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This qualitative study explores player and stakeholder perceptions of menstrual health support in elite female soccer.Semi-structured interviews were conducted with 47 participants including players (n = 12), parents (n = 9), coaches (n = 9), sport scientists (n = 7), nutritionists (n = 5) and medical staff (n = 5).Via thematic analysis, data demonstrate that elite female soccer players experience a range of physical and psychological symptoms primarily at the onset of and during menses (as also perceived by stakeholders), with most participants perceiving these symptoms to impact performance. Nonetheless, menstrual health support is perceived as minimal and although players have their menstrual status tracked, they report little understanding as to why or how this information is used. This confusion was also present among stakeholders, often as a result of uncertainty about the evidence supporting the need for menstrual health support. The perceived lack of support may also be reflective of a culture where conversations about the menstrual cycle are not normalised. Overall, this may result in failure to identify and treat menstrual irregularities despite non-coaching staff members perceiving them to be common amongst players.These data support the need for individualised support based on the lived experiences of individual players and support staff. Furthermore, our research identifies the need for organisational, stakeholder, and player centred education programmes (led by experts in female athlete health) that create an environment where players receive personalised menstrual health support.

This qualitative study explores player and stakeholder perceptions of the role of nutrition in supporting player development and performance in elite female soccer. Semi-structured interviews (36 ± 18 mins in length) were conducted with 47 participants, including players (n = 12), parents (n = 9), coaches (n = 9), sport scientists (n = 7), nutritionists (n = 5) and medical staff (n = 5). Via thematic analysis, data provided an insight into the nutrition culture within elite women's soccer. Data demonstrate that considerable confusion and misconceptions exist amongst players and stakeholders regarding the theoretical underpinning and practical application of meeting energy requirements, colloquially referred to as "fuelling". As such, it is perceived that players "under-fuel", which is likely caused by misunderstandings about the impact of carbohydrate intake on body composition, a fear of weight gain and the associated impacts upon body image. The "carbohydrate fear" that is experienced by players is exacerbated by external pressures arising from social media, key stakeholders (e.g., coaches) and the skinfold culture surrounding measurement of body composition. Such cultural issues are amplified by the lack of full-time professionally accredited nutritionists overseeing the provision of nutrition support. Indeed, the infrastructure supporting the women's game (e.g. staffing resource, on-site food provision, player education programmes etc.) was considered incomparable to the men's game. When taken together, our data provide a platform for which to develop organisational, stakeholder and player centred education and behaviour change interventions that strive to promote a positive performance nutrition culture within the women's game.

Neuroendocrine tumors (NETs) are rare, diverse malignancies; approximately two thirds originate in the gastrointestinal tract and pancreas and are known as gastroenteropancreatic NET. Most cases are diagnosed in the advanced or metastatic setting and overexpress somatostatin receptors. Recommended first-line treatment is somatostatin analogs; however, disease progression is common. [177Lu]Lu-DOTA-TATE is a radiolabeled peptide receptor radionuclide therapy (PRRT) indicated for the treatment of adult patients with somatostatin receptor-positive foregut, midgut, and hindgut gastroenteropancreatic NETs and progression on first-line somatostatin analogs. Many primary oncology practices may lack the staff, expertise, and infrastructure to treat patients with PRRT and primary oncologists may therefore refer their patients to a NET specialist at a tertiary center for treatment. Given the amount of organization required, PRRT treatment may seem to be complex; however, this process will be managed by a care coordinator who acts as a consistent point of contact for primary physicians regarding the care of their patients and ensures blood tests and scans are scheduled. In this article, we share our opinions, procedures, workflow, best practice, and roles and responsibilities when caring for patients receiving [177Lu]Lu-DOTA-TATE and focus on the role of the primary oncologist before, during, and after PRRT treatment.

The endogenous opioidergic system is critically involved in the cognitive modulation of pain. Slow-breathing-based techniques are widely used nonpharmacological approaches to reduce pain. Yet, the active mechanisms of actions supporting these practices are poorly characterized. Growing evidence suggest that mindfulness-meditation, a slow-breathing technique practiced by nonreactively attending to breathing sensations, engages multiple unique neural mechanisms that bypass opioidergically mediated descending pathways to reduce pain. However, it is unknown whether endogenous opioids contribute to pain reductions produced by slow breathing. The present double-blind, placebo-controlled crossover study examined behavioral pain responses during mindfulness-meditation (n = 19), sham-mindfulness meditation (n = 20), and slow-paced breathing (n = 20) in response to noxious heat (49°C) and intravenous administration (0.15 mg/kg bolus + 0.1 mg/kg/hour maintenance infusion) of the opioid antagonist, naloxone, and placebo saline. Mindfulness significantly reduced pain unpleasantness ratings across both infusion sessions when compared to rest, but not pain intensity. Slow-paced breathing significantly reduced pain intensity and unpleasantness ratings during naloxone but not saline infusion. Pain reductions produced by mindfulness-meditation and slow-paced breathing were insensitive to naloxone when compared to saline administration. By contrast, sham-mindfulness meditation produced pain unpleasantness reductions during saline infusion but this effect was reversed by opioidergic antagonism. Sham-mindfulness did not lower pain intensity ratings. Self-reported "focusing on the breath" was identified as the operational feature particularly unique to the mindfulness-meditation and slow paced-breathing, but not sham-mindfulness meditation. Across all individuals, attending to the breath was associated with naloxone insensitive pain-relief. These findings provide evidence that slow breathing combined with attention to breath reduces pain independent of endogenous opioids.

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.

Pancreatic adenocarcinoma is one of the most lethal cancers in oncology. Pancreatic cancer is the third most common cause of cancer-related mortality in the United States. As the years have progressed, the importance of a multidisciplinary and multimodal approach to pancreatic cancer care has been recognized and is now recommended in all major society guidelines. A subset of pancreatic cancer, borderline resectable pancreatic cancer (BRPC), has emerged as a distinct clinical entity for which specialized treatment plans are now being developed. The medical oncologist, surgical oncologist, and radiation oncologist must work jointly to help deliver the best clinical outcome for the patient with pancreatic cancer. In this discussion, we describe the current state of surgical, locoregional therapies and systemic therapy in BRPC.

Introduction Standard therapy for muscle invasive bladder cancer includes neoadjuvant chemotherapy followed by radical cystectomy with urinary diversion. Three decades of interest in primary radiation and chemotherapy for bladder preservation have yielded mature that deserve closer examination. Methods We reviewed the literature with an emphasis on outcomes from major clinical trials and prospective studies, while highlighting important aspects of effective treatment delivery and unanswered questions surrounding this approach. Results There are no randomized trials comparing radical cystectomy to primary chemotherapy and radiation for bladder preservation, and future phase III comparisons are unlikely to be planned. Mature results from single institution protocols and phase II cooperative group trials demonstrate favorable disease-specific survival and bladder preservation rates. Here we review the results of relevant clinical trials, including cancer-related and patient functional outcomes. We outline multi-modal treatment specifics with respect to radiation delivery, incorporation of transurethral resection and chemotherapy selection, and future directions for optimizing results of non-operative strategies. Conclusions Combination chemotherapy and radiation can be used as an alternative to conserve the native bladder in appropriately selected patients, mirroring successful non-operative treatment paradigms used for organ-preservation for other cancer sites.

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain.SIGNIFICANCE STATEMENTEndogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results demonstrate that meditation-based pain relief does not require endogenous opioids. Therefore, the treatment of chronic pain may be more effective with meditation due to a lack of cross-tolerance with opiate-based medications.

Understanding risk factors for locoregional recurrence (LRR) after accelerated partial breast irradiation (APBI) can help to guide patient selection for treatment with APBI. Published findings to date have not been consistent. More data are needed as these risk factors continue to be defined.A total of 277 women with early-stage invasive breast cancer underwent lumpectomy and were treated adjuvantly at our institution with APBI using high-dose rate brachytherapy. APBI was delivered using multicatheter interstitial brachytherapy (91 %) or single-entry catheter brachytherapy (9 %) to a dose of 32-34 Gy in 8-10 twice daily fractions. Failure patterns and risk factors for recurrence were analyzed.With a median follow-up of 61 months, the 5-year locoregional control rate was 94.4 %. Negative estrogen receptor (ER) status was strongly associated with LRR on multivariate analysis (p 0.005). Lobular histology, the presence of an extensive intraductal component, and lymphovascular invasion also were significant but to a lesser degree than ER-negative status. Patients with multiple risk factors were at highest risk for LRR. Age was not significantly associated with increased risk for LRR.The presence of specific pathological features, particularly ER negative status, was associated with increased risk of LRR in this cohort of women treated with APBI. Further investigation is warranted to determine whether patients with adverse pathological risk factors are at higher risk of LRR after APBI than after conventional whole breast irradiation (WBI), as these same features also may place women at risk for LRR after WBI.

Whole pelvic radiotherapy with concurrent chemotherapy is the standard of care for locally advanced cervical carcinoma. Published literature reports that the pelvic bone marrow (BM) dosimetric parameters of V10 > 90% and V20 > 80% are associated with higher rates of hematologic toxicities using this approach. Here, we investigate the ability of Tomotherapy based intensity modulated radiation therapy (IMRT) to reduce dose to pelvic BM while evaluating dose distribution to critical structures and planning target volume (PTV) coverage. Ten patients were selected for analysis. Normal structures, whole pelvic BM, PTV contours, and IMRT objects were standardized. Two whole pelvis Tomotherapy plans were created for each patient, one standard plan, and one with the addition of a BM sparing (BMS) constraint (V10

Purpose To evaluate outcomes among women with American Society for Radiation Oncology (ASTRO) consensus statement cautionary features treated with brachytherapy-based accelerated partial breast irradiation (APBI). Methods and Materials Between March 2001 and June 2006, 322 consecutive patients were treated with high-dose-rate (HDR) APBI at the University of Wisconsin. A total of 136 patients were identified who met the ASTRO cautionary criteria. Thirty-eight (27.9%) patients possessed multiple cautionary factors. All patients received 32 to 34 Gy in 8 to 10 twice-daily fractions using multicatheter (93.4%) or Mammosite balloon (6.6%) brachytherapy. Results With a median follow-up of 60 months, there were 5 ipsilateral breast tumor recurrences (IBTR), three local, and two loco-regional. The 5-year actuarial rate of IBTR was 4.8% ± 4.1%. The 5-year disease-free survival was 89.6%, with a cause-specific survival and overall survival of 97.6% and 95.3%, respectively. There were no IBTRs among 32 patients with ductal carcinoma in situ (DCIS) vs. 6.1% for patients with invasive carcinoma ( p = 0.24). Among 104 patients with Stage I or II invasive carcinoma, the IBTR rate for patients considered cautionary because of age alone was 0% vs. 12.7% in those deemed cautionary due to histopathologic factors ( p = 0.018). Conclusions Overall, we observed few local recurrences among patients with cautionary features. Women with DCIS and patients 50 to 59 years of age with Stage I/II disease who otherwise meet the criteria for suitability appear to be at a low risk of IBTR. Patients with tumor-related cautionary features will benefit from careful patient selection.

Cerebral cortical activity is heavily influenced by interactions with the basal ganglia. These interactions occur via cortico-basal ganglia-thalamo-cortical loops. The putamen is one of the major sites of cortical input into basal ganglia loops and is frequently activated during pain. This activity has been typically associated with the processing of pain-related motor responses. However, the potential contribution of putamen to the processing of sensory aspects of pain remains poorly characterized. In order to more directly determine if the putamen can contribute to sensory aspects of pain, nine individuals with lesions involving the putamen underwent both psychophysical and functional imaging assessment of perceived pain and pain-related brain activation. These individuals exhibited intact tactile thresholds, but reduced heat pain sensitivity and widespread reductions in pain-related cortical activity in comparison with 14 age-matched healthy subjects. Using magnetic resonance imaging to assess structural connectivity in healthy subjects, we show that portions of the putamen activated during pain are connected not only with cortical regions involved in sensory-motor processing, but also regions involved in attention, memory and affect. Such a framework may allow cognitive information to flow from these brain areas to the putamen where it may be used to influence how nociceptive information is processed. Taken together, these findings indicate that the putamen and the basal ganglia may contribute importantly to the shaping of an individual subjective sensory experience by utilizing internal cognitive information to influence activity of large areas of the cerebral cortex.

Purpose: To investigate the reliability, validity and feasibility of a computer-assisted manual segmentation method for determining the synovial membrane volume as a surrogate measure for synovitis in patients with rheumatoid arthritis (RA). Materials and Methods: The 3 Tesla (T) MRI scans were acquired in 22 early RA and 16 established RA patients. Synovial membrane volumes in postcontrast T1w axial images at three wrist joint regions were determined by two nonradiologist observers using a computer-assisted manual segmentation method. Results: Intraobserver reliability, measured by intraclass correlation coefficients (ICCs), was excellent in the early (ICC = 0.99) and established (ICC = 0.99) RA cohorts. Interobserver reliability (mean ICC [95% Confidence Interval]) was moderate to excellent in the early and established RA groups (ICCs = 0.87 [0.68,0.94] and 0.88 [0.66, 0.96], respectively). There was a strong correlation between the synovial membrane volumes derived by segmentation and the RA MRI scoring system (RAMRIS) scores for synovitis at all joints in the early (Spearman rho = 0.86–0.96) and established (Spearman rho = 0.85–0.93) RA cohorts. The entire segmentation technique took 19 to 21 min per patient. Conclusion: Measurement of MRI synovitis using a computer-assisted manual segmentation method demonstrated excellent intraobserver and very good interobserver reliability, content validity (represented by its strong correlation with RAMRIS synovitis), and moderate feasibility. J. Magn. Reson. Imaging 2011;33:1106–1113. © 2011 Wiley-Liss, Inc.

The subjective experience of one's environment is constructed by interactions among sensory, cognitive, and affective processes. For centuries, meditation has been thought to influence such processes by enabling a nonevaluative representation of sensory events. To better understand how meditation influences the sensory experience, we used arterial spin labeling functional magnetic resonance imaging to assess the neural mechanisms by which mindfulness meditation influences pain in healthy human participants. After 4 d of mindfulness meditation training, meditating in the presence of noxious stimulation significantly reduced pain unpleasantness by 57% and pain intensity ratings by 40% when compared to rest. A two-factor repeated-measures ANOVA was used to identify interactions between meditation and pain-related brain activation. Meditation reduced pain-related activation of the contralateral primary somatosensory cortex. Multiple regression analysis was used to identify brain regions associated with individual differences in the magnitude of meditation-related pain reductions. Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula, areas involved in the cognitive regulation of nociceptive processing. Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation, an area implicated in reframing the contextual evaluation of sensory events. Moreover, reductions in pain unpleasantness also were associated with thalamic deactivation, which may reflect a limbic gating mechanism involved in modifying interactions between afferent input and executive-order brain areas. Together, these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information.

Purpose To investigate the reliability, feasibility, and validity of a computer-assisted manual segmentation (outlining) technique for measuring magnetic resonance imaging (MRI) bone erosion and edema at the wrist in rheumatoid arthritis (RA). Materials and Methods The 3T MRI scans were obtained in 22 RA patients (

Abnormal 50- and 100-msec event-related brain activity derived from paired-click procedures are well established in schizophrenia. There is little agreement on whether group differences in the ratio score, i.e., the ratio of EEG amplitude after the second stimulus (S2) to the amplitude after the first stimulus (S1), reflect an encoding or gating abnormality. In addition, the functional implications remain unclear. In the present study, EEG and magnetoencephalography (MEG) were used to examine paired-click measures and cognitive correlates of paired-click activity.EEG and whole-cortex MEG data were acquired during the standard paired-click paradigm in 73 comparison subjects and 79 schizophrenia patients. Paired-click ratio scores were obtained at 50 msec (P50 evoked potential at Cz, M50 at left and right superior temporal gyrus [STG]) and 100 msec (N100 at Cz, M100 at left and right STG). A cognitive battery assessing attention, working memory, and long-delay memory was administered. IQ was also estimated.Groups differed on ratio score and amplitude of S1 response. Ratio scores at 50 msec and 100 msec and S1 amplitude predicted variance in attention (primarily S1 amplitude), working memory, and long-delay memory. The attention findings remained after removal of variance associated with IQ.Associations between paired-click measures and cognitive performance in patients support 50-msec and 100-msec ratio and amplitude scores as clinically significant biomarkers of schizophrenia. In general, cognitive performance was better predicted by the ability to encode auditory information than the ability to filter redundant information.

The inheritance of A-V conduction time in Polynesians has been examined, using ECGs taken from the population of the Tokelau Islands. As has been demonstrated in other racial groups, A-V conduction time was influenced by sex, age, and heart rate. Complex segregation analysis provides evidence for a significant polygenic influence on A-V conduction, but no evidence for a major gene. Familial correlations and commingling analysis are in agreement with this conclusion. The heritability of A-V conduction time was 0.46. The hypothesis of Moller & Heiberg (1980a) that a major gene could be influencing A-V conduction, is not supported by these data.

ABO blood group-incompatible kidney transplantation (ABOiKTx) outcomes are good, but complications are more common than in conventional transplantation. Regimens that use extracorporeal antibody removal therapy (EART) and enhanced immunosuppression are guided by titration of ABO blood group antibodies (using hemagglutination [HA] dilution assays), and these assays vary significantly in performance between centers. This study aims to describe the differences in titer measurement and the effect on clinical practice and outcomes.This multicentre, prospective cohort study of 100 ABOiKTx recipients assessed treatment and outcome data, including HA assay results measured retrospectively in a single central laboratory.Patient and allograft survival at 1 year was 99% and 94%, respectively. There were significant differences in the number of pretransplantation EART sessions in centers undertaking plasma exchange (PEx), compared with immunoadsorption (IA) (median, 6 vs. 4 sessions; p = 0.007). The pre-EART HA titer in both groups was the same when centrally assayed. The local HA assay used to guide treatment yielded significantly higher titers in centers undertaking PEx compared with IA (median, 128 vs. 32; p 0.005). Patients undergoing PEx rather than IA were significantly more likely to suffer postoperative hematoma (12.9% vs. 1.8%; p = 0.05) or any perioperative collection requiring drainage (19.4% vs. 3.6%; p = 0.02).The colinearity of HA assay sensitivity with the receipt of PEx and EART limits some conclusions regarding the likely direction of causation. However, the association of differences in clinical practice with recognized perioperative complications of ABOiKTx identifies targets for further investigation and quality improvement.

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p< 0.05). Mindfulness meditation reduced pain intensity (p= 0.032) and pain unpleasantness (p< 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p= 0.030) and pain unpleasantness (p= 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation.SIGNIFICANCE STATEMENTRecent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the “gold standard” for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy.

Our subjective sensory experiences are thought to be heavily shaped by interactions between expectations and incoming sensory information. However, the neural mechanisms supporting these interactions remain poorly understood. By using combined psychophysical and functional MRI techniques, brain activation related to the intensity of expected pain and experienced pain was characterized. As the magnitude of expected pain increased, activation increased in the thalamus, insula, prefrontal cortex, anterior cingulate cortex (ACC) and other brain regions. Pain-intensity-related brain activation was identified in a widely distributed set of brain regions but overlapped partially with expectation-related activation in regions, including the anterior insula and ACC. When expected pain was manipulated, expectations of decreased pain powerfully reduced both the subjective experience of pain and activation of pain-related brain regions, such as the primary somatosensory cortex, insular cortex, and ACC. These results confirm that a mental representation of an impending sensory event can significantly shape neural processes that underlie the formulation of the actual sensory experience and provide insight as to how positive expectations diminish the severity of chronic disease states.

Introduction Magnetic resonance imaging (MRI) is useful for detecting joint inflammation and damage in the inflammatory arthropathies. This study aimed to investigate MRI cartilage damage and its associations with joint inflammation in patients with gout compared with a group with rheumatoid arthritis (RA). Methods Forty patients with gout and 38 with seropositive RA underwent 3T-MRI of the wrist with assessment of cartilage damage at six carpal sites, using established scoring systems. Synovitis and bone oedema (BME) were graded according to Rheumatoid Arthritis MRI Scoring System criteria. Cartilage damage was compared between the groups adjusting for synovitis and disease duration using logistic regression analysis. Results Compared with RA, there were fewer sites of cartilage damage and lower total damage scores in the gout group (P = 0.02 and 0.003), adjusting for their longer disease duration and lesser degree of synovitis. Cartilage damage was strongly associated with synovitis in both conditions (R = 0.59, P

OBJECTIVES To determine parents9 views on autopsy after treatment withdrawal. DESIGN Face to face interviews with 59 sets of bereaved parents (108 individual parents) for whose 62 babies there had been discussion of treatment withdrawal. RESULTS All except one couple were asked for permission for postmortem examination; 38% refused. The main reasons for declining were concerns about disfigurement, a wish to have the child left in peace, and a feeling that an autopsy was unnecessary because the parents had no unanswered questions. The diagnosis, the age of the child, and the approach of the consultant appeared to influence consent rates. Of those who agreed to autopsies, 92% were given the results by the neonatologist concerned. Whether or not they had agreed to the procedure, at 13 months no parent expressed regrets about their decision. CONCLUSIONS Autopsy rates in the East of Scotland stand at 62%. Parents9 perceptions are an important element in consent to postmortem examination.

The reported study aimed to explore parents' perceptions of treatment withdrawal/withholding; their experience and their opinions. In-depth face-to-face interviews at 3 and 13 months after the baby's death were conducted with 108 parents of 62 babies from the East of Scotland. Of the parents, 56% (60/180) believed they had decided to stop treatment. A further 4/59 sets of parents subsequently wished they had taken responsibility. Only one parent who did decide felt guilt 3 months after the event. Parents identified two essential factors which minimise doubt: full and honest information and concrete evidence of a poor prognosis.The majority of parents wish to be active in decision making on behalf of their baby. Doing so does not appear to have adverse consequences. The pacing of events in the process of deciding and managing the dying is critical. Dissatisfaction is reduced if parents are given time and evidence to help them assimilate the reality at each stage.

The ethical issues around decision making on behalf of infants have been illuminated by two empirical research studies carried out in Scotland. In-depth interviews with 176 medical and nursing staff and with 108 parents of babies for whom there was discussion of treatment withholding/withdrawal, generated a wealth of data on both the decision making process and the management of cases. Both staff and parents believe that parents should be involved in treatment limitation decisions on behalf of their babies. However, whilst many doctors and nurses consider the ultimate responsibility too great for families to carry, the majority of parents wish to be the final arbiters. We offer explanations for the differences in perception found in the two groups. The results of these empirical studies provide both aids to ethical reflection and guidance for clinicians dealing with these vulnerable families. They demonstrate the value of empirical data in the philosophical debate.

OBJECTIVE To explore parents9 experiences of bereavement care after withdrawal of newborn intensive care. DESIGN Face to face interviews with 108 parents of 62 babies born over two calendar years in the East of Scotland. RESULTS Only 22% were seen by six weeks after the death, 10% were not recalled before 6–11 months, and 8% were not seen at all in the first year. All except one couple saw the neonatologist who had cared for their baby. Only 33% remembered a neonatal nurse being present. Most (88%) were seen in the study hospital. Parents highlighted a number of specific needs. Appointments should be: ( a ) scheduled soon after the death of the baby and certainly within two months of the death irrespective of whether or not autopsy results are available; ( b ) with the named neonatologist; ( c ) in a setting away from the hospital if possible. Parents value: ( a ) efforts to find out how they are coping; ( b ) full frank information given sensitively to enable them to build up a cohesive picture of what happened and assess their future risks; ( c ) reassurance where possible, but half truths, false reassurances, and broken promises are unacceptable. CONCLUSIONS Follow up care is a crucial part of the management of families from whose babies treatment has been withdrawn. Resources devoted to it should be re-examined to provide a service more in tune with parental need. In choosing the place, timing, and conduct of the meeting, staff should be sensitive to the expressed wishes of the parents themselves.

Aim To explore the contribution patients can make to medical education from both theoretical and empirical perspectives, to describe a framework for reviewing and monitoring patient involvement in specific educational situations and to generate suggestions for further research. Methods Literature review. Results Direct contact with patients can be seen to play a crucial role in the development of clinical reasoning, communication skills, professional attitudes and empathy. It also motivates through promoting relevance and providing context. Few studies have explored this area, including effects on the patients themselves, although there are examples of good practice in promoting more active participation. Conclusion The Cambridge framework is a tool for evaluating the involvement of patients in the educational process, which could be used by curriculum planners and teachers to review and monitor the extent to which patients are actively involved. Areas for further research include looking at the ‘added value’ of using real, as opposed to simulated, patients; more work on outcomes for patients (other than satisfaction); the role of real patients in assessment; and the strengths and weaknesses of different models of patient involvement.

Representatives from eight European countries compared the legal, ethical and professional settings within which decision making for neonates takes place. When it comes to limiting treatment there is general agreement across all countries that overly aggressive treatment is to be discouraged. Nevertheless, strong emphasis has been placed on the need for compassionate care even where cure is not possible. Where a child will die irrespective of medical intervention, there is widespread acceptance of the practice of limiting aggressive treatment or alleviating suffering even if death may be hastened as a result. Where the infant could be saved but the future outlook is bleak there is more debate, but only two countries have tested the courts with such cases. When it comes to the active intentional ending of life, the legal position is standard across Europe; it is prohibited. However, recognising those intractable situations where death may be lingering and unpleasant, Dutch paediatricians have reported that they do sometimes assist babies to die with parental consent. Two cases have been tried through the courts and recent official recommendations have set out standards by which such actions may be assessed.

Introduction Cartilage damage impacts on patient disability in rheumatoid arthritis (RA). The aims of this magnetic resonance imaging (MRI) study were to investigate cartilage damage over three years and determine predictive factors. Methods A total of 38 RA patients and 22 controls were enrolled at t = 0 (2009). After 3 years, clinical and MRI data were available in 28 patients and 15 controls. 3T MRI scans were scored for cartilage damage, bone erosion, synovitis and osteitis. A model was developed to predict cartilage damage from baseline parameters. Results Inter-reader reliability for the Auckland MRI cartilage score (AMRICS) was high for status scores; intraclass correlation coefficient (ICC), 0.90 (0.81 to 0.95) and moderate for change scores (ICC 0.58 (0.24 to 0.77)). AMRICS scores correlated with the Outcome MEasures in Rheumatoid Arthritis Clinical Trials (OMERACT) MRI joint space narrowing (jsn) and X-Ray (XR) jsn scores (r =0.96, P

The brain mechanisms by which sensory cues become transformed into expectations of impending events are a critical component of cognitive tuning of sensory processing. However, distinctions among the afferent processing of cue-related activity itself versus those mechanisms supporting the contextual meaning imparted to the cue remain limited. Do sensory cues with equal meaning engage similar patterns of brain activations even if they are delivered in separate modalities? To address this question, we used functional magnetic resonance imaging of an expectation paradigm in which cues were delivered with visual or innocuous thermal stimuli. Cues were designed to be highly meaningful because they predicted the delivery of high and low painful stimuli. As expected, the cues themselves activated unimodal sensory cortices. This cue modality-specific activation was transformed into a pattern of activity reflecting cue meaning. Cues signaling high pain produced greater activity in the left dorsolateral prefrontal cortex and anterior cingulate cortex. Such activity is consistent with the graded encoding of the magnitude of expected pain. In contrast, cues signaling low pain produced greater activity in the right intraparietal sulcus. This activation may reflect processes directing spatial attention to the stimulated body region in order to more accurately evaluate the relatively weak, low pain stimulus. Taken together, these findings indicate that cues arising from different sensory modalities ultimately engage common brain mechanisms that reflect the meaning of the cue. This meaning-related activity is presumably critical for preparing sensory systems to optimally process afferent information.

Anxiety is the cognitive state related to the inability to control emotional responses to perceived threats. Anxiety is inversely related to brain activity associated with the cognitive regulation of emotions. Mindfulness meditation has been found to regulate anxiety. However, the brain mechanisms involved in meditation-related anxiety relief are largely unknown. We employed pulsed arterial spin labeling MRI to compare the effects of distraction in the form of attending to the breath (ATB; before meditation training) to mindfulness meditation (after meditation training) on state anxiety across the same subjects. Fifteen healthy subjects, with no prior meditation experience, participated in 4 d of mindfulness meditation training. ATB did not reduce state anxiety, but state anxiety was significantly reduced in every session that subjects meditated. Meditation-related anxiety relief was associated with activation of the anterior cingulate cortex, ventromedial prefrontal cortex and anterior insula. Meditation-related activation in these regions exhibited a strong relationship to anxiety relief when compared to ATB. During meditation, those who exhibited greater default-related activity (i.e. posterior cingulate cortex) reported greater anxiety, possibly reflecting an inability to control self-referential thoughts. These findings provide evidence that mindfulness meditation attenuates anxiety through mechanisms involved in the regulation of self-referential thought processes.

The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain.

AIDS has challenged many concepts and practices within nursing. Because of the serious implications attending a positive diagnosis, and because patients with AIDS have become articulate and well informed, familiar principles have been exposed to renewed scrutiny. Anomalies and dilemmas have been revealed. Results from a recent Institute of Medical Ethics survey carried out by the author have illustrated some of the theoretical concepts. Confidentiality has assumed new dimensions. Partnership and mutual empowerment are seen as keys to sound practice involving the patient in decision-making. A vital ingredient relates to the preparation of professionals; they need to be aware of those attitudes and prejudices within themselves which potentially stand in the way of caring well.

Background The reason for the increased risk of death with fenoterol and isoproterenol in asthma is unknown but may relate to their cardiovascular effects. Deaths from asthma usually occur outside hospital where hypoxemia, with or without hypercapnia, may exist. Both of these states can influence the cardiovascular system. We investigated whether different gas mixtures modified the cardiovascular effects of isoproterenol. Method Nine healthy men were randomly assigned to receive each of three gas mixtures to achieve (1) normoxia-normocapnia, (2) hypercapnia (end-tidal Paco2, 50 mm Hg), (3) hypoxemia-hypercapnia (arterial oxygen saturation, 90%; Paco2, 50 mm Hg). Isoproterenol was administered with each of the gas mixtures. Cardiovascular measurements of heart rate, blood pressure, cardiac index, ejection fraction, fractional shortening, electromechanical systole, and the QTC interval were made before administration of the gases, as well as before and 5 minutes after isoproterenol administration. Results The changes after hypercapnia were not significantly different from those after nomoxia-normo-capnia. Hypoxemia-hypercapnia increased heart rate, systolic and diastolic blood pressure, QTC interval, cardiac index, ejection fraction, and fractional shortening. Isoproterenol increased heart rate, systolic blood pressure, QTC interval, cardiac index, ejection fraction, and fractional shortening while the subjects breathed the normoxia-normocapnia gas mixture. It caused similar changes with the other gas mixtures. The changes were additive. Conclusion Isoproterenol and hypoxemia-hypercapnia will increase myocardial oxygen demand and could prove to be detrimental in severe asthma. Clinical Pharmacology and Therapeutics (1994) 56, 302–308; doi:10.1038/clpt.1994.141

Auditory sensory gating deficits have been reported in subjects with post-traumatic stress disorder (PTSD), but the hemispheric and neuronal origins of this deficit are not well understood. The objectives of this study were to: (1) investigate auditory sensory gating of the 50-ms response (M50) in patients diagnosed with PTSD by utilizing magnetoencephalography (MEG); (2) explore the relationship between M50 sensory gating and cortical thickness of the superior temporal gyrus (STG) measured with structural magnetic resonance imaging (MRI); and (3) examine the association between PTSD symptomatology and bilateral sensory gating. Seven participants with combat-related PTSD and eleven controls underwent the paired-click sensory gating paradigm. MEG localized M50 neuronal generators to the STG in both groups. The PTSD group displayed impaired M50 gating in the right hemisphere. Thinner right STG cortical thickness was associated with worse right sensory gating in the PTSD group. The right S1 M50 source strength and gating ratio were correlated with PTSD symptomatology. These findings suggest that the structural integrity of right hemisphere STG cortices play an important role in auditory sensory gating deficits in PTSD.

Purpose Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5½ weeks. Methods and Materials Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months. Results The median follow-up time was 25.4 months (range, 4.2–57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose–volume descriptors correlated with GU toxicity, and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity ( p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 ± 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only. Conclusions Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients.

To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for patients with ≤ 6 brain metastases. We conducted an international study of WBRT (37.5 Gy in 15 fractions) and SRS (15-21 Gy) with the addition of MGd (5 mg/kg preceding each fraction beginning week 2). The primary endpoint was to evaluate the rate of irreversible grade 3 or any grade ≥ 4 neurotoxicity and establish feasibility in preparation for a phase III trial. Sixty-five patients were enrolled from 14 institutions, of which 45 (69%) received SRS with MGd as intended and were available for evaluation. Grade ≥ 3 neurotoxicity attributable to radiation therapy within 3 months of SRS was seen in 2 patients (4.4%), including generalized weakness and radionecrosis requiring surgical management. Immediately following the course of MGd plus WBRT, new brain metastases were detected in 11 patients (24.4%) at the time of the SRS treatment planning MRI. The actuarial incidence of neurologic progression at 6 months and 1 year was 17 and 20%, respectively. The median investigator-determined neurologic progression free survival and overall survival times were 8 (95% CI: 5-14) and 9 months (95% CI: 6-not reached), respectively. We observed a low rate of neurotoxicity, demonstrating that the addition of MGd does not increase the incidence or severity of neurologic complications from WBRT with SRS boost.

ObjectivesTo develop and test an MRI cartilage scoring system for use at the wrist in rheumatoid arthritis (RA).MethodsMRI scans were obtained using a 3T MRI scanner with dedicated wrist coil in 22 early and 16 established RA patients plus 22 controls. Axial and coronal T1-weighted (precontrast and postcontrast) and T2-weighted turbo spin echo sequences were obtained. Eight wrist joints were scored for cartilage narrowing: distal radioulnar, radiolunate, radioscaphoid, triquetrum-hamate, capitate-lunate, scaphotrapezoid, second metacarpal base-trapezoid and third metacarpal base-capitate, using a system based on the Sharp van der Heijde x-ray joint space narrowing (JSN) score by three radiologists. Fifteen sites at the wrist were also scored for synovitis, bone oedema and erosion using the RA MRI score.ResultsInterobserver (three-reader) and intraobserver reliability (readers 1 and 2) for the cartilage score were excellent: intraclass correlations (ICC (95% CI)) 0.91, (0.86 to 0.94), 0.98 (0.96 to 1.00) and 0.94 (0.87 to 1.00), respectively. Cartilage scores (median, range) were higher in the established RA group (11.9, 2.3–27.3) than the early RA group (2.15, 0–6) (p≤0.001) but early RA scores did not differ from healthy controls (2.3, 1–8.7). Cartilage scores correlated with synovitis (R=0.52), bone oedema (R=0.63) and erosion scores (R=0.66), pConclusionThis MRI cartilage score demonstrated excellent reliability when tested in a three-reader system. However, cartilage loss in early RA could not be distinguished from that seen in healthy controls.

BACKGROUND: The reason for the association of increased risk of death with fenoterol in patients with asthma in New Zealand is unknown but may relate to its cardiovascular effects. Most deaths from asthma occur outside hospital, where hypoxaemia is likely to be a complicating factor. The cardiovascular effects of fenoterol have been investigated therefore under conditions of normoxaemia and hypoxaemia. METHOD: Eight healthy men were studied on two occasions. Measurements of heart rate, blood pressure, total electromechanical systole (QS2I), electrocardiographic QTc interval, cardiac index, stroke volume, and ejection fraction were made under conditions of normoxaemia and hypoxaemia (arterial oxygen saturation 90%) before and after administration of 800 micrograms of fenoterol by a metered dose inhaler. The order in which treatments were applied was according to a Latin square design. RESULTS: Before inhalation of fenoterol hypoxaemia was associated with a significant increase in heart rate (8 beats/min) and QTc interval (15.6 ms). Under conditions of normoxaemia fenoterol caused a significant increase in heart rate (14.3 beats/min), systolic blood pressure (7.7 mm Hg), stroke volume (27.7 ml), cardiac index (1.6 1/min/m2), ejection fraction (11.48), and QTc interval (32.9 ms) and a fall in QS2I (-23.2 ms) and diastolic blood pressure (-8.4 mm Hg). Under conditions of hypoxaemia the changes after inhalation of fenoterol were similar to those recorded during normoxaemia; thus the effects of hypoxaemia and fenoterol were additive (heart rate 21.9 beats/min, QTc 43.5 ms with fenoterol and hypoxaemia). CONCLUSION: The chronotropic and electrophysiological effects of fenoterol were enhanced by conditions of hypoxaemia.

That having a baby in hospital undergoing intensive care is a stressful experience is beyond dispute. Every parent, no matter how well-developed their own personal resources, depends to some extent on the support of others within their social system to cope with this stress. Grandparents occupy a special place in support networks and their role was studied in families with a very low birthweight baby. Both professional and lay perspectives were investigated and 93 families participated. Questionnaires were sent to family members 1 month after the baby's birth and 1 month after discharge home. There was a general consensus that the principal role of grandparents was to provide emotional support. Many practical forms of help were seen to be expressions of their care and concern. There were, however, discrepancies between professional and parental expectations where both protection from problems and obtaining information on behalf of the parents were concerned. More was expected of grandmothers than of grandfathers and maternal grandmothers in particular were key figures. There were a number of areas of potential conflict of needs and rights and a recommendation has been made to give parents a greater voice on who they choose to support them.

Major methodological problems attend any attempt to measure coping. Some of these difficulties relate to the timeframe, the units of evaluation, and who should judge the effectiveness of coping behaviors. Account must be taken of factors as diverse as the social context of the individual and the balance of costs and benefits to a person as a result of adopting a given strategy. Although many instruments exist to measure aspects of coping, there is a need to lay a sure foundation in subjective assessments by patients and never to lose sight of the individuality of each person and situation. The article reports on research conducted in the Nursing Research Unit at the University of Edinburgh in which an attempt has been made to examine both measurement issues and the components that explain coping.

Pain can be very intense or only mild, and can be well localized or diffuse. To date, little is known as to how such distinct sensory aspects of noxious stimuli are processed by the human brain. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that discrimination of pain intensity, a nonspatial aspect of pain, activates a ventrally directed pathway extending bilaterally from the insular cortex to the prefrontal cortex. This activation is distinct from the dorsally directed activation of the posterior parietal cortex and right dorsolateral prefrontal cortex that occurs during spatial discrimination of pain. Both intensity and spatial discrimination tasks activate highly similar aspects of the anterior cingulate cortex, suggesting that this structure contributes to common elements of the discrimination task such as the monitoring of sensory comparisons and response selection. Together, these results provide the foundation for a new model of pain in which bidirectional dorsal and ventral streams preferentially amplify and process distinct sensory features of noxious stimuli according to top-down task demands.

This is a two-pronged critique of a study of the socialisation of neophyte nurses in a neonatal intensive care unit in the USA. The authors, respectively an educationalist and a nurse researcher experienced in neonatal intensive care, agreed in finding that the study fell short of what it promised, but differed as to their reasons. They decided to publish their critiques as a complementary pair, in the hope that those supervising research students would benefit from seeing a disappointing study simultaneously in two perspectives, educational and clinical.

Pain is a uniquely individual experience that is heavily shaped by evaluation and judgments about afferent sensory information. In visual, auditory, and tactile sensory modalities, evaluation of afferent information engages brain regions outside of the primary sensory cortices. In contrast, evaluation of sensory features of noxious information has long been thought to be accomplished by the primary somatosensory cortex and other structures associated with the lateral pain system. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that the prefrontal cortex, anterior cingulate cortex, posterior parietal cortex, thalamus, and caudate are engaged during evaluation of the spatial locations of noxious stimuli. Thus, brain mechanisms supporting discrimination of sensory features of pain extend far beyond the somatosensory cortices and involve frontal regions traditionally associated with affective processing and the medial pain system. These frontoparietal interactions are similar to those involved in the processing of innocuous information and may be critically involved in placing afferent sensory information into a personal historical context.