Evidence for conflict monitoring during speech recognition in noise.

During difficult tasks, conflict can benefit performance on a subsequent trial. One theory for such performance adjustments is that people monitor for conflict and reactively engage cognitive control. This hypothesis has been challenged because tasks that control for associative learning do not show such "cognitive control" effects. The current study experimentally controlled associative learning by presenting a novel stimulus on every trial of a picture-speech conflict task and found that performance adjustments still occur. Thirty-one healthy young adults listened to and repeated words presented in background noise while viewing pictures that were congruent or incongruent (i.e., phonological neighbors) with the word. Following conflict, participants had higher word recognition (+17% points) on incongruent but not congruent trials. This result was not attributable to posterror effects nor a speed-accuracy trade-off. An analysis of erroneous responses showed that participants made more phonologically related errors than nonrelated errors only on incongruent trials, demonstrating elevated phonological conflict when the picture was a neighbor of the target word. Additionally, postconflict improvements appear to be due to better resolution of phonological conflict in the mental lexicon rather than decreased attention to the picture or increased attention to the speech signal. Our findings provide new evidence for conflict monitoring and suggest that cognitive control helps resolve phonological conflict during speech recognition in noise.

Prospective Association of Unmet Mental Health Treatment Needs With Suicidal Behavior Among Combat-Deployed Soldiers.

OBJECTIVE: Military personnel frequently report discontinuing or not pursuing psychiatric treatment despite perceiving a need for services. This study aimed to examine how unmet need for treatment or support among U.S. Army soldiers relates to future suicidal ideation (SI) or suicide attempt (SA). METHODS: Mental health treatment need and help seeking in the past 12 months were evaluated for soldiers (N=4,645) who subsequently deployed to Afghanistan. Weighted logistic regression models were used to examine the prospective association of predeployment treatment needs with SI and SA during and after deployment, with adjustment for potential confounders. RESULTS: Compared with soldiers without predeployment treatment needs, those who reported not seeking help despite needing it had increased risk for SI during deployment (adjusted OR [AOR]=1.73), past-30-day SI at 2-3 months postdeployment (AOR=2.08), past-30-day SI at 8-9 months postdeployment (AOR=2.01), and SA through 8-9 months postdeployment (AOR=3.65). Soldiers who sought help and stopped treatment without improvement had elevated SI risk at 2-3 months postdeployment (AOR=2.35). Those who sought help and stopped after improving did not have increased SI risk during or 2-3 months after deployment but had elevated risks for SI (AOR=1.71) and SA (AOR=3.43) by 8-9 months postdeployment. Risks for all suicidality outcomes were also elevated among soldiers who reported receiving ongoing treatment before deployment. CONCLUSIONS: Unmet or ongoing needs for mental health treatment or support before deployment are associated with increased risk for suicidal behavior during and after deployment. Detecting and addressing treatment needs among soldiers before deployment may help prevent suicidality during deployment and reintegration periods.

Use of Tetrahydrocannabinol and Cannabidiol Products in the Perioperative Period Around Primary Unilateral Total Hip and Knee Arthroplasty.

BACKGROUND: Given the opioid crisis in America, patients are trying alternative medications including tetrahydrocannabinol (THC) and other cannabidiol (CBD) containing products in the perioperative period, especially in states where these products are legal. This study sought to analyze usage rates of CBD/THC products in the perioperative period for primary unilateral total hip and knee arthroplasty (THA/TKA) patients and identify a possible association with post-operative opioid use. METHODS: A prospective cohort of primary unilateral THA/TKA patients were enrolled at a single institution. Patients who completed detailed pain journals were retrospectively surveyed for CBD/THC product usage. Pain medications were converted to morphine milligram equivalents (MME). RESULTS: Data from 195 of the 210 patients (92.9% response rate) following primary arthroplasty were analyzed. Overall, 16.4% of arthroplasty-22.6% (n = 19) of TKA and 11.7% (n = 13) of THA-patients used CBD/THC products in the perioperative period. There was a wide variety of usage patterns among those using CBD/THC products. In comparing CBD/THC users and non-users, there was no significant difference in the length of narcotic use, total morphine milligram equivalents taken, narcotic pills taken, average post-op pain scores, the percentage of patients requiring a refill of narcotics, or length of stay. CONCLUSION: Understanding that CBD/THC usage was not consistent for patients who used these products, 22.6% of TKA and 11.7% of THA patients tried CBD/THC products in the perioperative period. In this small sample, CBD/THC use was not associated with a major effect on narcotic requirements. Further studies on the effects of CBD/THC are needed as these therapies become more widely available.

Opioid Use After Discharge Following Primary Unilateral Total Hip Arthroplasty: How Much Are We Overprescribing?

BACKGROUND: The opioid crisis pressures orthopedic surgeons to reduce the amount of narcotics prescribed for postoperative pain management. This study sought to quantify postoperative opioid use after hospital discharge for primary unilateral total hip arthroplasty (THA) patients. METHODS: A prospective cohort of primary unilateral THA patients were enrolled at a single institution. Detailed pain journals tracked all prescription and over-the-counter pain medication, quantity, frequency, and visual analog scale pain scores. Pain medications were converted to morphine milligram equivalents (MME). RESULTS: Data from 121 subjects were analyzed; the average visual analog scale pain score was 3.44 while taking narcotics. The average number of days taking narcotics was 8.46 days. The distribution of days taking narcotics was right shifted with 50.5% of patients off narcotics after 1 week, and 82.6% off by 2 weeks postoperatively. The average number of narcotic pills prescribed was significantly greater than narcotic pills taken (72.5 vs 28.8, P < .0001). The average MME prescribed was significantly greater than MME taken (452.1 vs 133.8, P < .0001). The average excess narcotic pills prescribed per patient was 51.7 pills. And 71.9% took fewer than 30 narcotic pills; 90.9% patients took fewer than 50 narcotic pills. Also, 10.7% did not require any narcotics; 9.9% required a refill of narcotics; and 33.1% went home the day of surgery. CONCLUSION: Significantly more narcotics were prescribed than were taken in the postoperative period following THA with an average 51.7 excess narcotic pills per patient. Adjusting prescribing patterns to match patient narcotic usage could reduce the excess narcotic pills following THA.

Reducing the Burden of Complex Medication Regimens: SImplification of Medications Prescribed to Long-tErm care Residents (SIMPLER) Cluster Randomized Controlled Trial.

OBJECTIVE: To assess the application of a structured process to consolidate the number of medication administration times for residents of aged care facilities. DESIGN: A nonblinded, matched-pair, cluster randomized controlled trial. SETTING AND PARTICIPANTS: Permanent residents who were English-speaking and taking at least 1 regular medication, recruited from 8 South Australian residential aged care facilities (RACFs). METHODS: The intervention involved a clinical pharmacist applying a validated 5-step tool to identify opportunities to reduce medication complexity (eg, by administering medications at the same time or through use of longer-acting or combination formulations). Residents in the comparison group received routine care. The primary outcome at 4-month follow-up was the number of administration times per day for medications charted regularly. Resident satisfaction and quality of life were secondary outcomes. Harms included falls, medication incidents, hospitalizations, and mortality. The association between the intervention and primary outcome was estimated using linear mixed models. RESULTS: Overall, 99 residents participated in the intervention arm and 143 in the comparison arm. At baseline, the mean resident age was 86 years, 74% were female, and medications were taken an average of 4 times daily. Medication simplification was possible for 62 (65%) residents in the intervention arm, with 57 (62%) of 92 simplification recommendations implemented at follow-up. The mean number of administration times at follow-up was reduced in the intervention arm in comparison to usual care (-0.36, 95% confidence interval -0.63 to -0.09, P = .01). No significant changes in secondary outcomes or harms were observed. CONCLUSIONS AND IMPLICATIONS: One-off application of a structured tool to reduce regimen complexity is a low-risk intervention to reduce the burden of medication administration in RACFs and may enable staff to shift time to other resident care activities.

Opioid Use After Discharge Following Primary Unilateral Total Knee Arthroplasty: How Much Are We Over-Prescribing?

BACKGROUND: The opioid crisis pressures orthopedic surgeons to reduce the amount of narcotics prescribed for post-operative pain management. This study sought to quantify post-operative opioid use after hospital discharge for primary unilateral total knee arthroplasty (TKA) patients. METHODS: A prospective cohort of primary unilateral TKA patients performed by one of 5 senior fellowship-trained arthroplasty surgeons were enrolled at a single institution. Detailed pain journals tracked all prescriptions and over-the-counter pain medications, quantities, frequencies, and visual analog scale pain scores. Narcotic and narcotic-like pain medications were converted to morphine milligram equivalents (MME). Statistical analysis was performed using Student's t-test with α < 0.05. RESULTS: Data from 89 subjects were analyzed; the average visual analog scale pain score was 6.92 while taking narcotics. The average number of days taking narcotics was 16.8 days. The distribution of days taking narcotics was right shifted with 52.8% of patients off narcotics after 2 week, and 74.2% off by 3 weeks post-op. The average MME prescribed was significantly greater than MME taken (866.6 vs 428.2, P < .0001). The average number of narcotic pills prescribed was significantly greater than narcotic pills taken (105.1 vs 52.0, P < .0001). The average excess narcotic pills prescribed per patient was 53.1 pills. About 48.3% took fewer than 40 narcotic pills; 75.3% took fewer than 75 narcotic pills. About 3.4% did not require any narcotics; 40.5% required a refill of narcotics. Also, 9.0% went home the day of surgery. CONCLUSION: Significantly more narcotics were prescribed than were taken in the post-operative period following TKA with an average 53.1 excess narcotic pills per patient. Adjusting prescribing patterns to match patient narcotic usage could reduce the excess narcotic pills following TKA.

Presence of substance P positive terminals on hypothalamic somatostatinergic neurons in humans: the possible morphological substrate of the substance P-modulated growth hormone secretion.

Substance P is an undecapeptide affecting the gastrointestinal, cardiovascular, and urinary systems. In the central nervous system, substance P participates in the regulation of pain, learning, memory, and sexual homeostasis. In addition to these effects, previous papers provided solid evidence that substance P exhibits regulatory effects on growth. Indeed, our previous study revealed that growth hormone-releasing hormone (GHRH) neurons appear to be densely innervated by substance P fibers in humans. Since growth hormone secretion is regulated by the antagonistic actions of both GHRH and somatostatin, in the present paper we have examined the possibility that SP may also affect growth via the somatostatinergic system. Therefore, we have studied the putative presence of juxtapositions between the substance P-immunoreactive (IR) and somatostatinergic systems utilizing double label immunohistochemistry combined with high magnification light microscopy with oil immersion objective. In the present study, we have revealed a dense network of substance P-IR axonal varicosities contacting the majority of somatostatin-IR neurons in the human hypothalamus. Somatostatinergic perikarya are often covered by these fiber varicosities that frequently form basket-like encasements with multiple en passant type contacts, particularly in the infundibular nucleus/median eminence and in the basal periventricular area of the tuberal region. In addition, numerous substance-P-somatostatinergic juxtapositions can be found in the basal perifornical zone of the tuberal area. If these contacts are indeed functional synapses, they may represent the morphological substrate of the control of substance P on growth. Indeed, the frequency and density of these juxtapositions indicate that in addition to the regulatory action of substance P on GHRH secretion, substance P also influences growth by regulating hypothalamic somatostatinergic system via direct synaptic contacts.

Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold.

A series of allosteric kidney-type glutaminase (GLS) inhibitors were designed and synthesized using 1,4-di(5-amino-1,3,4-thiadiazol-2-yl)butane as a core scaffold. A variety of modified phenylacetyl groups were incorporated into the 5-amino group of the two thiadiazole rings in an attempt to facilitate additional binding interactions with the allosteric binding site of GLS. Among the newly synthesized compounds, 4-hydroxy-N-[5-[4-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]-1,3,4-thiadiazol-2-yl]-benzeneacetamide, 2m, potently inhibited GLS with an IC50 value of 70 nM, although it did not exhibit time-dependency as seen with CB-839. Antiproliferative effects of 2m on human breast cancer lines will be also presented in comparison with those observed with CB-839.

Orbital radiotherapy for thyroid eye disease: case report with a review of the literature.

Thyroid eye disease (TED) is a condition mainly associated with Graves' disease. We report a patient with moderate-tosevere TED who underwent a combination of intravenous and oral steroids and orbital radiotherapy that improved her visual acuity and colour vision drastically, and decreased upper lid oedema. We review the clinical features of this unusual condition, our patient's history and treatment, and the knowledge base from the current literature.

An Evaluation of Two Approaches to Skin Bolus Design for Patients Receiving Radiotherapy for Head and Neck Cancers.

PURPOSE: This radiation treatment planning study compares two approaches to designing a bolus for patients with head and neck cancer. Our current approach, based on clinical examination, is compared with an alternative approach, based on the patient's computed tomographic image data set, to investigate potential improvements in delivering the prescribed dose to the superficial regions of the clinical target volume (CTV) while limiting the dose to normal skin. METHODS: Twelve consecutive head and neck radiotherapy plans requiring a bolus were selected. A clinically placed bolus was designed by a radiation oncologist through physical examination of the patient. A virtual bolus was designed using an algorithm that configured it to overlay only the superficial CTV delineated on the patient's CT data set. These two approaches were compared on the basis of dose-volume histograms of normal skin and the superficial CTV, as well as the total bolus area. RESULTS: Of 12 patients, the virtual bolus plan resulted in a decrease in the bolus area of at least 4 cm2 for nine patients, an increase in the bolus area of at least 30 cm2 for three patients, and an improvement in the minimum dose to the superficial CTV in six patients. Of these six patients, half had a reduction in the bolus area with a corresponding modest 2% improvement in the minimum dose to the superficial CTV, whereas the other half had an increase in the bolus area with a corresponding dramatic 10%-57% improvement in the minimum dose to the superficial CTV. CONCLUSIONS: Basing bolus design on computed tomography image data rather than on clinical examination reduced the area of normal skin under the bolus in 9 patients (75%) and improved dose coverage of the superficial CTV in 3 patients (25%). All plans benefited from the virtual bolus approach because it has been shown to be more appropriate for balancing skin sparing with target coverage.

Microstructural, densitometric and metabolic variations in bones from rats with normal or altered skeletal states.

BACKGROUND: High resolution µCT, and combined µPET/CT have emerged as non-invasive techniques to enhance or even replace dual energy X-ray absorptiometry (DXA) as the current preferred approach for fragility fracture risk assessment. The aim of this study was to assess the ability of µPET/CT imaging to differentiate changes in rat bone tissue density and microstructure induced by metabolic bone diseases more accurately than current available methods. METHODS: Thirty three rats were divided into three groups of control, ovariectomy and vitamin-D deficiency. At the conclusion of the study, animals were subjected to glucose ((18)FDG) and sodium fluoride (Na(18)F) PET/CT scanning. Then, specimens were subjected to µCT imaging and tensile mechanical testing. RESULTS: Compared to control, those allocated to ovariectomy and vitamin D deficiency groups showed 4% and 22% (significant) increase in (18)FDG uptake values, respectively. DXA-based bone mineral density was higher in the vitamin D deficiency group when compared to the other groups (cortical bone), yet µCT-based apparent and mineral density results were not different between groups. DXA-based bone mineral density was lower in the ovariectomy group when compared to the other groups (cancellous bone); yet µCT-based mineral density results were not different between groups, and the µCT-based apparent density results were lower in the ovariectomy group compared to the other groups. CONCLUSION: PET and micro-CT provide an accurate three-dimensional measurement of the changes in bone tissue mineral density, as well as microstructure for cortical and cancellous bone and metabolic activity. As osteomalacia is characterized by impaired bone mineralization, the use of densitometric analyses may lead to misinterpretation of the condition as osteoporosis. In contrast, µCT alone and in combination with the PET component certainly provides an accurate three-dimensional measurement of the changes in both bone tissue mineral density, as well as microstructure for cortical and cancellous bone and metabolic activity.

Two-stage arthroplasty for prosthetic joint infection: a systematic review of acute kidney injury, systemic toxicity and infection control.

Periprosthetic infections of hip and knee joints are now treated by two-stage revision arthroplasty with an infection control rate of 91%. The present systematic review studied the reported incidence of acute kidney injury (AKI) and infection recurrence from January 1989 to June 2012 to assess the risk-benefit ratio of antibiotic spacer use. Ten observational studies (n=544 patients) with clinical outcomes showed an average incidence of AKI of 4.8%. The average reported persistence or recurrence rate of infection was 11% during a follow-up period that ranged from 13 to 108 months. The risk-benefit ratio presently favors treatment although there appears to be higher complication rates and incidence of AKI than previously reported. Marked heterogeneity in practice and lack of detail in reporting precluded more robust quantitative synthesis. Clinicians need to be aware of the potential risk of AKI, particularly in high-risk patients; practice patterns for the use of antibiotic spacers need to be standardized.

Inducible immortality in hTERT-human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) are attractive candidates for tissue engineering and cell-based therapy because of their multipotentiality and availability in adult donors. However, in vitro expansion and differentiation of these cells is limited by replicative senescence. The proliferative capacity of hMSCs can be enhanced by ectopic expression of telomerase, allowing for long-term culture. However, hMSCs with constitutive telomerase expression demonstrate unregulated growth and even tumor formation. To address this problem, we used an inducible Tet-On gene expression system to create hMSCs in which ectopic telomerase expression can be induced selectively by the addition of doxycycline (i-hTERT hMSCs). i-hTERT hMSCs have inducible hTERT expression and telomerase activity, and are able to proliferate significantly longer than wild type hMSCs when hTERT expression is induced. They stop proliferating when hTERT expression is turned off and can be rescued when expression is re-induced. They retain multipotentiality in vitro even at an advanced age. We also used a selective inhibitor of telomere elongation to show that the mechanism driving immortalization of hMSCs by hTERT is dependent upon maintenance of telomere length. Thanks to their extended lifespan, preserved multipotentiality and controlled growth, i-hTERT hMSCs may prove to be a useful tool for the development and testing of novel stem cell therapies.

A new high affinity technetium-99m-bombesin analogue with low abdominal accumulation.

99mTc-labeled bombesin analogues have shown promise for noninvasive detection of many tumors that express bombesin (BN)/gastrin-releasing peptide (GRP) receptors. 99mTc-labeled peptides, however, have a tendency to accumulate in the liver and intestines due to hepatobiliary clearance as a result of the lipophilicity of the 99mTc chelates. This makes the imaging of lesions in the abdominal area difficult. In this study, we have synthesized a new high affinity 99mTc-labeled BN analogue, [DTPA1, Lys3(99mTc-Pm-DADT), Tyr4]BN, having a built-in pharmacokinetic modifier, DTPA, and labeled with 99mTc using a hydrophilic diaminedithiol chelator (Pm-DADT) to effect low hepatobiliary clearance. In vitro binding studies using human prostate cancer PC-3 cell membranes showed that the inhibition constant (Ki) for [DTPA1, Lys3(99Tc-Pm-DADT), Tyr4]BN was 4.1 +/- 1.4 nM. Biodistribution studies of [DTPA1, Lys3(99mTc-Pm-DADT), Tyr4]BN in normal mice showed very low accumulation of radioactivity in the liver and intestines (1.32 +/- 0.13 and 4.58 +/- 0.50% ID, 4 h postinjection, respectively). There was significant uptake (7.71 +/- 1.37% ID/g, 1 h postinjection) in the pancreas which expresses BN/GRP receptors. The uptake in the pancreas could be blocked by BN, partially blocked by neuromedin B, but not affected by somatostatin, indicating that the in vivo binding was BN/GRP receptor specific. Scintigraphic images showed specific, high contrast delineation of prostate cancer PC-3 xenografts in SCID mice. Thus, the new peptide has a great potential for imaging BN/GRP receptor-positive cancers located even in the abdomen.

A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier.

The bombesin (BN)/gastrin-releasing peptide (GRP) receptor is expressed in high density on the cell surface of a variety of tumors. This makes the receptors accessible as a molecular target for the detection of lesions in which they are expressed. In this study, we describe a high affinity hydrophilic (99m)Tc-labeled BN analogue, [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN, having diethylenetriaminepentaacetic acid (DTPA), as a build-in pharmacokinetic modifier, to direct its excretion through the urinary system in order to lower abdominal background activity. In vitro binding studies using [(125)I-Tyr(4)]BN (K(d), 0.1 nM) and human prostate cancer PC-3 cell membranes showed that the inhibition constant (K(i)) of [DTPA(1), Lys(3)((99)Tc-Hx-DADT), Tyr(4)]BN was 19.9 +/- 8.0 nM. Biodistribution studies in normal mice showed fast blood clearance (0.15 +/- 0.01% ID/g, 4 h postinjection), low intestinal accumulation (9.16 +/- 2.35% ID/g, 4 h postinjection), and significant uptake in BN/GRP receptor rich tissues such as the pancreas (21.83 +/- 2.88% ID/g, 15 min postinjection). The pancreas/blood, pancreas/muscle, and pancreas/liver ratios were highest at 2 h postinjection at 23, 74, and 8.4, respectively. The uptake in the pancreas could be blocked by BN (11.96 +/- 1.17 vs 0.65 +/- 0.16% ID/g), partially blocked by neuromedin B (11.96 +/- 1.17 vs 6.66 +/- 0.51% ID/g), but not affected by somatostatin (11.96 +/- 1.17 vs 12.91 +/- 2.53% ID/g), indicating that the binding of [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN to the receptors was specific. Scintigraphic imaging of human PC-3 prostate cancer xenografts in SCID mice gave a high target to nontarget ratio on the image. Thus, [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN has the potential for imaging BN/GRP receptor-positive lesions.