Multivariate spatial feature selection in fMRI.

Multivariate neuroimaging analyses constitute a powerful class of techniques to identify psychological representations. However, not all psychological processes are represented at the same spatial scale throughout the brain. This heterogeneity is apparent when comparing hierarchically organized local representations of perceptual processes to flexible transmodal representations of more abstract cognitive processes such as social and affective operations. An open question is how the spatial scale of analytic approaches interacts with the spatial scale of the representations under investigation. In this article, we describe how multivariate analyses can be viewed as existing on a spatial spectrum, anchored by searchlights used to identify locally distributed patterns of information on one end, whole brain approach used to identify diffuse neural representations at the other and region-based approaches in between. We describe how these distinctions are an important and often overlooked analytic consideration and provide heuristics to compare these different techniques to choose based on the analyst's inferential goals.

Response to Lynch et al: On measuring head motion and effects of head molds during fMRI.

We recently presented evidence indicating limited efficacy of custom-molded headcases in reducing head motion in two naturalistic experimental contexts - passive movie watching, and speaking in the scanner (Jolly et al., 2020). In a commentary on this work, Lynch et al (2020) present additional data that support the original findings of (Power et al., 2019) and raise several potential issues with our recent work. We appreciate the opportunity to address these criticisms and raise additional points that should be considered when interpreting these conflicting findings. We do not believe that their criticisms diminish the value of our work, but instead, along with this reply, help better elucidate the key factors researchers should consider to make the most informed choice about their own research protocols.

Custom-molded headcases have limited efficacy in reducing head motion during naturalistic fMRI experiments.

Effectively minimizing head motion continues to be a challenge for the collection of functional magnetic resonance imaging (fMRI) data. The use of individual-specific custom molded headcases is a promising solution to this issue, but there has been limited work to date. In the present work, we examine the efficacy of headcases in a larger group of participants engaged in naturalistic scanning paradigms including: long movie-watching scans (~20 to 45min) and a recall task that involved talking aloud inside the MRI. Unlike previous work, we find that headcases do not reliably reduce motion during movie viewing compared to alternative methods such as foam pillows or foam pillows plus medical tape. Surprisingly, we also find that motion is worse when participants talk aloud while wearing headcases. These differences appear to be driven by large, brief rotations of the head as well as translations in the z-plane as participants speak. Smaller, constant head movements appear equivalent with or without headcases. The largest reductions in head motion are observable when participants were situated with both foam pillows and medical tape. Altogether, this work suggests that in a healthy adult population, custom-molded headcases may provide limited efficacy in reducing head motion beyond existing tools available to researchers. We hope this work can help improve the quality of custom headcases, motivate the investigation of additional solutions, and provide additional information about head motion in naturalistic contexts.

Relationship between testosterone, estradiol and circulating PCSK9: Cross-sectional and interventional studies in humans.

BACKGROUND: Circulating PCSK9 levels are higher in women than men, in postmenopausal than premenopausal women, and in pregnant than non-pregnant women, suggesting that sex hormones may be related to PCSK9 levels. We have examined the relationship between serum estradiol (E2) and testosterone (T) and PCSK9, and the impact of E2 replacement therapy in women and T replacement and ablation therapy in men on circulating PCSK9. METHODS: We conducted a cross-sectional study to examine the correlation between serum T (in males) and E2 (in females) and serum PCSK9. We also conducted interventional studies to examine the effect of hormonal therapy on serum PCSK9 levels. RESULTS: In men, (1) serum T does not correlate with circulating PCSK9 or with LDLC in the basal state, (2) T replacement therapy does not have any effect on circulating PCSK9, and (3) T ablation therapy has mixed results. In women, (1) E2 correlates inversely with circulating PCSK9 and directly with serum LDLC, but (2) E2 replacement therapy does not have any effect on circulating PCSK9. CONCLUSIONS: We demonstrate differences between men and women in the relationship of their major sex hormones with circulating PCSK9. In men, circulating PCSK9 is not related to or affected by T except for a possible effect during T ablation therapy. In women, E2 is inversely related to circulating PCSK9 but the lack of effect of E2 therapy on circulating PCSK9 suggests that the E2-related differences in PCSK9 levels may be the result of differences in receptor-mediated PCSK9 clearance through E2-induced changes rather than production of PCSK9. The studies were registered with ClinicalTrials.gov NCT00848276.

Preformed donor HLA-DP-specific antibodies mediate acute and chronic antibody-mediated rejection following renal transplantation.

Donor-specific HLA alloantibodies may cause acute and chronic antibody-mediated rejection (AMR) and significantly compromise allograft survival. The clinical relevance of antibodies directed against some HLA class II antigens, particularly HLA-DP, is less clear with conflicting reports on their pathogenicity. We report two patients with high levels of pretransplant donor-specific HLA-DP antibodies who subsequently developed recurrent acute AMR and graft failure. In both cases, there were no other donor-specific HLA alloantibodies, suggesting that the HLA-DP-specific antibodies may be directly pathogenic.

SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype.

OBJECTIVE: Germline loss-of-function mutations in the SPRED1 gene have recently been identified in patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1 (neurofibromin 1) mutation found, suggesting a neurofibromatosis type 1-like syndrome. METHODS: 61 index cases with NF1 clinical diagnosis but no identifiable NF1 mutation were screened for SPRED1 mutation. RESULTS: We describe one known SPRED1 mutation (c.190C>T leading to p.Arg64Stop) and four novel mutations (c.637C>T leading to p.Gln213Stop, c.2T>C leading to p.Met1Thr, c.46C>T leading to p.Arg16Stop, and c.1048_1060del leading to p.Gly350fs) in five French families. Their NF1-like phenotype was characterised by a high prevalence of café-au-lait spots, freckling, learning disability, and an absence of neurofibromas and Lisch nodules in agreement with the original description. However, we did not observe Noonan-like dysmorphy. It is noteworthy that one patient with the p.Arg16Stop mutation developed a monoblastic acute leukaemia. CONCLUSIONS: In our series, SPRED1 mutations occurred with a prevalence of 0.5% in NF1 patients and in 5% of NF1 patients displaying an NF1-like phenotype. SPRED1 mutated patients did not display any specific dermatologic features that were not present in NF1 patients, except for the absence of neurofibromas that seem to be a specific clinical feature of NF1. The exact phenotypic spectrum and the putative complications of this NF1 overlapping syndrome, in particular haematological malignancies, remain to be further characterised. NIH diagnostic criteria for NF1 must be revised in view of this newly characterised Legius syndrome in order to establish a specific genetic counselling.

Effects of supplemental oxygen during activity in patients with advanced COPD without severe resting hypoxemia.

STUDY OBJECTIVES: To assess oxygen desaturation during activities and to evaluate the short-term effects of supplemental O(2) use in patients with severe COPD who do not qualify for long-term O(2) therapy. DESIGN: A double-blind, randomized, placebo-controlled trial. SETTING: Outpatients from the pulmonary diseases division of a tertiary-care university hospital. PATIENTS: Twenty patients with stable COPD with FEV(1)/FVC ratios of < 50%, FEV(1) levels < 55% of the predicted normal value, and PaO(2) levels of > 60 mm Hg when resting. INTERVENTIONS: Patients were initially evaluated with pulmonary function tests, blood gas analysis, and Doppler echocardiography, and they underwent the following three 6-min walking tests (WTs) in a random sequence: basal WT (BWT); WT while breathing compressed air (CAWT); and WT while breathing O(2) (O(2)WT). MEASUREMENTS AND RESULTS: The distance walked was recorded in meters. Dyspnea was measured by Borg scale measurement before and after the tests, and arterial oxygen saturation measured by pulse oximetry (SpO(2)) was continuously monitored. Results were analyzed by grouping patients in the following manner: desaturators (DSs) (ie, patients with a drop in SpO(2) of at least 5% and < 90% during the WT) vs nondesaturators (NDSs); and O(2) responders (ie, patients with an increase of at least 10% in the distance walked and/or a decrease of at least 3 points in Borg index score) vs nonresponders. During the BWT, 11 of 20 patients (55%) were defined as desaturators. During the O(2)WT, the SpO(2) remained at > 90% in every patient. The distance walked increased by 22% (p < 0.02), and dyspnea decreased 36% (p < 0.01) in DS patients. In NDS patients, O(2) administration reduced dyspnea by 47% (p < 0.001), but the distance walked did not improve. Responses were markedly different from one patient to another. No significant differences were noticed between the results of the BWT and CAWT in any of the groups. Thirteen O(2) responders did not differ from 7 nonresponders either in basal data or in desaturation measure during the BWT, except that all walking responders (five patients) were above the median of basal left ventricle performance. CONCLUSIONS: Most of the studied COPD patients desaturated during the BWT. O(2) administration avoided desaturation and could increase the distance walked and reduce dyspnea, but these effects were not related to walking desaturation in individual cases. Improvements were not a placebo effect. The therapeutic role of O(2) during activities in some patients with severe COPD needs to be individually assessed.

The psychometric properties of patient preferences in osteoporosis.

OBJECTIVE: Osteoporosis is a chronic disease manifested by wrist, vertebral, and hip fractures that results in significant morbidity and burden to society. About 30% of postmenopausal women have osteoporosis according to the WHO criteria. Women with one vertebral fracture have a 4-fold increased risk of a subsequent fracture. The goal of treatment is to prevent fractures and improve quality of life. Preferences or utilities are now recommended for incorporating quality of life into evaluations of the cost effectiveness of new therapeutic interventions. We evaluated the psychometric properties of preference based measures in osteoporosis. METHODS: Preference scenarios were constructed with a health state classification system. The reliability and validity of the feeling thermometer and the standard gamble was assessed by interviewing 42 women from 4 different patient groups. The sensitivity to change of the feeling thermometer and standard gamble was compared with the Health Utilities Index Mark 2 (HUI2) and SF-36. All subgroups were reassessed about 2 months after their first interview. RESULTS: Preference measurement was feasible in women of different age groups. The reliability coefficients for health states ranged from 0.65 to 0.87. The preference scores for the marker states demonstrated content validity. Convergent validity of the feeling thermometer was supported by a significant correlation with the HUI2 (r = 0.38, p < 0.05) and the physical health summary of the SF-36 (r = 0.56, p < 0.005). The standard gamble did not correlate with the HUI2 (r = 0.15) or the feeling thermometer (r = 0.09), but correlated with 2 domains of the SF-36. The preference measures were sensitive to change, with the efficiency scores ranging from 0.78 to 1.0. CONCLUSION: Preference measurements in the evaluation of osteoporosis are feasible. The feeling thermometer and standard gamble appear to be related to different aspects of health related quality of life. Both instruments were sensitive to change over a 2 month period.

Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women.

OBJECTIVE: We sought to compare the uterine effects of raloxifene with those of continuous-combined hormone replacement therapy. STUDY DESIGN: This randomized, double-blind 24-month study involved 136 postmenopausal women who received raloxifene 150 mg/d or conjugated equine estrogens 0.625 mg/d with medroxyprogesterone acetate 2.5 mg/d. After baseline evaluations, endometrial biopsy specimens were obtained, and endometrial thickness was measured annually by means of transvaginal ultrasonography. Statistical analyses were performed with an intention-to-treat approach. RESULTS: In the raloxifene group at the end point of the study 94.4% of biopsy specimens showed normal benign postmenopausal endometrium and 5.6% were classified as benign stimulatory endometrium. In the continuous-combined hormone replacement therapy group at the end point of the study 78.7% of biopsy specimens showed normal benign postmenopausal endometrium, 19. 1% were classified as benign stimulatory endometrium, and 2.1% showed benign abnormal postmenopausal endometrium. Mean endometrial thickness was unchanged from baseline with raloxifene and was increased significantly by 0.5 mm at 12 months with continuous-combined hormone replacement therapy. CONCLUSION: Raloxifene 150 mg/d did not increase endometrial thickness or cause endometrial proliferation in healthy postmenopausal women.

Women's decisions about hormone replacement therapy after education and bone densitometry.

BACKGROUND: The decisions that postmenopausal women make about whether to start hormone replacement therapy may depend on the potential risks and benefits of such therapy as well as their risk for osteoporosis-related fractures. This study examined the decisions made by women at risk for osteoporosis-related fractures who were educated about hormone replacement therapy and who were given information about their bone mineral density. METHODS: The study employed a prospective cohort design. Thirty-seven post--menopausal women with risk factors for osteoporosis-related fractures were recruited from an orthopedic clinic at a teaching hospital in Hamilton, Ont. The women were given an education kit (consisting of an audio tape and a work-book) to clarify the benefits and risks of hormone replacement therapy. Two to 4 weeks later, densitometry of the hip and the lumbar spine was performed. A summary of the risks, the densitometry findings and decisions about hormone replacement therapy were given to the women's family physicians for follow-up. Outcome measures included decisions about hormone replacement therapy, as well as use of such therapy and other medications at 12 months. RESULTS: After the education component alone, 10 (27%) of the women requested hormone replacement therapy. After densitometry testing, 4 more requested hormone replacement therapy (for a total of 14 women [38%]). At 12 months, 2 (5%) of the women had been lost to follow-up. Of the remaining 35, 6 (17%) were receiving hormone replacement therapy, 7 (20%) were using bisphosphonates, and 24 (68%) were taking calcium supplements. INTERPRETATION: These preliminary findings suggest that the combination of education about hormone therapy and feedback about bone density is associated with an increase in the use of hormone replacement therapy and other preventive medications by women at risk for osteoporosis-related fractures. However, the observed increase was small and so the clinical significance must be confirmed and clarified.

A decision aid for women considering hormone therapy after menopause: decision support framework and evaluation.

Although postmenopausal women are advised to consider their values when deliberating about potential benefits and risks of hormone therapy (HRT), feasible, effective methods of decision support in primary care have yet to be established. Using an explicit decision support framework, we developed a self-administered HRT decision aid and evaluated it in a before/after study of 94 women from six family practices. An audiotape guided women through an illustrated booklet including: detailed information about HRT benefits and risks tailored to a woman's clinical risk, and a values clarification exercise to promote informed decision making consistent with personal values. After using the decision aid participants: had better general knowledge and more realistic personal expectations of HRT benefits and risks; and, felt more certain, informed, clear about values, and supported in decision making. Women's values elicited in the clarification exercise were 84% accurate in discriminating between decisions. Women with polarized preferences at baseline did not change their minds, but were better informed. Changes in preferences occurred in the uncertain group, with equal numbers accepting or declining HRT. Most participants found the decision aid comprehensible, acceptable in length and pace, and balanced. Decision aids are useful in preparing women for decision making about this complex, personal issue.

Randomized trial of a portable, self-administered decision aid for postmenopausal women considering long-term preventive hormone therapy.

Although practice guidelines suggest that postmenopausal women learn about the benefits and risks and consider their values when deciding about hormone therapy, the optimal decision-support method has not been established. In a randomized controlled trial, the authors compared the efficacy of a general educational pamphlet with that of a tailored decision aid. The pamphlet briefly summarized benefits, risks, and likely beneficiaries in general terms. The decision aid, delivered via booklet and audiotape, provided: detailed benefits and risks using functional terms and probabilities tailored to clinical risk; and steps for considering the issue in a woman's own situation, including a value-clarification exercise. Compared with the pamphlet group, the decision-aid group had statistically significant (p < 0.05) improvements in terms of realistic personal expectations of the benefits and risks, decisional conflict, and perceived acceptability of the intervention. Levels of general knowledge about the main benefits and risks were comparable for the two interventions. It is concluded that tailored decision aids prepare women for decision making better than do general pamphlets.

Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia.

STUDY OBJECTIVE: To define the impact of BAL data on the selection of antibiotics and the outcomes of patients with ventilator-associated pneumonia (VAP). DESIGN: Prospective observation and bronchoscopy with BAL, performed within 24 h of establishing a clinical diagnosis of a new episode of hospital-acquired VAP or progression of a prior episode of nosocomial pneumonia (NP). SETTING: A 15-bed medical and surgical ICU. PATIENTS: One hundred thirty-two patients hospitalized for more than 72 h, who were mechanically ventilated and had a new or progressive lung infiltrate plus at least two of the following three clinical criteria for VAP: abnormal temperature (> 38 degrees C or < 35 degrees C), abnormal leukocyte count (> 10,000/mm3 or < 3,000/mm3), purulent bronchial secretions. INTERVENTIONS: Bronchoscopy with BAL within 24 h of establishing a clinical diagnosis of VAP or progression of an infiltrate due to prior VAP or NP. All patients received antibiotics, 107 prior to bronchoscopy and 25 immediately after bronchoscopy. RESULTS: Sixty-five of the 132 patients were BAL positive (BAL[+]), satisfying a microbiologic definition of VAP (> 10(4) cfu/mL), while 67 were BAL negative (BAL[-]). The BAL(+) patients had no differences in mortality, prior antibiotic use, and demographic features when compared with the BAL(-) patients. More of the BAL(+) patients (38/65) satisfied all three clinical criteria of VAP than did BAL(-) patients (24/67) (p < 0.05). A total of 50 BAL(+) patients received antibiotic therapy prior to bronchoscopy, and when this prior therapy was adequate (n = 16), as defined by the results of BAL, then mortality was 38%, while if prior therapy was inadequate (n = 34), mortality was 91% (p < 0.001), and if no therapy was given (n = 15), mortality was 60%. When therapy changes were made after bronchoscopy, more patients (n = 42) received adequate therapy, but mortality in this group was comparable to mortality among those who continued to receive inadequate therapy (n = 23). A total of 46 of the 65 BAL(+) patients died, with 23 of these deaths occurring during the 48 h after the bronchoscopy, before BAL results were known. When BAL data became available, 37 of the 42 surviving patients received adequate therapy, but their mortality was comparable to the patients who continued to receive inadequate therapy. CONCLUSIONS: Patients with a strong clinical suspicion of VAP have a high mortality rate, regardless of whether BAL cultures confirm the clinical diagnosis of VAP. When adequate antibiotic therapy is initiated very early (ie, before performing bronchoscopy), mortality rate is reduced if this empiric therapy is adequate, compared to when this therapy is inadequate or no therapy is given. If adequate therapy is delayed until bronchoscopy is performed or until BAL results are known, mortality is higher than if it had been given at the time of first establishing a clinical diagnosis of VAP. When patients were changed from inadequate antibiotic therapy to adequate therapy, based on the results of BAL, mortality was comparable to those who continued to receive inadequate therapy. Thus, even if bronchoscopy can accurately define the microbial etiology of VAP, this information becomes available too late to influence survival.

[Community-acquired pneumonia in adults. Clinical practice guideline for Argentina. Study Group on Community Acquired Pneumonia]. / Neumonía adquirida en la comunidad (NAC) en adultos. Guía de práctica clínica para la Argentina. Grupo de Estudio de las NAC.

Community-acquired pneumonia (CAP) affects approximately 1% of the population annually. Initial antimicrobial therapy is most often empirical. Guidelines designed in other countries for the empirical management of CAP are not recommended for use in Argentina. Studies from other countries were considered together with unpublished local data to define the potential etiologic microorganisms and their antimicrobial susceptibility. Recommended diagnostic tests, groups of patients for different therapies and hospitalization criteria were defined. Severe CAP requiring intensive care was distinguished from the rest because of its distinct spectrum of etiologic agents and its high mortality, requiring a more focused therapy. Age, coexisting conditions and severity of illness were taken into account in the election of therapy.

Regulation of PHO4 nuclear localization by the PHO80-PHO85 cyclin-CDK complex.

PHO4, a transcription factor required for induction of the PHO5 gene in response to phosphate starvation, is phosphorylated by the PHO80-PHO85 cyclin-CDK (cyclin-dependent kinase) complex when yeast are grown in phosphate-rich medium. PHO4 was shown to be concentrated in the nucleus when yeast were starved for phosphate and was predominantly cytoplasmic when yeast were grown in phosphate-rich medium. The sites of phosphorylation on PHO4 were identified, and phosphorylation was shown to be required for full repression of PHO5 transcription when yeast were grown in high phosphate. Thus, phosphorylation of PHO4 by PHO80-PHO85 turns off PHO5 transcription by regulating the nuclear localization of PHO4.