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The purpose of this study was to test the hypothesis that changes in cerebral vasomotor reactivity (CVMR) after 1-yr aerobic exercise training (AET) are associated with cognitive performances in individuals with amnestic mild cognitive impairment (MCI). Seventy sedentary patients with amnestic MCI were randomized to 1-yr moderate-to-vigorous intensity AET or stretching and toning (SAT) interventions. Cerebral blood flow velocity (CBFV) with transcranial Doppler, mean arterial pressure (MAP) with finapres plethysmograph, and EtCO2 with capnography were measured during hyperventilation (hypocapnia) and a modified rebreathing protocol (hypercapnia) to assess CVMR. Cerebrovascular conductance index (CVCi) was calculated by CBFV/MAP, and CVMR by ΔCBFV/ΔEtCO2 and ΔCVCi/ΔEtCO2. Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Cardiorespiratory fitness was assessed by peak oxygen uptake (V̇o2peak). A total of 37 patients (19 in SAT and 18 in AET) completed 1-yr interventions and CVMR assessments. AET improved V̇o2peak, increased hypocapnic CVMR, but decreased hypercapnic CVMR. The effects of AET on cognitive performance were minimal when compared with SAT. Across both groups, there was a negative correlation between changes in hypocapnic and hypercapnic CVMRs in CBFV% and CVCi% (r = −0.741, r = −0.725, P < 0.001). Attenuated hypercapnic CVMR, but not increased hypocapnic CVMR, was associated with improved cognitive test scores in the AET group. In conclusion, 1-yr AET increased hypocapnic CVMR and attenuated hypercapnic CVMR which is associated cognitive performance in patients with amnestic MCI. [ABSTRACT FROM AUTHOR]

Background Computerized clinical decision support systems (CDSS) have shown promising effectiveness in improving outpatient antibiotic prescribing. Methods We developed an intervention in the form of EPIC (Verona, WI, USA) order sets comprised of outpatient treatment pathways for 3 pediatric bacterial acute respiratory infections (ARIs) coupled with educational sessions. Four pediatric clinics were randomized into intervention and control arms over pre- and postimplementation study periods. In the intervention clinics, education was provided in between the 2 study periods and EPIC order sets became available at the beginning of the postimplementation period. The primary end point was the percentage of first-line antibiotic prescribing, and the secondary end points included antibiotic duration and antibiotic prescription modification within 14 days. Results A total of 2690 antibiotic prescriptions were included. During the pre-implementation phase, there was no difference in first-line antibiotic prescribing (74.9% vs 77.7%; P =.211) or antibiotic duration (9.69 ± 0.96 days vs 9.63 ± 1.07 days; P >.999) between the study arms. Following implementation, the intervention clinics had a higher percentage of first-line antibiotic prescribing (83.1% vs 77.7%; P =.024) and shorter antibiotic duration (9.28 ± 1.56 days vs 9.79 ± 0.75 days; P <.001) compared with the control clinics. The percentage of modified antibiotics was small in all clinics (1.1%–1.6%) and did not differ before and after the intervention (for all statistical comparisons, P ≤.354). Conclusions A computerized CDSS involving treatment pathways in the form of order sets coupled with educational sessions was associated with a higher percentage of first-line antibiotic prescribing and shorter antibiotic duration for the outpatient treatment of pediatric bacterial ARIs. [ABSTRACT FROM AUTHOR]

We examined whether the efficacy of steady-state cerebral autoregulation (CA) is reduced in older adults with amnestic mild cognitive impairment (aMCI), a prodromal stage of clinical Alzheimer disease (AD). Forty-two patients with aMCI and 24 cognitively normal older adults (NC) of similar age, sex, and education underwent stepwise decreases and increases in mean arterial pressure (MAP) induced by intravenous infusion of sodium nitroprusside and phenylephrine, respectively. Changes in cerebral blood flow (CBF) were measured repeatedly in the internal carotid and vertebral artery. Linear mixed modeling, including random effects of both individual intercept and regression slope, was used to quantify the MAP-CBF relationship accounting for nonindependent, repeated CBF measures. Changes in end-tidal CO2 (EtCO2) associated with changes in MAP were also included in the model to account for their effects on CBF. Marginal mean values of MAP were reduced by 13-14 mmHg during sodium nitroprusside and increased by 20-24 mmHg during phenylephrine infusion in both groups with similar doses of drug infusion. A steeper slope of changes in CBF in response to changes in MAP was observed in aMCI relative to NC, indicating reduced efficacy of CA (MAP × Group, P = 0.040). These findings suggest that cerebrovascular dysfunction may occur early in the development of AD. NEW & NOTEWORTHY Cerebral autoregulation is a fundamental regulatory mechanism to protect brain perfusion against changes in blood pressure that, if impaired, may contribute to the development of Alzheimer's disease. Using a linear mixed model, we demonstrated that the efficacy of cerebral autoregulation, assessed during stepwise changes in arterial pressure, was reduced in individuals with amnestic mild cognitive impairment, a prodromal stage of Alzheimer's disease. These findings support the hypothesis that cerebrovascular dysfunction may be an important underlying pathophysiological mechanism for the development of clinical Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Because acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF. Method: Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls. Results: Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups–non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL. Summary/Conclusions: While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting. [ABSTRACT FROM AUTHOR]

Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology-Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ2(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group. In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered. [ABSTRACT FROM AUTHOR]

Introduction: The risk reduction for Alzheimer's disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community-dwelling older adults at increased risk for Alzheimer's disease., Methods: Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site's project team were conducted upon study completion., Results: Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non-professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization., Discussion: Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non-professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches., Highlights: Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions.The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles.The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants.The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site.The greatest yield of eligible/randomized participants came from non-professional contacts and mail/phone contact from a site.Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements., Competing Interests: The authors report no conflicts of interest. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Patients with heart failure with preserved ejection fraction (HFpEF) exhibit cardiopulmonary abnormalities that could affect the predictability of exercise [Formula: see text] from the Jones corrected partial pressure of end-tidal CO 2 (PJ CO 2 ) equation (PJ CO 2  = 5.5 + 0.9 × [Formula: see text] - 2.1 × V T ). Since the dead space to tidal volume (V D /V T ) calculation also includes [Formula: see text] measurements, estimates of V D /V T from PJ CO 2 may also be affected. Because using noninvasive estimates of [Formula: see text] and V D /V T could save patient discomfort, time, and cost, we examined whether partial pressure of end-tidal CO 2 ([Formula: see text]) and PJ CO 2 can be used to estimate [Formula: see text] and V D /V T in 13 patients with HFpEF. [Formula: see text] was measured from expired gases measured simultaneously with radial arterial blood gases at rest, constant-load (20 W), and peak exercise. V D /V T[art] was calculated using the Enghoff modification of the Bohr equation, and estimates of V D /V T were calculated using [Formula: see text] (V D /V T[ET] ) and PJ CO 2 (V D /V T[J] ) in place of [Formula: see text]. [Formula: see text] was similar to [Formula: see text] at rest (-1.46 ± 2.63, P = 0.112) and peak exercise (0.66 ± 2.56, P = 0.392), but overestimated [Formula: see text] at 20 W (-2.09 ± 2.55, P = 0.020). PJ CO 2 was similar to [Formula: see text] at rest (-1.29 ± 2.57, P = 0.119) and 20 W (-1.06 ± 2.29, P = 0.154), but underestimated [Formula: see text] at peak exercise (1.90 ± 2.13, P = 0.009). V D /V T[ET] was similar to V D /V T[art] at rest (-0.01 ± 0.03, P = 0.127) and peak exercise (0.01 ± 0.04, P = 0.210), but overestimated V D /V T[art] at 20 W (-0.02 ± 0.03, P = 0.025). Although V D /V T[J] was similar to V D /V T[art] at rest (-0.01 ± 0.03, P = 0.156) and 20 W (-0.01 ± 0.03, P = 0.133), V D /V T[J] underestimated V D /V T[art] at peak exercise (0.03 ± 0.04, P = 0.013). Exercise [Formula: see text] and V D /V T[ET] provides better estimates of [Formula: see text] and V D /V T[art] than PJ CO 2 and V D /V T[J] does at peak exercise. Thus, estimates of [Formula: see text] and V D /V T should only be used if sampling arterial blood during CPET is not feasible. NEW & NOTEWORTHY  [Formula: see text] provides a better estimate of [Formula: see text] than PJ CO 2 at peak exercise, and V D /V T[ET] provides a better estimate of V D /V T[art] than V D /V T[J] at peak exercise. Although we reported significant correlations, we did not find an identity between [Formula: see text] and estimates of [Formula: see text], nor did we find an identity between V D /V T[art] and estimates of V D /V T[art] . Thus, caution should be taken and estimates of [Formula: see text] and V D /V T should only be used if sampling arterial blood during CPET is not feasible.

Psychological distress in cancer is a well-documented phenomenon, but additional information is needed about demographic and disease correlates in diverse populations with different forms of cancer. This study focused on gynecologic cancers. Using the Distress Thermometer and the Hospital Anxiety and Depression Scale, this study examined distress levels in 94 women with gynecologic cancer who were being treated as outpatients at a large urban medical center. The distress levels in this sample were lower than in comparable studies, raising questions about openness to reporting distress. Those who reported higher levels of distress were more likely to also report a mental health diagnosis or psychiatric medication. This suggests that an alternate form for distress screening may involve inquiring about mental health treatment. In this sample, younger women and those with higher educational achievement or private health insurance had higher levels of distress. Conversely, there were no relations between distress levels and disease characteristics, indicating that, for example, women with early stage disease have just as much risk of distress as those with later-stage disease.

IFN-related pathways have not been studied in morphea, and biomarkers are needed. We sought to characterize morphea serum cytokine imbalance and IFN-related gene expression in blood and skin to address this gap by performing a case-control study of 87 participants with morphea and 26 healthy control subjects. We used multiplexed immunoassays to determine serum cytokine concentrations, performed transcriptional profiling of whole blood and lesional morphea skin, and used double-staining immunohistochemistry to determine the cutaneous cellular source of CXCL9. We found that CXCL9 was present at increased concentrations in morphea serum (P < 0.0001), as were other T helper type 1 cytokines. CXCL9 serum concentration correlated with the modified Localized Scleroderma Skin Severity Index (r = 0.44, P = 0.0001), a validated measure of disease activity. CXCL9 gene expression was also increased in inflammatory lesional morphea skin (fold change = 30.6, P = 0.006), and preliminary transcriptional profiling showed little evidence for IFN signature in whole blood. Double-staining immunohistochemistry showed CXCL9 co-localized with CD68 + dermal macrophages. In summary, inflammatory morphea is characterized by T helper type 1 cytokine imbalance in serum, particularly CXCL9, which is associated with disease activity. CXCL9 expression in lesional macrophages implicates the skin as the source of circulating cytokines. CXCL9 is a promising biomarker of disease activity in morphea., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)