for themes. Results: Four themes were identified: (1) mechanics of communication; (2) role specification and expectations; (3) education and understanding; and (4) climate of clinical practice. Physician-pharmacist communication primarily occurred indirectly through patients or staff and perceived challenges to collaboration included; lack of trust, stigma, and fear of regulatory oversight. Physicians also indicated the two professionals may lack clear roles and responsibilities as well as common expectations for treatment plans. Conclusions: Communication between DATA-waivered physicians and community pharmacists is influenced by multiple factors. Further research is warranted to improve physician-community pharmacist collaboration (PCPC) in the context of OUD pharmacotherapy and addiction treatment.

Community pharmacist engagement in opioid use disorder prevention and treatment behaviors: A descriptive analysis.

OBJECTIVES: This study describes community pharmacists' opioid analgesic and medication for opioid use disorder (MOUD) practice behaviors and behavioral intentions in the context of primary, secondary, and tertiary prevention of opioid use disorder (OUD). METHODS: The study sampling frame consisted of 2302 Tennessee community-practice pharmacists who were asked to complete a mailed, paper questionnaire. Behavioral intentions were elicited by asking pharmacists to indicate the number of times (0 to 10) they engage in a behavior, given 10 patients in 3 distinct vignettes. Perceptions of evidence-based MOUD and pain management patient care practices were also elicited. RESULTS: A response rate of 19.7% was achieved. Pharmacists reported using a brief questionnaire to evaluate risk of opioid misuse with 2.1 ± 3.7 (mean ± SD) out of 10 patients, screening 2.1 ± 3.7 patients for current opioid misuse, discussing co-dispensing of naloxone with 2.9 ± 3.4 to 3.3 ± 4 out of 10 patients at a risk of overdose, and dispensing buprenorphine/naloxone to a mean of 4.6 ± 4.2 patients when they presented a prescription. Respondents perceived 38% of pain management and 30% of MOUD prescribers in their area to practice evidenced-based care. CONCLUSION: Pharmacists have an opportunity to improve the outcomes for patients prescribed opioids by increasing engagement across OUD prevention levels.

Variation in CT use for paediatric head injuries across different types of emergency departments in Australia and New Zealand.

OBJECTIVES: CT of the brain (CTB) for paediatric head injury is used less frequently at tertiary paediatric emergency departments (EDs) in Australia and New Zealand than in North America. In preparation for release of a national head injury guideline and given the high variation in CTB use found in North America, we aimed to assess variation in CTB use for paediatric head injury across hospitals types. METHODS: Multicentre retrospective review of presentations to tertiary, urban/suburban and regional/rural EDs in Australia and New Zealand in 2016. Children aged <16 years, with a primary ED diagnosis of head injury were included and data extracted from 100 eligible cases per site. Primary outcome was CTB use adjusted for severity (Glasgow Coma Scale) with 95% CIs; secondary outcomes included hospital length of stay and admission rate. RESULTS: There were 3072 head injury presentations at 31 EDs: 9 tertiary (n=900), 11 urban/suburban (n=1072) and 11 regional/rural EDs (n=1100). The proportion of children with Glasgow Coma Score ≤13 was 1.3% in each type of hospital. Among all presentations, CTB was performed for 8.2% (95% CI 6.4 to 10.0) in tertiary hospitals, 6.6% (95% CI 5.1 to 8.1) in urban/suburban hospitals and 6.1% (95% CI 4.7 to 7.5) in regional/rural. Intragroup variation of CTB use ranged from 0% to 14%. The regional/rural hospitals admitted fewer patients (14.6%, 95% CI 12.6% to 16.9%, p<0.001) than tertiary and urban/suburban hospitals (28.1%, 95% CI 25.2% to 31.2%; 27.3%, 95% CI 24.7% to 30.1%). CONCLUSIONS: In Australia and New Zealand, there was no difference in CTB use for paediatric patients with head injuries across tertiary, urban/suburban and regional/rural EDs with similar intragroup variation. This information can inform a binational head injury guideline.

Efficacy and safety of gadobutrol-enhanced MRA of the renal arteries: Results from GRAMS (Gadobutrol-enhanced renal artery MRA study), a prospective, intraindividual multicenter phase 3 blinded study.

PURPOSE: To compare the performance of magnetic resonance angiography (MRA) with 1M gadobutrol, a high relaxivity macrocyclic contrast agent, to 2D time-of-flight MRA (ToF-MRA) using computed tomographic angiography (CTA) as the standard of reference. Primary objectives were evaluation for superiority of structural delineation and noninferiority for detection and exclusion of clinically significant disease. MATERIALS AND METHODS: In all, 315 subjects underwent unenhanced and contrast-enhanced MRA with 1M gadobutrol (CE-MRA) and were scanned with 1.5T MRI equipped with an at least 6-element body coil. Evaluations were based on both centralized blinded read (BR) performed by six readers as well as investigator site interpretations for the 292 subjects who completed the study. Quantitative evaluations including percent stenosis and normal vessel measurements were also performed. Secondary endpoints included identification of accessory renal arteries, diagnosis of fibromuscular dysplasia (FMD), diagnostic confidence, and need for additional imaging. RESULTS: A total of 292 patients suspected of renal artery disease completed the study. CE-MRA demonstrated statistically significant improvement in assessability of vascular segments compared to ToF: 95.9% vs. 77.6% (P < 0.0001). In the BR, the sensitivity and specificity of CE-MRA were noninferior to ToF-MRA (53.4% vs. 46.6% and 95.1% vs. 85.7%, respectively). There was less error in the CE-MRA stenosis measurements (0.15 mm gadobutrol vs. 0.41 mm ToF, P < 0.05). FMD was correctly diagnosed more frequently, 10% more accessory renal arteries were identified (P < 0.01), diagnostic confidence increased (P < 0.01), and fewer additional imaging studies were recommended (P < 0.01). CONCLUSION: Gadobutrol-enhanced MRA of the renal arteries has superior visualization, more accurate vessel measurements, and may serve as a CTA alternative without any ionizing radiation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:572-581.

Mass Media Campaign to Reduce Consumption of Sugar-Sweetened Beverages in a Rural Area of the United States.

OBJECTIVES: To evaluate a mass media campaign to reduce the consumption of sugar-sweetened beverages (SSBs). METHODS: We disseminated messages emphasizing the health risks of SSBs through television, digital channels, and local organizations over 15 weeks in 2015-2016 in the Tri-Cities region of northeast Tennessee, southwest Virginia, and southeast Kentucky. We evaluated the campaign with pre- and post-telephone surveys of adults aged 18 to 45 years in the intervention area and by examining changes in beverage sales in the intervention and a matched comparison area in western Virginia. RESULTS: Fifty-four percent of postcampaign respondents recalled seeing a campaign advertisement. After the campaign, 53% of respondents believed SSBs were a cause of heart disease, and respondents were more likely postcampaign to consider SSBs a "big cause of diabetes" (75% vs 60%; P < .001). Compared with 12 months before, after the start of the campaign, SSB sales decreased 3.4%, including a 4.1% decrease in soda sales in the intervention area relative to the comparison area (P < .01). CONCLUSIONS: This brief media campaign on SSBs was followed by intended changes in beliefs and consumption. Public Health Implications. Additional media campaigns on SSBs should be attempted and evaluated.

A theoretical explanation of naloxone provision among primary care physicians and community pharmacists in Tennessee.

BACKGROUND: Increasing access to naloxone reduces opioid-related morbidity and mortality. Primary care and community pharmacy settings are critical access points, yet limited theoretical research has examined naloxone prescribing and dispensing behaviors. OBJECTIVES: To determine if the theory of planned behavior (TPB) combined with theoretical constructs from communication science explains intentions to co-prescribe and discuss co-dispensing naloxone among primary care physicians and community pharmacists, respectively. METHODS: This cross-sectional study surveyed cohorts of licensed primary care physicians and community pharmacists in Tennessee in 2017. Intentions were measured using profession-specific case vignettes, whereby they were asked given 10 similar patients, how many times (0-10) would they co-prescribe or discuss co-dispensing naloxone. Bivariate and multivariable analyses were used. RESULTS: The analytic sample included 295 physicians (response rate = 15.6 %) and 423 pharmacists (response rate = 19.4 %). Approximately 65 % of physicians reported never intending to co-prescribe naloxone (0 out of 10 patients), while 47 % of pharmacists reported never intending to discuss co-dispensing. All TPB constructs-attitudes (AOR = 1.32, CI = 1.16-1.50), subjective norms (AOR = 1.17, CI = 1.06-1.30), and perceived behavioral control (AOR 1.16, CI = 1.02-1.33)-were associated with an increased likelihood of pharmacists always (versus never) discussing co-dispensing. Similarly, two TPB constructs-attitudes (AOR = 1.41, CI = 1.19-1.68) and subjective norms (AOR = 1.22, CI = 1.08-1.39)-were associated with an increased likelihood of physicians always co-prescribing. Among physicians only, one communication construct-self-perceived communication competence (AOR = 1.19, CI = 1.01-1.41)-was associated with an increased likelihood of always co-prescribing. CONCLUSION: Findings support the value of theory, particularly TPB, in explaining primary care physician intentions to co-prescribe and community pharmacist intentions to discuss co-dispensing naloxone.

Novel Peripheral Intravenous Catheter Securement for Children and Catheter Failure Reduction: A Randomized Clinical Trial.

Importance: Peripheral intravenous catheters (PIVCs) facilitate essential treatment. Failure of these essential devices is frequent and new securement strategies may reduce failure and improve patient outcomes. Objective: To evaluate clinical effectiveness of novel PIVC securement technologies for children to reduce catheter failure. Design, Setting, and Participants: A 3-arm, parallel group, superiority randomized clinical trial was conducted at 2 regional Australian hospitals from February 5, 2020, to January 14, 2022. Children aged 6 months to 8 years who were anticipated to require admission with a PIVC for at least 24 hours of in hospital treatment were eligible. Data were analyzed from May 25, 2022, to February 20, 2024. Interventions: Participants were randomly allocated in a 1:1:1 ratio to standard care, bordered polyurethane (Tegaderm [3M]), integrated securement dressing (SorbaView SHIELD [Medline]), and integrated securement dressing with tissue adhesive (Secureport IV). One catheter was studied per patient. Main Outcomes and Measures: Primary outcome was PIVC failure, defined as premature cessation of PIVC function for any reason prior to completion of planned treatment. Secondary outcomes were PIVC complications (any time dislodgement, occlusion, infiltration, partial dislodgement, extravasation, device leaking, phlebitis, pain), PIVC longevity, intervention acceptability (clinicians, participants, caregivers; 0-10 scale), and pain on removal (participants and caregivers; 0-10 scale relevant to age), adverse events, and health care costs. Results: A total of 383 patients (51% female; median age 36 [25th-75th percentiles, 22-72] months) were randomized 134 to standard care, 118 to integrated securement dressing, and 131 to integrated securement dressing with tissue adhesive. PIVC failure was lowest in integrated securement dressing with tissue adhesive (15 [12%]; adjusted hazard ratio [aHR], 0.47; 95% CI, 0.26-0.84) compared with integrated securement dressing (24 [21%]; aHR, 0.78; 95% CI, 0.47-1.28) and standard care (43 [34%]). Direct costs were significantly lower for integrated securement dressing with tissue adhesive (median, Australian dollars [A$], 312 [A$1 is equal to $0.65 US dollars]; IQR, A$302-A$380) and integrated securement dressing (median, A$303; IQR, A$294-A$465) compared with standard care (median, A$341; IQR, A$297-A$592; P ≤ .002) when considering the economic burden related to failure of devices. PIVC longevity and intervention acceptability were similar across all groups. Conclusions and Relevance: In this study, PIVCs secured with integrated securement dressings and tissue adhesive, in comparison with standard care, bordered polyurethane dressings, were associated with significantly reduced PIVC failure, for children admitted to hospital via the emergency department. Further research should focus on implementation in inpatient units where prolonged dwell and reliable intravenous access is most needed. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12619001026112.

Clinically Silent, Metastatic Renal Cell Carcinoma Detected on Routine Screening Mammogram: A Report of a Rare Case and Review of Literature.

Renal cell carcinoma (RCC) is the most common and the most lethal urogenital malignancy, and can metastasize rapidly via hematogenous spread. Even so, RCC metastasis within the breast is extremely rare and may appear deceptively benign on screening mammograms. In this article, we present a rare case of RCC that remained undiagnosed until an intra-mammary metastasis was detected on a routine screening mammogram. Further imaging workup and core needle biopsy of the mass ultimately confirmed a new diagnosis of metastatic clear cell RCC. Given that the presence of an RCC breast metastasis indicated advanced-stage RCC, the patient in this case underwent treatment with systemic immunotherapy. This case report describes key imaging features of metastatic RCC on common breast imaging modalities. It underscores the vital role that screening mammography can play in the initial detection of clinically silent, extra-mammary malignancies, including RCC. Thorough imaging workup and tissue biopsy are essential to distinguish a primary breast lesion from intra-mammary metastatic disease, to inform the management plan, and to prevent lumpectomy or mastectomy when it does not benefit the patient.

Phase I study of novel SYK inhibitor TAK-659 (mivavotinib) in combination with R-CHOP for front-line treatment of high-risk diffuse large B-cell lymphoma.

Background: TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We report results of a phase I single-institution escalation study of front-line treatment with R-CHOP and TAK-659 in treatment-naïve high-risk DLBCL. Methods: Patients with high-risk DLBCL were treated with R-CHOP for 1 cycle, followed by combined R-CHOP and TAK-659 for an additional five cycles, with TAK-659 dosing escalated from 60 mg, to 80 mg, to 100 mg daily, based on a 3 + 3 design. The primary objective was to determine the safety and establish the maximum tolerated dose (MTD) of TAK-659 in this setting. Results: Twelve patients were enrolled. Dose level 3 (100 mg) was established as the MTD. Dose level 1 (60 mg) maintained a similar area under the curve (AUC) to the MTD. With a median follow-up of 21 months, 92% of patients achieved complete response (CR). The most common treatment-emergent adverse events were lymphopenia (100%), infection (50%, n = 3 opportunistic), aspartate aminotransferase elevation (100%), and alanine aminotransferase elevation (83%). Conclusion: A TAK-659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R-CHOP and TAK-659 in patients with newly diagnosed high-risk DLBCL produces promising CR rates.

Motives for nonmedical use of prescription stimulants in community college students.

Objective: The present study identified common motives for nonmedical use of prescription stimulants (NMUS) among community college (CC) students and examined behavioral and demographic correlates of certain motives. Participants: The survey was completed by 3,113 CC students (72.4% female; 81.7% White). Methods: Survey results from 10 CCs were evaluated. Results: NMUS was reported by 9% (n = 269) participants. The most common motive for NMUS was to "focus on studies or to improve academic performance" (67.5%) followed by to "have more energy" (52.4%). Females were more likely to report NMUS for weight loss, and males were more likely to report NMUS to experiment. The motive "to feel good or get high" was linked to polysubstance use. Conclusions: CC students report similar motives for NMUS to those commonly endorsed by 4-year university students. These findings may help identify CC students susceptible to risky substance use.

Bolus Versus Continuous Nasogastric Feeds for Infants With Bronchiolitis: A Randomized Trial.

BACKGROUND AND OBJECTIVES: Infants hospitalized with bronchiolitis are commenced on nasogastric feeding to maintain hydration. Feeding strategies vary according to physician or institution preference. The current study hypothesized that continuous nasogastric feeding would prolong length of stay (LOS) when compared to bolus feeding. METHODS: A randomized, parallel-group, superiority clinical trial was performed within an Australian children's hospital throughout 2 bronchiolitis seasons from May 2018 to October 2019. Infants <12 months hospitalized with bronchiolitis and requiring supplemental nasogastric feeding were randomly assigned to continuous or bolus nasogastric regimens. LOS was the primary outcome. Secondary outcome measures included pulmonary aspirations and admissions to intensive care. RESULTS: The intention-to-treat analysis included 189 patients: 98 in the bolus nasogastric feeding group and 91 in the continuous group. There was no significant difference in LOS (median LOS of the bolus group was 54.25 hours [interquartile range 40.25-82] and 56 hours [interquartile range 38-78.75] in the continuous group). A higher proportion of admissions to intensive care was detected in the continuous group (28.57% [26 of 91] of the continuous group vs 11.22% [11 of 98] of the bolus group [P value 0.004]). There were no clinically significant pulmonary aspirations or statistically significant differences in vital signs between the groups within 6 hours of feed initiation. CONCLUSIONS: No significant difference in LOS was found between bolus and continuous nasogastric feeding strategies for infants hospitalized with bronchiolitis. The continuous feeding group had a higher proportion of intensive care admissions, and there were no aspiration events.

Primary care physicians' opioid-related prevention behaviors and intentions: A descriptive analysis.

OBJECTIVE: Primary care physicians (PCPs) are positioned to mitigate opioid morbidity and mortality, but their engagement in primary, secondary, and tertiary opioid-related prevention behaviors is unclear. The objective of this study was to evaluate Tennessee PCPs' engagement in and intention to engage in multiple opioid-related prevention behaviors. METHODS: A survey instrument was developed, pretested, and pilot tested with practicing PCPs. Thereafter, a census of eligible Tennessee PCPs was conducted using a modified, four-wave tailored design method approach. Three patient scenarios were employed to assess physician intention to engage in 10 primary, secondary, and tertiary prevention behaviors. Respondents were asked to report, given 10 similar scenarios, the number of times (0-10) they would engage in prevention behaviors. Descriptive statistics were calculated using SPSS version 25. RESULTS: A total of 296 usable responses were received. Physician intention to engage in prevention behaviors varied across the 10 behaviors studied. Physicians reported frequently communicating risks associated with prescription opioids to patients (8.9 ± 2.8 out of 10 patients), infrequently utilizing brief questionnaires to assess for risk of opioid misuse (1.7 ± 3.3 out of 10 patients), and screening for current opioid misuse (3.1 ± 4.3 out of 10 patients). Physicians reported seldomly co-prescribing naloxone for overdose reversal and frequently discharging from practice patients presenting with an opioid use disorder. CONCLUSIONS: This study noted strengths and opportunities to increase engagement in prevention behaviors. Understanding PCPs' engagement in opioid-related prevention behaviors is important to effectively target and implement morbidity and mortality reducing interventions.

Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation.

NMDA receptors (NMDARs) are critical mediators of activity-dependent synaptic plasticity, but the differential roles of NR2A- versus NR2B-containing NMDARs have been controversial. Here, we investigate the roles of NR2A and NR2B in long-term potentiation (LTP) in organotypic hippocampal slice cultures using RNA interference (RNAi) and overexpression, to complement pharmacological approaches. In young slices, when NR2B is the predominant subunit expressed, LTP is blocked by the NR2B-selective antagonist Ro25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol]. As slices mature and NR2A expression rises, activation of NR2B receptors became no longer necessary for LTP induction. LTP was blocked, however, by RNAi knockdown of NR2B, and this was rescued by coexpression of an RNAi-resistant NR2B (NR2B*) cDNA. Interestingly, a chimeric NR2B subunit in which the C-terminal cytoplasmic tail was replaced by that of NR2A failed to rescue LTP, whereas the reverse chimera, NR2A channel with NR2B tail, was able to restore LTP. Thus, expression of NR2B with its intact cytoplasmic tail is required for LTP induction, at an age when channel activity of NR2B-NMDARs is not required for LTP. Overexpression of wild-type NR2A failed to rescue LTP in neurons transfected with the NR2B-RNAi construct, despite restoring NMDA-EPSC amplitude to a similar level as NR2B*. Surprisingly, an NR2A construct lacking its entire C-terminal cytoplasmic tail regained its ability to restore LTP. Together, these data suggest that the NR2B subunit plays a critical role for LTP, presumably by recruiting relevant molecules important for LTP via its cytoplasmic tail. In contrast, NR2A is not essential for LTP, and its cytoplasmic tail seems to carry inhibitory factors for LTP.

Controversies of prophylactic hypothermia and the emerging use of brain tissue oxygen tension monitoring and decompressive craniectomy in traumatic brain-injured children.

BACKGROUND: Despite being the leading cause of death and disability in the paediatric population, traumatic brain injury (TBI) in this group is largely understudied. Clinical practice within the paediatric intensive care unit (PICU) has been based upon adult guidelines however children are significantly different in terms of mechanism, pathophysiology and consequence of injury. AIM: To review TBI management in the PICU and gain insight into potential management strategies. METHOD: To conduct this review, a literature search was conducted using MEDLINE, PUBMED and The Cochrane Library using the following key words; traumatic brain injury; paediatric; hypothermia. There were no date restrictions applied to ensure that past studies, whose principles remain current were not excluded. RESULTS: Three areas were identified from the literature search and will be discussed against current acknowledged treatment strategies: Prophylactic hypothermia, brain tissue oxygen tension monitoring and decompressive craniectomy. CONCLUSION: Previous literature has failed to fully address paediatric specific management protocols and we therefore have little evidence-based guidance. This review has shown that there is an emerging and ongoing trend towards paediatric specific TBI research in particular the area of moderate prophylactic hypothermia (MPH).

ACR Appropriateness Criteria® Pancreatic Cyst.

Incidental pancreatic cysts are increasingly detected on imaging studies performed for unrelated indications and may be incompletely characterized on these studies. Adequate morphological characterization is critical due to the small risk of malignant degeneration associated with neoplastic pancreatic cysts, as well as the risk of associated pancreatic adenocarcinoma. For all pancreatic cysts, both size and morphology determine management. Specifically, imaging detection of features, such as pancreatic ductal communication and presence or absence of worrisome features or high-risk stigmata, have important management implications. The recommendations in this publication determine the appropriate initial imaging study to further evaluate a pancreatic cyst that was incidentally detected on a nondedicated imaging study. The recommendations are designed to maximize the yield of diagnostic information in order to better risk-stratify pancreatic cysts and assist in guiding future management. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Circulating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer.

PURPOSE: This study evaluated epithelial cell death ELISAs that measure circulating cytokeratin 18 in mice bearing small-cell lung cancer xenografts treated with a proapoptotic dose of the BH-3 mimetic ABT-737. EXPERIMENTAL DESIGN: H146 tumor-bearing and non-H146 tumor-bearing severe combined immunodeficient (SCID)/bg mice were treated with ABT-737 or vehicle control. Plasma collected before and 2 to 360 hours after treatment was analyzed by M30 (caspase-cleaved cytokeratin 18) and M65 (intact and cleaved cytokeratin 18) ELISA. In parallel, tumors were interrogated for cleaved caspase-3 and cleaved cytokeratin 18 as biomarkers of apoptosis. RESULTS: ABT-737-treated tumors regressed by 48 hours (P < 0.01) compared with controls, correlating with increased cleaved cytokeratin 18 (P < 0.01; 6 and 24 hours) and increased intact cytokeratin 18 (P < 0.01; 24 hours). Cleaved cytokeratin 18 levels decreased below baseline between 72 and 360 hours for ABT-737-treated and control mice whereas intact cytokeratin 18 decreased below the level of detection at 8 and 15 days in ABT-737-treated mice only. Apoptosis in tumors reflected changes in circulating cytokeratin 18 (cleaved caspase-3, P < 0.05 at 2 hours and P < 0.001 at 6, 12, and 24 hours; caspase-cleaved cytokeratin 18, P < 0.05 at 15 days, for drug treated versus controls). CONCLUSIONS: ABT-737 caused tumor regression by apoptosis in H146 xenografts that mapped to a drug-specific, early increase in circulating cleaved cytokeratin 18 that subsequently declined. Circulating, intact cytokeratin 18 levels correlated with tumor burden. Cleaved caspase-3 and caspase-cleaved cytokeratin 18 in tumor correlated with treatment (P < 0.05, 2 hours; P < 0.001, 6, 12, and 24 hours; cleaved caspase-3, P < 0.05, 15 days; caspase-cleaved cytokeratin 18), indicating that events in plasma were tumor derived. These circulating biomarker data will be translated to clinical trials wherein serial tumor biopsies are rarely obtained.

ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo.

ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G(0)-G(1) arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G(0) cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma.