Comparison of lithium levels between suicide and non-suicide fatalities: Cross-sectional study.
Ecological studies have suggested the protective effect of micro-dose lithium in drinking water against suicide, however, the association between body lithium level and suicide is unknown. We aimed to compare body lithium levels between suicide and non-suicide fatalities. This cross-sectional study included 12 suicides and 16 non-suicides who were examined or dissected at the Tokyo Medical Examiner's Office from March 2018 to June 2021. The aqueous humor lithium concentration was measured twice using inductively coupled plasma mass spectrometry. Analysis of covariance (ANCOVA) was used to compare the lithium concentration between suicides and non-suicides. Mixed-effects model was conducted to account for all lithium concentration data. The aqueous humor lithium concentration did not change after death (t(7) = -0.70, [Formula: see text], SE = 0.03, 95% CI = [-0.09, 0.05], P = 0.51, Cohen's d = 0.01). The aqueous humor lithium concentration was lower in suicides (mean 0.50 μg/L (variance s2 0.04)) than in non-suicides (mean 0.92 μg/L (s2 0.07)) (t(26) = 4.47, [Formula: see text], SE = 0.09, 95% CI = [0.22 to 0.61], P < 0.001, Cohen's d = 1.71). The ANCOVA showed that death by suicide was significantly associated with lower lithium concentration (F(1, 24) = 8.57, P = 0.007), and the effect size was large (ηp2 = 0.26). The random intercept model showed a significant effect of suicide on aqueous humor lithium concentration (b = -0.261, SE = 0.102, 95% CI = [-0.471 to -0.051], t(24) = -2.568, P = 0.017). The results of this study demonstrate that even micro-dose lithium is associated with suicide death. Clinical studies are warranted to examine the effects of micro-dose lithium on suicide prevention.


Primary cerebral lymphoma in acquired immunodeficiency syndrome (AIDS)--CT manifestations.
Primary lymphoma of the brain in AIDS is being observed with increased frequency; five pathologically proven cases are presented. Although the CT patterns may correlate well with patterns previously described in lymphoma, occasionally an irregular ring-like lesion may occur which is difficult to distinguish from toxoplasmosis or other inflammatory processes without appropriate pathological material.


[Nonlinear temporal summation of EPSP in mollusk neurons].
Temporal summation of monosynaptic EPSPs produced by paired afferent stimuli was studied in the experiments on identified neurons of mollusc Planorbis corneus. Nonlinear properties of the summation were shown; there were three types of the summation: facilitation, depression and mixed type. It was shown that summation functions (characterizing the dependence of the ratio between the test and conditioning EPSP amplitudes and the value of the corresponding interstimulus++ interval) had some local extremum in most cases. The value of the interstimulus++ interval corresponding to this extremum was in correlation with single EPSP parameters. Possible localization of mechanisms responsible for the EPSP summation properties is discussed.


Integrating biologic therapies into a dermatology practice: practical and economic considerations.
This article discusses the issues involved in the integration of biologic therapies for psoriasis into a dermatology practice. The requirements for staff, space, and other office adaptations are reviewed for infliximab, efalizumab, etanercept, and alefacept in their current injectable forms. Dermatologists will likely elect to offer some or all of these therapies depending on the adjustments necessary within their current practice, patient satisfaction, and the economic possibilities. This article provides information needed to guide dermatology practices in practical decisions regarding the use of biologic therapies.


Publication rate and factors associated with publication of research projects by obstetrics residents in an academic department over 10 years.
To determine the publication rate of mandatory research projects conducted by obstetrics residents and to evaluate the publication-associated factors and reported obstacles. This retrospective cohort study included all consecutive residents in an academic obstetrics-gynecology department in Paris, France, between 2010 and 2020. All residents were required to conduct a research project. Information about publication was collected by searching PubMed. A closed-ended questions questionnaire was sent to former residents about their characteristics, subsequent professional development, and research project characteristics. Factors associated with publication were identified by univariable and multivariable analysis with logistic regression. During the study period, 156 residents trained in our obstetrics-gynecology department. The overall publication rate was 30.8% (48/156) and the median time to publication 27 months (IQR, 18-37). The resident was first author in 36 (75.0%) publications. Among the 130 (83.3%) residents who completed the questionnaire, 43 (33%) had published their research project. Overall, 74/130 (60.8%) residents used their project for their mandatory medical thesis. Factors associated with publication in univariable analysis were younger age (median), completion of a PhD, planned career in academic medicine, prospective study design, presentation at a conference or congress and use their project for their medical thesis. The only factors associated with publication in the multivariable analysis were planned career in academic medicine (aOR 5.62 95 %CI[1.84-17.19]) and the prospective study design of the research project (aOR 6.1 95 %CI[1.24-29.56]). The main reasons for nonpublication reported by resident were lack of time and failure to complete the project. Among the mandatory clinical research projects conducted by obstetrics residents over a decade in our department, 30.8% were published. The main factors associated with publication were planned career in academic medicine and a prospective design of the research project.


Effects of blindfolding a unilateral eye on so-called central nystagmus.
A bipolar stimulating electrode was chronically implanted at the mesodiencephalon in the rabbit to induce so-called central nystagmus. The nystagmus was remarkably facilitated in either darkness by blindfolding an eye ipsilateral to the stimulation site, but the nystagmus was almost never facilitated by blindfolding an eye contralateral to the stimulation site. This is a phenomenon related to photic inhibition. This phenomenon disappeared after ablation of the flocculus and paraflocculus ipsilateral to the stimulation site. The neural pathway responsible for it is considered to be by way of the flocculus.


Karyotyping of bone-marrow cells in hematologic diseases.
Cultures of bone-marrow cells incubated for 5 h at 4 degrees had cells in metaphase with elongated chromosomes which were easily Giemsa banded. Colcemid was not necessary for metaphase arrest at this temperature. This technique made possible routine karyotyping of patients with leukemia and other hematological diseases in which the detection of aberrations was otherwise difficult.


Effect of CP-96,345, a non-peptide NK1 receptor antagonist, against substance P-, bradykinin- and allergen-induced airway microvascular leakage and bronchoconstriction in the guinea pig.
We have investigated the effect of a new non-peptide NK1 receptor antagonist, CP-96,345, against substance P (SP)-, bradykinin (BK)- and allergen-induced airway microvascular leakage, bronchoconstriction and hypotension in anesthetized guinea pigs. Lung resistance (RL) and mean systemic blood pressure (BP) were measured for 6 min after challenge, followed by measurement of extravasation of Evans blue dye into airway tissues, used as an index of airway microvascular leakage. I.v. (2 nmol/kg) and inhaled (1 mM, 45 breaths) SP, i.v. (15 nmol/kg) and inhaled (1 mM, 45 breaths) BK and aerosolized allergen (5 mg/ml of ovalbumin, 30 breaths) induced a significant increase in RL and leakage of dye at all airway levels, and decreased BP significantly except for inhaled BK. CP-96,345 (2 mg/kg i.v.) abolished the dye extravasation induced by both SP. CP-96,345 partly inhibited the responses induced by both BK but not by allergen. CP-96,345 markedly inhibited the increase in RL and fall in BP induced by SP but not by BK or allergen. NK1 receptor-mediated mechanisms may contribute to SP- and BK-induced airway microvascular leakage and SP-induced bronchoconstriction and hypotension. These mechanisms are not important in the acute airway responses induced by inhaled allergen.


Rare small bowel obstruction: Right paraduodenal hernia. Case report.
Paraduodenal hernia (paramesocolic hernia), a rare congenital anomaly due to a midgut malrotation during fetal development, is recognized as the most frequent internal hernias. Two variants have been described: left and right, the latter less common than the first one. We report a right paraduodenal hernia case in a 86 years old female patient who developed an acute bowel obstruction syndrome. Final diagnosis was achieved by imaging techniques as abdomen X-ray and CT and confirmed only after surgical operation. Surgical approach was via median laparotomy, consisting in hernia reduction, replacement and stitching of the bowel in its anatomical orientation, and fixing of the posterior wall defect. At 15 months follow-up from surgical procedure the patient is asymptomatic. Paraduodenal hernia is a rare pathology but its involvement in bowel obstruction syndrome should be always taken into account during diagnostic process.


Unipolar sensing abnormalities: incidence and clinical significance of skeletal muscle interference and undersensing in 228 patients.
Compared to bipolar lead configurations, unipolar pacing systems presumably enhance sensing of cardiac electrical events but are ore susceptible to electrical interference, including skeletal myopotentials. The incidence and clinical significance of oversensing and of undersensing by unipolar R-wave inhibited pacemakers in 228 patients were assessed by 24-hour Holter monitoring and/or by pectoral muscle exercises. Overall, 38% of patients exhibited oversensing and false inhibition due to skeletal myopotentials. Symptoms due to oversensing occurred in 14% of patients and 58% of these required corrective intervention. The presence of silastic coating on the pulse generator had no effect on the sensing of myopotentials. In addition, the incidence of undersensing as assessed by Holter monitoring was 17% despite adequate implantation R wave amplitudes. Thus, oversensing remains a major clinical problem when using unipolar pacemaker systems and their use has not eliminated undersensing.


Test-retest repeatability of the Strain Index.
Fifteen raters individually, and in five teams of three, evaluated the test-retest repeatability of published data collection and rating methods of the Strain Index by analyzing 61 job video files twice over a 5-month period. Raters estimated average and peak hand forces, measured Duration of Exertion, cycle time, and exertions per job cycle, calculated percent Duration of Exertion and Efforts per Minute, and assigned ratings for five of the six Strain Index task variables. Twelve additional jobs were analyzed to determine Strain Index Score and hazard classification. Intraclass correlation (ICC) coefficients for task variable ratings and accompanying data ranged from 0.66 to 0.95 for both individuals and teams. The Strain Index Score ICC(2,1) for individuals and teams were 0.56 and 0.82, respectively. Intra-rater reliability for the hazard classification was 0.81 for individuals and 0.88 for teams. The results indicate that the Strain Index has good test-retest reliability.


Alcoholism and depression in adopted-out daughters of alcoholics.
Forty-nine daughters of alcoholics were compared to 47 daughters of nonalcholics; both groups of women (average age, 35 years) had been adopted by nonrelatives early in life. Two women in each group were alcoholic or problem drinkers. Although this is above the expected rate of alcoholism among women, the numbers are too small to draw definite conclusions. Almost all were light drinkers. Daughters of alcoholics had no more depression than controls, indicating that alcoholism in the biological parents did not increase the risk of depression in daughters raised by foster parents. Environmental factors may be important in both alcoholism and depression in women, since both tended to be correlated with psychopathology in the foster parents.


Membrane Progesterone Receptors (mPRs/PAQRs) Differently Regulate Migration, Proliferation, and Differentiation in Rat Schwann Cells.
Several studies in the last decade demonstrated that progestogens play an important role in the biology of Schwann cells, the main neuroglial cells of the peripheral nervous system. Since a recent study showed that the S42 rat Schwann cell line expressed membrane progesterone receptors (mPRs), members of the PAQR family, in this study, we examined mPR expression in a more physiological model, primary rat Schwann cells. We demonstrated that primary rat Schwann cells show a different pattern of mPR expression compared to the previously studied model; mPRα (PAQR7) and β (PAQR8) isoforms were the major mPR members identified, with different sub-cellular localizations. Activation of the nuclear progesterone receptor (PR) with the specific agonist R5020 upregulated mPR expression, while activation of mPRs with the specific agonist Org OD 02-0 changed their sub-cellular localization. An in-depth analysis revealed additional effects of mPR activation, such as AKT activation, reduced expression of the myelin-associated glycoprotein (MAG), morphological changes, altered expression of several Schwann cell differentiation markers, and increased Schwann cell migration and proliferation. In conclusion, we identified mPRα and mPRβ in primary rat Schwann cells, and our findings suggest a putative role for mPRs in the regulation of Schwann cell migration, proliferation, and differentiation. Therefore, mPRs are a potential pharmacological target for Schwann cell-related disorders and neurodegenerative diseases, especially those in which Schwann cell-mediated axon remyelination is desirable.


The effects of habitat complexity on the macroinvertebrates colonising wood substrates in a lowland stream.
Woody debris is a major structural component of south-eastern Australian lowland streams, and the decayed wood substrates provide a structurally complex habitat for macroinvertebrate colonization. I tested for the presence of a species richness-habitat complexity relationship for macroinvertebrate species inhabiting the surfaces of decayed submerged logs (snags) in a lowland stream in northern Victoria. The species-habitat complexity relationship is defined as the increase in species richness due to increased structural complexity of a habitat when area is held constant. The response of macroinvertebrates to seven treatments of artificial and natural substrates of differing levels and types of structural complexity were examined using cluster analyses and MANOVAs. These analyses revealed a significant species-habitat complexity relationship. In addition, a comparison of species evenness between simple and complex habitats supported the hypothesis that more complex habitats contained more species because they possessed more resources. Analysis of species richness, though informative, masked the complexity of species responses revealed by multivariate analyses of species abundances. These analyses showed that different species groups selected different microhabitats on snags, particularly in response to the level of sediment deposition, which was greater on more structurally complex snags. In comparison with the benthos, snags were significantly richer in species abundances, possibly related to low levels of dissolved oxygen in benthic habitats.


Revascularization of skeletal muscle transplanted into the hamster cheek pouch: intravital and light microscopy.
Small fiber bundles from the extensor digitorum longus (EDL) muscle were transplanted into the hamster cheek pouch to observe the process of revascularization. We tested the hypothesis that blood vessels of a graft degenerate and that revascularization results from the ingrowth of blood vessels from the cheek pouch into the graft. Degeneration and regeneration of muscle fibers followed a pattern similar to that reported for autografts of whole muscles in rats. Blood vessels in the graft that were adjacent to vascularized host tissue survived. At 1 day, surviving blood vessels in the graft had normal structure but erythrocytes were packed tightly in the lumen. At 2 days, sprouts from surviving graft vessels had grown into the cheek pouch. Between 2 and 2.5 days, anastomoses of blood vessels from the graft with those of the cheek pouch reestablished circulation. After circulation was established, the blood vessels contained well-spaced erythrocytes. By 3 days, blood vessels which increased in number and diameter throughout the graft occupied 40-60% of the graft. Over the next 24 hr, blood vessels in the graft regressed toward the control value. We conclude that blood vessels in muscle grafts in the cheek pouch survive transplantation, and that circulation in grafts is reestablished by the anastomoses of blood vessel sprouts from the graft with the blood vessels of the host.


Using a pocket card to improve end-of-life care on internal medicine clinical teaching units: a cluster-randomized controlled trial.
End-of-life care is suboptimally taught in undergraduate and postgraduate education in Canada. Previous interventions to improve residents' knowledge and comfort have involved lengthy comprehensive educational modules or dedicated palliative care rotations. To determine the effectiveness of a cheap, portable, and easily implemented pocket reference for improving residents' knowledge and comfort level in dealing with pain and symptom management on the medical ward. Cluster-randomized controlled trial conducted from August 2005 to June 2006. Medical clinical teaching units (CTUs) in 3 academic hospitals in Toronto, Canada. All residents rotating through the medical CTUs who consented to participate in the study. Residents at 1 hospital received a pocket reference including information about pain and symptom control, as well as 1-2 didactic end-of-life teaching sessions per month normally given as part of the rotation. Residents at the other 2 hospitals received only the didactic sessions. A 10-question survey assessing knowledge and comfort level providing end-of-life care to medical inpatients, as well as focus group interviews. One hundred thirty-six residents participated on 3 CTUs for a participation rate of approximately 75%. Comfort levels improved in both control (p < .01) and intervention groups (p < .01), but the increase in comfort level was significantly higher in the intervention group (z = 2.57, p < .01). Knowledge was not significantly improved in the control group (p = .06), but was significantly improved in the intervention group (p = .01). Greater than 90% of residents in the intervention group used the card at least once per week, and feedback from the focus groups was very positive. Our pocket card is a feasible, economical, and educational intervention that improves resident comfort level and knowledge in delivering end-of-life care on CTUs.


Torsade de pointes in a patient with complex medical and psychiatric conditions receiving low-dose quetiapine.
Describe potential cardiac complications of low-dose quetiapine and other atypical antipsychotic drugs. We present a case report of a 45-year-old Black woman with multiple medical and psychiatric problems taking low-dose quetiapine. Coincident with a generalized seizure, the patient developed 'ventricular fibrillation'. She was countershocked with restoration of normal sinus rhythm. The initial electrocardiogram showed QT interval prolongation. Shortly thereafter, classical torsade de pointes appeared, lasted 10 min, and resolved spontaneously. Hypomagnesemia was present. A cardiac electrophysiologist was concerned that the very slow shortening of the prolonged QTc interval after magnesium replacement implicated quetiapine as a risk factor for QTc interval prolongation and torsade de pointes. A psychosomatic medicine consultant asserted that the fragmented medical and psychiatric care almost certainly contributed to the patient's medical problems. We discuss other cases of QT interval prolongation by newer antipsychotic drugs and previous reports by our group concerning the association of psychotropic drugs, QT interval prolongation, and torsade de pointes. Atypical antipsychotic drug administration, when accompanied by risk factors, may contribute to cardiac arrhythmias including torsade de pointes.


The therapeutic role of ketamine and esketamine in treating psychopathological domains of depression.
Over the past two decades, ketamine has emerged as a novel effective and rapid-acting antidepressant. While the vast majority of studies on ketamine have focused on its ability to reduce the severity of depression broadly, its effectiveness in specific domains such as cognition, anhedonia, suicidality, and workplace/social/scholastic functionality has been neglected. Similarly, current treatments (e.g., SSRIs and SNRIs) aim to improve overall depression severity, which often results in the persistence of one or more residual symptom domains and prevents full recovery to premorbid functionality. In this review, we narratively synthesize the literature pertaining to the effectiveness of ketamine in treating key domains of depressive symptomatology (i.e., cognition, anhedonia, suicidality, and psychosocial functionality). Our findings suggest that ketamine is effective across domains varyingly, with the strongest evidence being for its ability to reduce suicidality. The rapid acting nature of ketamine further supports its use in treating suicidality and potentially preventing the completion of suicide. Evidence for the effectiveness of ketamine in other domains is weak, primarily due to a lack of robust studies specifically designed to assess these domains as primary outcomes. Future studies should scrutinize the effects of ketamine on specific domains of depression to optimize its implementation.


Physical correlates of the ultrasonic reflectivity of lipid dispersions suitable as diagnostic contrast agents.
The objective of this study was to determine the physical basis of ultrasound (US) reflectivity of echogenic lipid dispersions. These dispersions were made using a process previously described involving sonication of the lipid in water, addition of mannitol, freezing, lyophilization and rehydration. The component lipids were egg phosphatidylcholine, dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylglycerol and cholesterol in a molar ratio of 69:8:8:15. Ultrasound reflectivity, as assessed with a 20-MHz intravascular US catheter and analyzed using computer-assisted videodensitometry, was found to be sensitive to variations in ambient pressure; echogenicity was greatly reduced by exposure to 0.5 atm vacuum for 10 s or 1.5 atm pressure for 10 s. Pressure changes of the magnitude that obtain in the arterial circulation had little effect on echogenicity. Vacuum treatment resulted in the release of approximately 100 microL air from a standard preparation of 10 mg lipid in 1 mL. Maximum ultrasonic reflectivity required the presence of 0.1-0.2 mol/L mannitol during the lyophilization step; mere addition of mannitol to the lipid lyophilized in the absence of mannitol produced nonreflective dispersions. Inclusion of sodium phosphate or other electrolytes reduced echogenicity. High echogenicity was associated with the presence of large-volume freeze-dried cakes and fusion of liposomes (which led to a 10 times increase in liposome diameters) during freezing before lyophilization. Lyophilization from water led to liposome fusion, but the cakes were small and US reflectivity was weak. Lyophilization from solutions of cryoprotectants such as trehalose produced large cakes, but little liposome fusion and also led to weak US reflectivity. Filtration through defined pores revealed that approximately 50% of the echogenicity originated from particles smaller than 1 microm and about 2/3 from particles smaller than 3 microm. These results indicate that lyophilization from 0.2 mol/L mannitol solution generates a disrupted array of lipid bilayers that, upon rehydration, fuse and trap small amounts of air distributed among liposome-size particles.


Effects of intrathecal capsaicin on autonomic and behavioral heat loss responses in the rat.
Capsaicin and Tween 80 were injected into the lumbar subarachnoid space of rats via a chronic cannula, and the thermoregulatory effects compared. The rats were placed in a climatic chamber at an ambient temperature (Ta) of 20 and 30 degrees C. In the first series of experiments the rats had no access to the fan lever. Intrathecal (IT) capsaicin injection produced a fall in rectal temperature, with a rise in cutaneous temperatures due to vasodilation. On the contrary, IT or the intraperitoneal (IP) Tween 80 injection route had no effect on body temperature. In addition capsaicin-administered IP induced a fall in spinal cord temperature (Tsp). In the second series of experiments the rats had access to a lever activating a fan that drew cool outside air into the climatic chamber. After IT capsaicin injection, the rats increased bar-pressing behavior for fresh air. This was significant at both Ta 20 and 30 degrees C. The results tend to support the hypothesis of capsaicin action somewhere on the thermal afferent pathways. Furthermore, it is possible that the action of capsaicin on thermoregulatory behavior is mediated by the release of substance P from primary afferent terminals.


Estrone sulfate (E1S), a prognosis marker for tumor aggressiveness in prostate cancer (PCa).
Seeking insight into the possible role of estrogens in prostate cancer (PCa) evolution, we assayed serum E2, estrone (E1), and estrone sulfate (E1S) in 349 PCa and 100 benign prostatic hyperplasia (BPH) patients, and in 208 control subjects in the same age range (50-74 years). E1 (pmol/L+/-S.D.) and E1S (nmol/L+/-S.D.) in the PCa and BPH patients (respectively 126.1+/-66.1 and 2.82+/-1.78, and 127.8+/-56.4 and 2.78+/-2.12) were significantly higher than in the controls (113.8+/-47.6 and 2.11+/-0.96). E2 was not significantly different among the PCa, BPH, and control groups. These assays were also carried out in PCa patients after partition by prognosis (PSA, Gleason score (GS), histological stage, and surgical margins (SM)). Significantly higher E1S levels were found in PCa with: PSA>10 ng/L (3.05+/-1.92) versus PSA<or=10 ng/mL (2.60+/-1.55), stage pT3-T4 (2.99+/-1.80) versus pT2 (2.58+/-1.58), and positive (3.26+/-1.95) versus negative margins (2.52+/-1.48). E1 was higher in poor- than in better-prognosis PCa. E2 was significantly higher in PCa with GS>or=4+3 (109.5+/-43.8) versus GS<or=3+4 (100.6+/-36.5) and increased significantly when GS increased from 3+3 to 4+4. Estrogens, especially E1S appeared to be possible markers of PCa progression. Attempting to identify potential sources of E2 in PCa according to prognosis, as well as in BPH, we found a significant correlation coefficient between E1S and E2 (0.266-0.347) in poor-prognosis PCa and no correlation in BPH (0.026) and better-prognosis PCa (0.013-0.104). It is as though during progression of PCa from good to poor prognosis there were a shift in the E1 to E2 metabolic pathway from predominantly oxidative to predominantly reductive.


Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial.
Metastatic castration-resistant prostate cancer (mCRPC) is immunologically "cold" and predominantly resistant to immune checkpoint therapy due to few tumor-infiltrating T cells. Ipilimumab (anti-CTLA-4) or anti-PD-1/PD-L1 monotherapy failed to show a significant benefit. Although the PD-1/PD-L1 pathway is minimally expressed in prostate tumors, we previously demonstrated that PD-1/PD-L1 expression increases as a compensatory inhibitory pathway in parallel with an ipilimumab-induced increase in tumor-infiltrating T cells. Here, we report the largest trial to date in mCRPC with anti-CTLA-4 plus anti-PD-1 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; CheckMate 650, NCT02985957). With median follow-ups of 11.9 and 13.5 months in cohorts 1 (pre-chemotherapy; n = 45) and 2 (post-chemotherapy; n = 45), objective response rate was 25% and 10%, and median overall survival was 19.0 and 15.2 months, respectively. Four patients, two in each cohort, had complete responses. Exploratory studies identify potential biomarkers of response. Grade 3-4 treatment-related adverse events have occurred in ∼42%-53% of patients, with four treatment-related deaths. Therefore, dose/schedule modifications have been implemented.


Re-examining current breast cancer screening: An analysis of the 2009 U.S. Preventive Services Task Force guidelines for breast cancer screening.
The U.S. Preventive Services Task Force (USPSTF) released new mammography screening guidelines in November 2009. The panel's comprehensive review of evidence for this preventive service concluded that the net benefit of screening mammography was too small to justify universal screening for women younger than 50 years of age but advocated continuing universal screening, though biennially rather than annually, for women ages 50-74 years. Under these new recommendations, it is possible undetected early breast cancers may increase and result in increases in breast cancer morbidity. This policy analysis assessed the impact of the new guidelines regarding whether the policy changes have affected breast cancer detection and treatment in the ensuing 5 years, and whether these guidelines may affect morbidity and mortality from breast cancer in the future. Trade-offs are present in cost-effectiveness and earlier detection with better treatment for women ages 40-49 years. Follow-up studies will be crucial to monitor changes in outcome for mortality and surgical intervention and ascertain the full impact of the new guidelines for women younger than 50 years.


Effects of intraarticular administration of basic fibroblast growth factor with hyaluronic acid on osteochondral defects of the knee in rabbits.
Growth factors including basic fibroblast growth factor (bFGF) are expected to be useful tools for enhancing osteochondral repair. However, suitable carriers are required to deliver a growth factor to the injury site. We evaluated the effects of intraarticular injection of bFGF with hyaluronic acid (HA) on osteochondral repair and the potential carrier role of HA in this treatment. Osteochondral defect was created in the medial femoral condyle of rabbits and received single or weekly intraarticular injection of bFGF (1 or 10 microg) with or without HA. Prior to the administration, bFGF was incubated with HA or vehicle-saline for 24 h at 4 degrees C. Four weeks after the initial injection, the animals were killed and the defect was evaluated grossly (12-point scale) and histologically (16-point scale). The effect of single injection of bFGF (1 microg) with HA was also compared to that of the carrier known as gelatin microspheres (GM) incorporating bFGF. Weekly-administered bFGF alone induced undesirable side effects such as inflammatory responses and osteophyte formation. However, weekly-administered 1 mug of bFGF with HA yielded significantly better osteochondral repair than each treatment alone in gross and histological examinations with minimal side effects (P < 0.05). Single administration of 1 microg bFGF with HA but not GM incorporating bFGF showed significantly better osteochondral repair comparing to the vehicle control (P < 0.05). Low-dose bFGF with HA was effective for osteochondral repair in rabbits. The significant osteochondral reparative role of bFGF with HA comparing with GM incorporating bFGF might be explained by the potential carrier role of HA and possible synergistic action between these two agents. The combination of HA with bFGF significantly suppressed the side effects resulting from single use of bFGF.


Neuro-oncological patients admitted in intensive-care unit: predictive factors and functional outcome.
The prognosis of oncology patients admitted to the intensive care unit (ICU) is considered poor. Our objective was to analyze the characteristics and predictive factors of death in the ICU and functional outcome following ICU treatment for neuro-oncology patients. A retrospective study was conducted on all patients with primary brain tumor admitted to our institutional ICU for medical indications. Predictive impact on the risk of death in the ICU was analyzed as well as the functional status was evaluated prior and following ICU discharge. Seventy-one patients were admitted to the ICU. ICU admission indications were refractory seizures (41 %) and septic shock (17 %). On admission, 16 % had multi-organ failure. Ventilation was necessary for 41 % and catecholamines for 13 %. Twenty-two percent of patients died in the ICU. By multivariate analysis, predictive factors associated with an increased risk of ICU death were: non-neurological cause of admission [p = 0.045; odds ratio (OR) 5.405], multiple organ failure (p = 0.021; OR 8.027), respiratory failure (p = 0.006; OR 9.615), and hemodynamic failure (p = 0.008; OR 10.111). In contrast, tumor type (p = 0.678) and disease control status (p = 0.380) were not associated with an increased risk of ICU death. Among the 35 evaluable patients, 77 % presented with a stable or improved Karnofsky performance status following ICU hospitalization compared with the ongoing status before discharge. In patients with primary brain tumor admitted to the ICU, predictive factors of death appear to be similar to those described in non-oncology patients. ICU hospitalization is generally not associated with a subsequent decrease in the functional status.


High performance, single crystal gold bowtie nanoantennas fabricated via epitaxial electroless deposition.
Material quality plays a critical role in the performance of nanometer-scale plasmonic structures and represents a significant hurdle to large-scale device integration. Progress has been hindered by the challenges of realizing scalable, high quality, ultrasmooth metal deposition strategies, and by the poor pattern transfer and device fabrication yields characteristic of most metal deposition approaches which yield polycrystalline metal structure. Here we highlight a novel and scalable electrochemical method to deposit ultrasmooth, single-crystal (100) gold and to fabricate a series of bowtie nanoantennas through subtractive nanopatterning. We investigate some of the less well-explored design and performance characteristics of these single-crystal nanoantennas in relation to their polycrystalline counterparts, including pattern transfer and device yield, polarization response, gap-field magnitude, and the ability to model accurately the antenna local field response. Our results underscore the performance advantages of single-crystal nanoscale plasmonic materials and provide insight into their use for large-scale manufacturing of plasmon-based devices. We anticipate that this approach will be broadly useful in applications where local near-fields can enhance light-matter interactions, including for the fabrication of optical sensors, photocatalytic structures, hot carrier-based devices, and nanostructured noble metal architectures targeting nano-attophysics.


Methods and Protocols for Using Extracellular Vesicles as Delivery Vehicles in Neuronal Research.
Extracellular vesicles (EVs) transport nucleic acids, proteins, and lipid molecules for intercellular communication. The biomolecular cargo from EVs can modify the recipient cell genetically, physiologically, and pathologically. This innate ability of EVs can be harnessed to deliver the cargo of interest to a specific organ or a cell type. Importantly, due to their ability to cross the blood-brain barrier (BBB), the EVs can be used as delivery vehicles to transport therapeutic drugs and other macromolecules to inaccessible organs such as the brain. Therefore, the current chapter includes laboratory techniques and protocols focusing on the customization of EVs for neuronal research.


Sub-differentiating equivocal PI-RADS-3 lesions in multiparametric magnetic resonance imaging of the prostate to improve cancer detection.
To evaluate sub-differentiation of PI-RADS-3 prostate lesions using pre-defined T2- and diffusion-weighted (DWI) MRI criteria, to aid the biopsy decision process. 143 patients with PIRADS-3 index lesions on MRI underwent targeted transperineal-MR/US fusion biopsy. Radiologists with 2 and 7-years experience performed blinded retrospective second-reads using set criteria and assigned biopsy recommendations. Inter-reader agreement, Gleason score (GS), positive (PPV) predictive values (±95% confidence intervals) were calculated and compared by Fisher's exact test with Bonferroni-Hom correction. 43% (61/143) patients had GS 6-10 and 21% (30/143) GS≥3+4 cancer. For peripheral zone lesions, significant differences in any cancer detection were found for shape (0.26±0.13 geographical vs. 0.69±0.23 rounded; p=0.0055) and ADC (mild 0.21±0.12 vs marked 0.81±0.19; p=0.0001). For transition zone, significantly increased cancer detection was shown for location (anterior 0.63±0.15 vs. mid/posterior 0.31±0.14; p=0.0048), border (pseudo-capsule 0.32±0.14 vs. ill-defined 0.61±0.15; p=0.0092), and ADC (mild 0.35±0.12 vs marked restriction 0.68±0.17; p=0.0057). Biopsy recommendations had 62% inter-reader agreement (89/143). Experienced reader PPVs were significantly higher for any cancer with "biopsy-recommended" 0.61±0.11 vs. "no biopsy" 0.21±0.10 (p=0.0001), and for GS 7-10 cancers: 0.32±0.10 vs. 0.08±0.07, respectively (p=0.0003). Identification of certain objective imaging criteria as well as a subjective biopsy recommendation from an experienced radiologist can help to increase the predictive value of equivocal prostate lesions and inform the decision making process of whether or not to biopsy.


Infantile leukemia presenting with cholestasis secondary to massive pancreatic infiltration.
We present a 10-week-old infant who presented with cholestasis. Biliary obstruction secondary to massive pancreatic infiltration was demonstrated by ultrasound. A diagnosis of acute lymphoid leukemia was confirmed. Enlargement of the pancreas is unusual both in this age group and in leukemia. Infantile leukemia, although rare and usually not associated with gastrointestinal presentations, should be considered as a cause of pancreatic enlargement and neonatal cholestasis.


Accuracy of galactomannan testing on tracheal aspirates in COVID-19-associated pulmonary aspergillosis.
Our aim was to evaluate the performance of two galactomannan (GM) assays (Platelia Aspergillus EIA, Bio-Rad® , and Aspergillus GM LFA, IMMY® ) in tracheal aspirate (TA) samples of consecutive critically ill patients with COVID-19. We included critically ill patients, performed GM-EIA and GM-Lateral Flow Assay (GM-LFA) in TA and followed them until development of COVID-19-associated pulmonary aspergillosis (CAPA) or alternate diagnosis. CAPA was defined according to the modified AspICU criteria in patients with SARS-CoV-2 infection. We estimated sensitivity, specificity, positive and negative predictive values for GM-EIA, GM-LFA, the combination of both or either positive results for GM-EIA and GM-LFA. We explored accuracy using different breakpoints, through ROC analysis and Youden index to identify the optimal cut-offs. We described antifungal treatment and 30-day mortality. We identified 14/144 (9.7%) patients with CAPA, mean age was 50.35 (SD 11.9), the median time from admission to CAPA was 8 days; 28.5% received tocilizumab and 30-day mortality was 57%. ROC analysis and Youden index identified 2.0 OD as the best cut-off, resulting in sensitivity and specificity of 57.1% and 81.5% for GM-EIA and 60% and 72.6% for GM-LFA, respectively. The diagnostic performance of GM in tracheal aspirates improved after using a cut-off of 2 OD. Although bronchoalveolar lavage testing is the ideal test, centres with limited access to bronchoscopy may consider this approach to identify or rule out CAPA.


The Assessment of Limb Length Discrepancy Before Total Hip Arthroplasty.
The clinical relevance of limb length discrepancy (LLD) after total hip arthroplasty gains attention as the number of total hip arthroplasties increases. Although several techniques are commonly used to assess LLD using a pelvic radiograph, their accuracy is not well established. This study measures LLD using different techniques viewing the pelvis and compares the measurements with the true LLD. Pelvic landmarks used included the femoral head, lesser trochanter, acetabular teardrop, ischial tuberosity, and tibial plafond. The true LLD was determined by finding the difference in distance between the lowest point of the ischial tuberosity and the tibial plafond as well as the top of the femoral head to the center of the tibial plafond for each lower limb. Using pelvic landmarks to assess LLD is significantly different (P < .001) from the true LLD. The difference in distance from the center of the tibial plafond to the ischial tuberosity was not significantly different from the measurement from the top of the femoral head to the center of the tibial plafond (P = .08). Also, using the acetabular teardrop as a landmark has less reliability when compared to the ischial tuberosity. Owing to the extensive variety of pathologies that are associated with LLD, preoperative planning should include an assessment of any preexisting LLD. Although it may be reasonable to compare pelvic measurements preoperatively and postoperatively to assess for changes, the data from this study do not support the estimation of the true LLD using a pelvic radiograph.


Urinary antibiotic concentrations in preschool children from eastern China and health risk assessment.
Despite limited biomonitoring studies suggesting extensive antibiotic exposure in general population, the body burden of antibiotics in young children and their potential health risks remain unclear. To assess the antibiotic exposure levels in young children, 508 preschoolers aged 3-6 years were recruited from eastern China in 2022, and a total of 50 representative antibiotics from 8 categories, including 17 human antibiotics (HAs), 4 antibiotics preferred as HAs (PHAs), 16 veterinary antibiotics (VAs), and 13 antibiotics preferred as VAs (PVAs), were analyzed by UPLC-MS/MS. Hazard quotient (HQ) and hazard index (HI) were calculated to evaluate the health risks, and multivariate logistic regression was applied to examine diet with antibiotic exposure. Our results showed that there were 41 antibiotics detected in children's urine, and the overall detection frequency was as high as 100%. Sulfonamides, macrolides, β-lactams, quinolones, and azoles were the predominant categories of antibiotic detected. Among the studied children, 6.5% had a sum of estimated daily intake (EDI) of all VAs and PVAs larger than 1 μg/kg/day. Notably, 10.0% of the children had a microbiological HI value exceeding 1, primarily contributed by ciprofloxacin. Children with higher consumption of seafood had a relatively increased exposure to multiple categories of antibiotics, including HAs, VAs, quinolones, azoles, and others. Principal component analysis suggested that "Aquatic products and viscera preferred dietary pattern" scores were positively correlated with the exposure levels of ciprofloxacin (OR: 1.23; 95% CI: 1.02-1.47) and carbadox (OR: 1.32; 95% CI: 1.10-1.59), and a relatively increased exposure of PHAs was realized in children with higher "Meat-egg preferred dietary pattern" scores (OR: 1.24; 95% CI: 1.03-1.50). In conclusion, there was a widespread exposure to antibiotics among preschool children from eastern China, and children who consumed more animal-derived foods may had an increased exposure to antibiotics.


Is there a role for second-look capsule endoscopy in patients with obscure GI bleeding after a nondiagnostic first test?
Long-term follow-up data on patients with obscure GI bleeding subjected to capsule endoscopy (CE) are missing. Our purpose was to follow up patients with a nondiagnostic test and determine whether a second-look CE would be beneficial. We enrolled 293 subjects. CE studies were classified as diagnostic (positive findings) or nondiagnostic (findings of uncertain significance/no findings). Patients were followed up for a mean (SD) 24.8 (5.2) months. Outcome was defined as continued or complete resolution of bleeding. Patients with a nondiagnostic test were subjected to a repeat CE if they manifested a new bleeding episode or a drop in hemoglobin >or=2 g/dL. Positive findings, findings of uncertain significance, and no findings were identified in 41.6%, 16.0%, and 42.3% of our patients, respectively. Therapeutic intervention was possible in 72.1% of those with positive findings and in 30% of those with findings of uncertain significance. Complete resolution of bleeding occurred more often in patients with a diagnostic test (65.2%) compared with those with a nondiagnostic test (35.4%, P < .001). Second-look CE was performed in a subgroup of our patients (n = 76) and was diagnostic in those whose presentation changed from occult to overt or those whose hemoglobin dropped >or=4 g/dL. In patients with obscure GI bleeding, a diagnostic CE leads to therapeutic interventions and a favorable outcome. Patients with a nondiagnostic test would definitely benefit from a second-look CE if the bleeding presentation changes from occult to overt or if the hemoglobin value drops >or=4 g/dL.


Low-grade myofibroblastic sarcoma of the tongue.
Low-grade myofibroblastic sarcoma is a neoplasm of atypical myofibroblasts with fibromatoseslike features and a predilection for head and neck sites, including the oral cavity. These lesions have only been characterized in the last 2 decades, and controversies in the concept of neoplastic myofibroblasts still exist. Lack of obvious cytological atypia may result in their being mistaken for reactive fascitislike lesions or fibromatosis and architectural similarities to fibrosarcoma or leiomyosarcoma may complicate the diagnostic process. This paper describes a spindle cell neoplasm in a 40-year-old man that was diagnosed 9 years ago as an unclassifiable myofibroblastic proliferation. The recurrent tumor, which presented 6 years following excision of the original tumor, was subsequently classified as a low-grade myofibroblastic sarcoma. The morphological, immunohistochemical, and electron microscopic features of this unusual sarcoma and the most likely differential diagnoses are discussed.


Dietary per- and polyfluoroalkyl substance (PFAS) exposure in adolescents: The HOME study.
Diet is the primary exposure pathway for per- and polyfluoroalkyl substances (PFAS) in non-occupationally exposed populations. Few studies have examined associations of dietary quality and macronutrient intake with PFAS exposure among US adolescents. To assess relationships of self-reported dietary quality and macronutrient intake with serum PFAS concentrations in adolescents. We used cross-sectional data from 193 Cincinnati, Ohio area adolescents (median age 12.3 years) collected from 2016 to 2019. Using 24-h food recalls completed by adolescents on three separate days, we derived Healthy Eating Index (HEI) scores, HEI components, and macronutrient intake. We measured perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) concentrations in fasting serum samples. Using linear regression, we estimated covariate-adjusted associations between dietary variables and serum PFAS concentrations. The median HEI score was 44 and median serum PFOA, PFOS, PFHxS, and PFNA concentrations were 1.3, 2.4, 0.7, and 0.3 ng/mL respectively. In adjusted models, higher total HEI scores, whole fruit and total fruit HEI component scores, and total dietary fiber intake were associated with lower concentrations of all four PFAS. For example, serum PFOA concentrations were 7% lower (95% CI: -15, 2) per standard deviation increase in total HEI score and 9% lower (95% CI: -18, 1) per standard deviation increase in dietary fiber. Given adverse health effects associated with PFAS exposure, it is crucial to understand modifiable exposure pathways. Findings from this study may inform future policy decisions aiming to limit human exposure to PFAS.


The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder.
Berk M, Dodd S, Dean OM, Kohlmann K, Berk L, Malhi GS. The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder. The phenomenology of unipolar and bipolar disorders differ in a number of ways, such as the presence of mixed states and atypical features. Conventional depression rating instruments are designed to capture the characteristics of unipolar depression and have limitations in capturing the breadth of bipolar disorder. The Bipolar Depression Rating Scale (BDRS) was administered together with the Montgomery Asberg Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in a double-blind randomised placebo-controlled clinical trial of N-acetyl cysteine for bipolar disorder (N = 75). A factor analysis showed a two-factor solution: depression and mixed symptom clusters. The BDRS has strong internal consistency (Cronbach's alpha = 0.917), the depression cluster showed robust correlation with the MADRS (r = 0.865) and the mixed subscale correlated with the YMRS (r = 0.750). The BDRS has good internal validity and inter-rater reliability and is sensitive to change in the context of a clinical trial.


ING4 regulates a secretory phenotype in primary fibroblasts with dual effects on cell proliferation and tumor growth.
ING proteins have an essential role in the control of a variety of cellular functions whose deregulation is associated with tumor formation and dissemination, such as proliferation, apoptosis, senescence or invasion. Accordingly, loss of function of ING proteins is a frequent event in many types of human tumors. In this report, we have studied the function of ING4, a member of the ING family of tumor suppressors, in the context of normal, non-transformed primary fibroblasts. We show that ING4 negatively regulates cell proliferation in this cell type. The antiproliferative action of ING4 requires its ability to recognize chromatin marks, it is p53-dependent at least in part, and it is lost in an ING4 cancer-associated mutant. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. The secretory phenotype regulated by ING4 in primary fibroblasts displays a selective paracrine effect on proliferation, fostering the division of tumor cells, while inhibiting division in primary fibroblasts. Consistently, ING4-expressing fibroblasts promoted tumor growth in vivo in co-injection tumorigenesis assays. Collectively, our results show that ING4 not only can regulate the proliferation of primary non-transformed human fibroblasts, but also orchestrates a secretory phenotype in these cells that promotes tumor cell proliferation in vitro and in vivo. These findings support a critical role for ING4 expression in normal cells in the non-cell-autonomous regulation of tumor growth.


Safety and efficacy of zero fluoroscopy transseptal puncture with different approaches.
Atrial fibrillation (AF) ablation requires access to the left atrium (LA) via transseptal puncture (TP). TP is traditionally performed with fluoroscopic guidance. Use of intracardiac echocardiography (ICE) and three-dimensional mapping allows for zero fluoroscopy TP. To demonstrate safety and efficacy of zero fluoroscopy TP using multiple procedural approaches. Patients undergoing AF ablation between January 2015 and November 2017 at five institutions were included. ICE and three-dimensional mapping were used for sheath positioning and TP. Variable technical approaches were used across centers including placement of J wire in the superior vena cava with ICE guidance followed by dragging down the transseptal sheath into the interatrial septum, or guiding the transseptal sheath directly to the interatrial septum by localizing the ablation catheter with three-dimensional mapping and replacing it with the transseptal needle once in position. In patients with pacemaker/implantable cardiac defibrillator leads, pre-/poststudy device interrogation was performed. A total of 747 TPs were performed (646 patients, age 63.1 ± 13.1, 67.5% male, LA volume index 34.5 ± 15.8 mL/m2 , ejection fraction 57.7 ± 10.9%) with 100% success. No punctures required fluoroscopy. Two pericardial effusions, two pericardial tamponades requiring pericardiocentesis, and one transient ischemic attack were observed during the overall ablation procedure, with a total complication rate of 0.7%. There were no other periprocedural complications related to TP, including intrathoracic bleeding, stroke, or death both immediately following TP and within 30 days of the procedure. In patients with intracardiac devices, no device-related complications were observed. TP can be safely and effectively performed without the need for fluoroscopy.


Management of gout and hyperuricemia.
The medical management of gout follows a logical course in eventually controlling the underlying hyperuricemia. Approached properly, it is one of the most gratifying rheumatic diseases for a physician to treat.


Coherent phenomena in photosynthetic light harvesting: part one-theory and spectroscopy.
The role of non-trivial quantum mechanical effects in biology has been the subject of intense scrutiny over the past decade. Much of the focus on potential "quantum biology" has been on energy transfer processes in photosynthetic light harvesting systems. Ultrafast laser spectroscopy of several light harvesting proteins has uncovered coherent oscillations dubbed "quantum beats" that persist for hundreds of femtoseconds and are putative signatures for quantum transport phenomena. This review describes the language and basic quantum mechanical phenomena that underpin quantum transport in open systems such as light harvesting and photosynthetic proteins, including the photosystem reaction centre. Coherent effects are discussed in detail, separating various meanings of the term, from delocalized excitations, or excitons, to entangled states and coherent transport. In particular, we focus on the time, energy and length scales of energy transport processes, as these are critical in understanding whether or not coherent processes are important. The role played by the protein in maintaining chromophore systems is analysed. Finally, the spectroscopic techniques that are used to probe energy transfer dynamics and that have uncovered the quantum beats are described with reference to coherent phenomena in light harvesting.


Identifying Core Competencies of Infection Control Nurse Specialists in Hong Kong.
To confirm a core competency scale for Hong Kong infection control nurses at the advanced nursing practice level from the core competency items proposed in a previous phase of this study. This would serve as the foundation of competency assurance in Hong Kong hospitals. A cross-sectional survey design was used. All public and private hospitals in Hong Kong. All infection control nurses in hospitals of Hong Kong. The 83-item proposed core competency list established in an earlier study was transformed into a questionnaire and sent to 112 infection control nurses in 48 hospitals in Hong Kong. They were asked to rate the importance of each infection prevention and control item using Likert-style response categories. Data were analyzed using the Rasch model. The response rate of 81.25% was achieved. Seven items were removed from the proposed core competency list, leaving a scale of 76 items that fit the measurement requirements of the unidimensional Rasch model. Essential core competency items of advanced practice for infection control nurses in Hong Kong were identified based on the measurement criteria of the Rasch model. Several items of the scale that reflect local Hong Kong contextual characteristics are distinguished from the overseas standards. This local-specific competency list could serve as the foundation for education and for certification of infection control nurse specialists in Hong Kong. Rasch measurement is an appropriate analytical tool for identifying core competencies of advanced practice nurses in other specialties and in other locations in a manner that incorporates practitioner judgment and expertise.


Pharmacokinetic Modeling of Optimized Midazolam and Pentobarbital Dosing Used in Treatment Protocols of Refractory Status Epilepticus.
To model bolus dosing, infusion rate, and weaning rate on theoretical serum concentration of midazolam and pentobarbital used in the treatment of refractory status epilepticus (RSE). One- and two-compartment in silico pharmacokinetic models of midazolam and pentobarbital. Not applicable. Not applicable. We compared the model variables used in midazolam and pentobarbital protocols for standard RSE. Standard RSE treatment protocols result in steady-state serum concentrations that are 6.2-9.0-fold higher for the one-compartment model and 2.3-4.7-fold higher for the two-compartment model. In the model, not including bolus doses delays the achievement of serum steady-state concentration by 0.5 and 2.7 hours for midazolam and pentobarbital, respectively. Abrupt discontinuation of these medications reduces modeled medication exposure by 1.1 and 6.4 hours, respectively. Our in silico pharmacokinetic modeling of standard midazolam and pentobarbital dosing protocols for RSE suggests potential variables to optimize in future clinical studies.


Recycling of the insulin-responsive glucose transporter Glut4 regulated by the small GTPase RalA and the exocyst complex.
Endocytic recycling represents a major mechanism for continuous supply of molecules to the plasma membrane. Particularly, outbound trafficking of the recycling endosome (RE) or RE-derived vesicles can be upregulated by cellular signaling, through mobilization of specialized protein complexes acting as transport machineries. Therefore, biochemical and functional characterization of cell signaling molecules that operate multimeric protein complexes in membrane transport provides important insights to signaling-regulated trafficking events. In this chapter, we described biochemical approaches and reporter assays in differentiated adipocytes to determine the activity and function of the small GTPase RalA, which relays upstream insulin signaling to the exocyst complex that targets intracellular vesicles bearing the Glut4 transporter to the plasma membrane. The experimental design outlined in this chapter can be applied to other regulated transport events facilitated by the exocyst complex, as well as other GTPases that operate distinct transport complexes in specific physiological settings.


Neutral and acid sphingomyelinases: somatotopographical distribution in human brain and distribution in rat organs. A possible relationship with the dopamine system.
Acid and neutral sphingomyelinase activities have been measured in 22 regions of human brain, and in several rat organs. In general, acid sphingomyelinase activity was similar in most brain regions examined. By contrast neutral sphingomyelinase activity decreased 30-fold between the globus pallidus and white matter. In grey matter structures activity decreased in the order globus pallidus greater than substantia nigra greater than or equal to putamen greater than head of caudate greater than thalamus greater than cortical structures. Under the conditions of assay and in the presence of several possible donors or acceptors, there was no evidence of transfer of phosphoryl-choline to other lipid acceptors. Acid sphingomyelinase was ubiquitously distributed in all rat tissues examined, highest in liver and lowest in adipose tissue. Neutral sphingomyelinase activity was highest in brain; activity from 25 to 10% of that in brain was observed in testis, adrenal gland and aorta. Activity in the other organs examined was less than 10% of that in brain. We suggest that the neutral enzyme serves a special function in brain, perhaps related to the dopaminergic systems.


Avidin binding of biotinylated analogues of substance P.
We report the bioactivities of three biotinylated analogues of Substance P, [alpha-biotinyl-Lys3]Substance P-(3-11), [alpha-biotinyl-Arg1]Substance P, [epsilon-biotinyl-Lys3]Substance P, as well as the bioactivities of their complexes with avidin on guinea pig ileum. The rate of dissociation of an [alpha-biotinyl-Arg1]Substance P-avidin complex has been determined in the presence of 2-(4'-hydroxyazobenzene) benzoic acid and [3H]biotin. The biphasic dissociation of a 4:4 complex between [alpha-biotinyl-Arg1]Substance P and avidin led us to postulate the existence of two sets of binding sites, with the following rates of dissociation, at 4 degrees C, kappa-1 = 6 x 10(-4) x s-1 and kappa-1 = 1.2 x 10(-5) x s-1. We have confirmed this non-equivalence of the four binding sites of avidin by nuclear magnetic resonance using a spin-echo technique. The [alpha-biotinyl-Arg1]Substance P-avidin may be used for the affinity chromatography of Substance P receptors and the decreased affinity of this complex may be taken as an advantage since it can be displaced under mild conditions, i.e. by biotin-containing buffer.


MRI Profile and Collateral Status in Patients with a Transient Ischemic Attack and an Intracranial Artery Occlusion.
Transient ischemic attack may rarely reveal an intracranial artery occlusion. We analyzed acute magnetic resonance imaging (MRI) patterns and early outcome after reperfusion therapy in these cases. Clinical and imaging data were taken retrospectively from our comprehensive stroke center registry. Two MRI patterns were determined. Pattern A: full mismatch with negative diffusion-weighted imaging (DWI) and perfusion defect. Pattern B: large mismatch with positive DWI and perfusion defect. MRI-derived collateral flow maps were automatically generated from the raw of dynamic susceptibility contrast MRI. Patients were treated either by recombinant tissue plasminogen activator (rtPA) alone or in combination with mechanical thrombectomy. From October 1, 2010 to May 15, 2016, 1,019 patients were admitted and treated by t-PA within 4.5 hours of stroke onset of them; 14 had a transient ischemic attack (TIA) within the 6 hours preceding MRI. Perfusion imaging was performed in 11 patients. An arterial occlusion was found in all of them, 11 patients had a distal anterior circulation occlusion, whereas 3 patients (21%) had a proximal occlusion. According to MRI, 6 patients showed pattern A, whereas 5 patients had pattern B. Good collaterals were observed in 10 patients (6 patients with grade 3 and 4 patients with grade 4), whereas 1 patient had poor collaterals (grade 2). The day 1 National Institutes of Health Stroke Scale median was 0. Modified Rankin Scale median at 3 months was 0. TIAs may reveal acute intracranial artery occlusion. Acute MRI may able to assist in therapeutic decision.


A network perspective on body dysmorphic disorder and major depressive disorder.
Body dysmorphic disorder (BDD) is a highly debilitating mental disorder associated with notable psychosocial impairment and high rates of suicidality. This study investigated BDD from a network perspective, which conceptualizes mental disorders as systems of symptoms that cause and exacerbate one another (e.g., preoccupation with perceived appearance defect triggering compulsive checking in the mirror). In a sample of BDD patients (N = 148), we used cross-sectional network models to explore the network structure of 1) BDD symptoms and 2) BDD symptoms and major depressive disorder (MDD) symptoms, and tested which symptoms were most central (i.e., most strongly associated to other symptoms). Interference in functioning due to appearance-related compulsions (BDD), feelings of worthlessness (MDD), and loss of pleasure (MDD) were most central. These symptoms were most strongly predictive of other BDD and MDD symptoms and may be features of BDD that warrant prioritization in theory development and treatment. A limitation of our study is that the precision of these findings may be limited due to a small sample size relative to the number of parameters. Replication studies in larger samples of BDD patients are needed.


A Two-Year Retrospective Analysis of the Clinical Outcomes of Immediate Submuscular Breast Reconstructions With Native® Acellular Dermal Matrix.
Implant-based submuscular breast reconstruction (SBR) can be performed with the aid of acellular dermal matrices (ADM) for implant coverage on their inferolateral pole, aiming at providing a biological interface for hiding the implant and therefore reducing the risk of complications. The purpose of this study is to assess the long-term post-operative outcomes obtained using the SBR-specific Native® ADM (DECO med s.r.l., Marcon, Venice, Italy). All cases of Native®-assisted immediate SBR performed at our institution between October 2016 and March 2020 were retrospectively analysed. Demographic and surgical data were collected, and post-operative outcomes, including minor and major complications, were evaluated. Particular attention was paid to complications emerging before and after patient discharge. Dependence analyses were performed to uncover statistically significant relationships between risk factors and reconstructive outcomes. Data on 100 patients were collected, for a total of 128 breasts. The mean age of the cohort was 49.5 years, the mean BMI was 23.4 kg/m2, and the mean follow-up was 24 months. Out of this, 14.1% of patients received pre-operative radiotherapy, while 16.4% underwent post-mastectomy radiotherapy. Breasts appeared to develop short-term minor complications more likely during hospitalisation (11.7% vs. 7.8%), while short-term major complications occurred more often after discharge (7.8% vs. 15.6%). The most frequent long-term complications were capsular contracture and contour defects (both 9.4%). Risk factors that showed a statistically significant relationship with complications were pre- and post-mastectomy radiotherapy and post-operative chemotherapy. The retrospective analysis showed results in line with clinical outcomes reported in the literature for the same reconstructive technique. The use of Native® ADM in SBR is safe and effective in the long term.


Clinical course and factors associated with outcomes among 1904 patients hospitalized with COVID-19 in Germany: an observational study.
In Germany the coronavirus disease 2019 (COVID-19) pandemic situation is unique among large European countries in that incidence and case fatality rate are distinctly lower. We describe the clinical course and examine factors associated with outcomes among patients hospitalized with COVID-19 in Germany. In this retrospective cohort study we included patients with COVID-19 admitted to a national network of German hospitals between February 12 and June 12, 2020. We examined demographic characteristics, comorbidities and clinical outcomes. We included 1904 patients with a median age of 73 years, 48.5% (924/1904) of whom were female. The mortality rate was 17% (317/1835; 95% confidence interval (95%CI) 16-19), the rate of admission to the intensive care unit (ICU) was 21% (399/1860; 95%CI 20-23), and the rate of invasive mechanical ventilation was 14% (250/1850: 95%CI 12-15). The most prominent risk factors for death were male sex (hazard ratio (HR) 1.45; 95%CI 1.15-1.83), pre-existing lung disease (HR 1.61; 95%CI 1.20-2.16), and increased patient age (HR 4.11 (95%CI 2.57-6.58) for age >79 years versus <60 years). Among patients admitted to the ICU, the mortality rate was 29% (109/374; 95%CI 25-34) and higher in ventilated (33% [77/235; 95%CI 27-39]) than in non-ventilated ICU patients (23%, 32/139; 95%CI 16-30; p < 0.05). In this nationwide series of patients hospitalized with COVID-19 in Germany, in-hospital and ICU mortality rates were substantial. The most prominent risk factors for death were male sex, pre-existing lung disease, and greater patient age.


The Molecular Interaction Process.
Noncovalent molecular interactions, which are central to life, are thermodynamic processes that follow common interaction pathways. This commentary provides a foundation for both considering noncovalent interactions and the interplay between the protein properties and the solvent properties in determining the energetics. In biopharmaceutics, noncovalent interactions are a 2-edged sword. Foremost, they provide a core function for biopharmaceutical agents, binding to targets, substrates, or receptors. At the same time, they are at the root of the solubility and viscosity difficulties encountered in the manufacture, formulation, and delivery of protein-based pharmaceuticals. This commentary describes the interaction process and summarizes the energetics of the interaction pathway. The focus will be on protein-protein interactions, while recognizing that the processes and energetics are entirely general and applicable to all solution interactions. The contributions of protein molecular properties and protein colloidal properties to the pathway are described, and the relationship between the two is developed. The processes leading to protein-protein binding are described with respect to the attractive interactions that lead to aggregation and high viscosity. The concept of emergent heterogeneity is introduced, and a model presented for how noncontacting interactions may lead to high viscosities without simultaneously causing low solubility.


Finding the missing and unknown: Novel educational approaches to warming up cold cases.
In recent years, students in police academies and higher education institutions around the world have worked together to analyse cold cases including long-term missing persons cases in collaboration with investigators and prosecutors. In 2020, three European organisations, the Police Expert Network on Missing Persons (PEN-MP), AMBER Alert Europe and Locate International, succeeded in connecting these educational organisations enabling them to work collectively on cases and conduct cold case analyses (CCA) across international borders. The International Cold Case Analysis Project (ICCAP) learning objectives were to 1) collect the necessary information about the victim, 2) reconstruct the crime, and 3) investigate trace control. In a learning objective-based evaluation using Computer-Assisted Web Interviewing, 76 participating students from the German and International ICCAP teams were asked to complete a pre- and post-review questionnaire to self-assess their personal competence development. Participants reported significant increases in competence in all evaluated areas, thus demonstrating that authentic and relevant collaborations can enrich the learning environment, promote the use of professional skills, and provide significant knowledge exchange opportunities between academia and industry. Drawing on case studies of cold case missing persons' investigations and unidentified found remains, this article shares how university academics, students and community volunteers can work together nationally and internationally to find out what has happened to missing people and how we can more effectively identify the previously unidentified. In so doing, we share the expertise required to progress these cold cases and provide recommendations to support other institutions and organisations in adopting this innovative approach.


Laparoscopic cholecystectomy for acute cholecystitis: is the surgery still safe beyond the 7-day barrier? A multicentric observational study.
Timing for early laparoscopic cholecystectomy (ELC) in patients with acute calculous cholecystitis (ACC) is still controversial. This study assesses ELC for ACC with delayed presentation, according to hospital volume. Multicentric retrospective analysis of 1868 ELC. Patients were classified into two groups according to the timing of surgery from clinical onset and centre volume. Group 1 (G1) within the first 7 days, group 2 (G2) beyond that. Then centres were classified in low volume centres (LVC) and higher volume centres (HVC) according to the number of ELC performed per year. Overall, G2 showed increased conversion rate (17.7% vs 10.7%; p = 0.004), intraoperative complications (7.3% vs 2.9%; p = 0.001); postoperative haemorrhage (3.6% vs 0.8%; p < 0.001), infections (16.6% vs 9.3%; p = 0.003) and global complications (27.6% vs 19.8%; p = 0.011). HVC in comparison with LVC presented decreased conversion rate (17.1% vs 7.6%; p < 0.001), intraoperative bleeding (2.1% vs 1%; p = 0.047), postoperative bile leakage (4.1% vs 2.1%; p = 0.011), infectious (13.7% vs 7.5%; p < 0.001) and global complications (25.7% vs 17.1%; p < 0.001). HVC did not show an increase in any of the above-mentioned outcomes when G1 and G2 were compared. ELC must be indicated cautiously in patients with ACC and more than 1 week of symptom duration. It should be performed in centres with sufficient experience in the management of this disease.


miRNA expression in serum and PBMCs isolated from middle-aged and elderly patients during asthma exacerbation.
microRNAs are short, noncoding RNA molecules involved in many inflammatory processes including bronchial asthma. Rhinoviruses are the main cause of acute asthma attack and may be involved in miRNA profile dysregulation. The aim of the study was to investigate the serum miRNA profile during asthma exacerbation in middle-aged and elderly patients. We also evaluated in this group in vitro response to rhinovirus 1b exposure. Seventeen middle-aged and elderly asthmatics were admitted to an outpatient clinic during asthma exacerbation and within a period of 6-8 weeks later. Blood samples were collected from the subjects and PBMCs were isolated. Cells were cultured in the presence of Rhinovirus 1b and with the medium only, and, after 48 h. miRNA expression (miRNA-19b, -106a, 126a, and -146a) isolated from serum and PBMCs (cultures) was evaluated with RT-PCR. Cytokines (INF-γ, TNF-α, IL6, and Il-10) in culture supernatants were evaluated with flow cytometry. On exacerbation visit patients demonstrated higher expression of serum miRNA-126a and -146a as compared to follow-up visit. There was a positive correlation between asthma control test results and miRNA-19, -126a, -146a. There was no other significant association between patient characteristics and the miRNA profile. Rhinovirus exposure did not changed miRNA expression in PBMCs as compared to medium on both visits. Cytokine production in culture supernatants significantly increased after rhinovirus infection. The group of middle-aged and elderly patients demonstrated changed levels serum miRNA during asthma exacerbation as compared to follow-up visit; however, correlations between their expression and clinical features were hardly noticeable. Rhinovirus did not affect expression of miRNA in PBMCs; yet, it induced cytokine production.


Congenital obstructive distal urethral membrane.
We present a rare case of complete distal urethral obstruction caused by a distal meatal membrane in a newborn boy. A cystic lesion of the distal penis was detected and excised, revealing a hypospadiac urethra. Further examination showed bilateral vesico-ureteral reflux with a dilated posterior urethra and urethral lesion, suggesting posterior urethral valves (PUV); these were confirmed at 2 months and resected endoscopically. At 16 months a left nephrectomy was performed due to impaired renal function on that side; there was no longer reflux on the right side. The obstruction probably did not become severe until late in gestation, but still led to functional loss of one kidney. The PUV do not seem to have been the cause of renal deterioration. The cystic lesion may have been a remnant of the cloacal membrane, but this is difficult to prove histologically.


[Depression in old age].
Depression is the most frequent psychiatric disorder in old age. Some patients have had depressive episodes or other psychological disorder in an earlier part of their life span. Older people show more somatic or cognitive complaints compared to younger depressives. Risk factors for depression in old age are (incident) physical disorders, sleep disorders or loss of spouse. Depression worsens course and prognosis of comorbid somatic disorders. A major consequence is the high suicide rate in the elderly. Depression is also a risk factor for other disorders like dementia or institutionalisation. The interplay between depression and dementia and other organic brain disorders is complex und still unresolved. Depression in the elderly is a challenge for our health system. Recognition and treatment rates are still too low. Integrative treatment plans for depression with comorbid physical disorders or in various settings should be developed. With the growing elderly population the available evidence for treatment urgently has to be increased. In current practice drug therapies--mostly inadequate--dominate. Psychotherapy should be promoted and the number of old age psychotherapists increased.


Bi(III)-catalyzed intermolecular reactions of (Z)-pent-2-en-4-yl acetates with ethynylarenes for the construction of multisubstituted fluorene skeletons through a cascade electrophilic addition/cycloisomerization sequence.
A Bi(III)-catalyzed method for the synthesis of highly conjugated aromatic multisubstituted fluorene with (Z)-pent-2-en-4-yl acetates and ethynylarenes via domino reaction is described. In this process, the reaction appears to be very general and suitable for a variety of multisubstituted fluorene.


PAH Growth from the pyrolysis of CPD, indene and naphthalene mixture.
In this study, the addition of cyclopentadienyl (CPDyl) moieties to aromatic rings has been investigated experimenNaphthalene was selected as the representative aromatic compound and its pyrolytic reactivity was studied first to obtain background information for the pyrolysis of cyclopentadiene-indene-naphthalene mixture. The experiments were conducted in a 5 s laminar flow reactor over the temperature range of 700-850 degrees C with 50 degrees C increments. PAH growth from naphthalene pyrolysis is mainly attributed to aryl-aryl addition of naphthyl radicals and naphthalene fragmentation, with lower product formation rates comparing with hydrocarbons with CPDyl moieties. The results indicate that naphthalene is less reactive than the CPDyl containing hydrocarbon radical-molecule addition of CPDyl radicals to naphthalene results in phenanthrene, which can also be formed substantially from other growth pathways. This addition occurs mainly at low temperatures and is less favored due to the competition from more reactive indenyl and CPDyl radicals. CPDyl radical addition to naphthalene exhibits limited aromatic growth due to the aromaticity restrictions of naphthalene. The studies of hydrocarbons with and without CPDyl moieties suggest that the reaction pathways of CPDyl bearing hydrocarbons are different from those without these moieties and cannot be adequately accounted for by the existing acetylene addition and aryl-aryl addition mechanisms.


Preparation of highly purified monomeric human serum albumin as secondary reference material for standardization of urinary albumin immunoassays.
International external quality assessments have shown variation in results of urinary albumin among various immunoassays. A well-defined candidate reference material for urine albumin (cRM-UA) was prepared to improve standardization. cRM-UA was prepared from a commercially available preparation of human serum albumin by using gel-filtration HPLC. The value was assigned by transfer from ERM-DA470 using immunoassay systems qualified based on the linearity and variability observed in dilution tests of pooled urine and the calibrators. Effectiveness of recalibration using the cRM-UA was evaluated by measuring 129 urine specimens. The cRM-UA had a monomeric albumin peak which accounted for 98.9% of the total area by gel filtration HPLC. The lyophilized preparation of the cRM-UA had suitable homogeneity, and short- and long-term stability. Nine of 14 immunoassays met the criteria were used for value assignment. The assigned concentration was 225.1±9.11 mg/l [mean±U: expanded uncertainty with k=2] when reconstituted with 3.00 ml of purified water on weight basis. Recalibration of 7 qualified immunoassays using the cRM-UA resulted in between-method CV of 6.6%. The cRM-UA was successful in achieving standardization of urine albumin results among 7 immunoassays which possess performance attributes representing uniform reactivity to both cRM-UA and clinical urine samples.


Synergistic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and N-nitrosodiethylamine on cell malignant transformation.
The present paper aims to investigate the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and N-nitrosodiethylamine (DEN) on tumorigenesis and its potential mechanism. The potentials of TCDD and DEN in separation or in combination to induce malignant transformation were tested in Balb/c 3T3 cells by using a cell transformation assay method. The possible mechanism of observed effects was studied further by adding α-naphthoflavone (α-NF), a competitive binding agent of TCDD, to the Aryl hydrocarbon receptor (AhR) pathway. The mRNA expressions of Cyp1a1 and Cyp2a5 gene in Balb/c 3T3 cells treated by DEN and TCDD in separation or in combination with or without presence of α-NF were measured with fluorescence quantification RT-PCR technique. The cell transformation frequency (TF) was significantly higher in case of induction with TCDD in combination with DEN, as compared to that with either TCDD or DEN alone. These effects were not inhibited via α-NF. The mRNA expression levels of both Cyp1a1 and Cyp2a5 were enhanced by TCDD treatment alone, but this inducible effect was blocked in cells treated by TCDD and DEN in combination. TCDD and DEN had a significant synergistic effect on tumorigenesis when they were used in combination. AhR pathway may not be the key mechanism of this synergistic effect. Thus, it is necessary to further test the potential mechanism involved in cancer development.


The COVID-19 pandemic impact on wellbeing and mental health in people with psychotic and bipolar disorders.
The COVID-19 pandemic affects people globally, but it may affect people with psychotic and bipolar disorders disproportionally. Our aims were to investigate the pandemic impact on perceived wellbeing and mental health in this population, including which pandemic-related factors have had an impact. People with psychotic and bipolar disorders (N = 520; female = 81%; psychotic disorders n = 75/bipolar disorder n = 445) completed an online survey about wellbeing and mental health in the early phase of the COVID-19 pandemic (June 5-July 5, 2020). Many participants experienced deteriorated wellbeing and mental health after the pandemic outbreak, especially in life satisfaction, meaning in life, positive feelings, depression, anxiety, and self-harm/suicidal ideation. Experienced recovery from mental health difficulties was significantly lower after compared to before the outbreak. Participants with psychotic disorders had significantly poorer wellbeing and mental health than participants with bipolar disorders, although they experienced significantly more worsening only of psychotic symptoms. Nearly half the participants reported coping with the situation; however, most factors potentially important to wellbeing and mental health changed adversely, including sufficiency and quality of treatment. More loneliness, low coping, insufficient mental health treatment during the COVID-19 pandemic, pandemic worry, more insomnia symptoms, and increased alcohol use predicted poor wellbeing and poor mental health. During a pandemic, it is particularly important that mental health services strive to offer the best possible treatment under the current conditions and target loneliness, coping strategies, pandemic worry, insomnia, and increased alcohol use to uphold wellbeing and reduce mental health difficulties. For some, teletherapy is an agreeable substitute for traditional therapy.


Effect of oxybrasion on selected skin parameters.
Oxybrasion is one of the types of microdermabrasion. This method removes a superficial epidermal layer with the use of a stream of 0.9% saline solution and compressed air. The assessment of skin hydration, sebum, pH, TEWL (transepidermal water loss), and pigmentation using oxybrasion. The study involved 27 female subjects. Five treatments were performed every 2 weeks using the oxygen microdermabrasion. Measurements of the skin parameters were taken before each treatment and 2 weeks after the last procedure. The measurement points were on the forehead, the cheek, and on the petal of the nose. Sebum measurement showed some statistically significant differences between the sebum level on the cheek and the nose after a series of treatments. A higher hydration level was found at all measurement points. There were no statistically significant differences in TEWL parameter. pH measurement showed that the pH value decreased after each of the procedures. Most of the pigmentation measurements differed in a statistically significant way. Results of the study indicate that the oxybrasion treatments increase the skin hydration and they have a significant influence on the decrease of the skin hydrolipid coat and pH.


Finger massage versus a novel massage device after trabeculectomy.
Ocular massage is a common technique employed after trabeculectomy to aid filtration. This pilot study compares a novel ocular massage device (MD) with finger massage (FM) after trabeculectomy. The device provides the patient with audio feedback about correctly applied force, and the force applied can be customized for each patient. A prospective, randomized study was performed comparing the effects of FM versus MD on intraocular pressure (IOP) and complication rates. All patients were given a standardized tutorial in ocular massage. The efficiency of their massage technique was evaluated at 1 week by having the patient perform the massage in front of the ophthalmologist, with IOP measurements taken before and after massage. Information on bleb morphology, IOP, ocular medications, and complications were recorded on a weekly basis. The patient perspective was recorded by questionnaire at 1 week, 1 month, and 3 months after initiation of the massage. Twenty-five patients were enrolled in the study, 12 randomly assigned to the FM and 13 to the MD groups. Patients in the MD group were much more confident that they were doing the massage correctly (p = 0.009) and reported a greater ease of use and lower pain scores. The mean difference in IOP in the 2 groups was not statistically significant in the first 3 weeks, and IOP after 3 months was statistically similar in both groups. Laser suture lysis was performed in 8 patients (66%) in the FM versus 6 (46%) in the MD group (p = 0.42). Wound leaks developed in 4 patients (3 in the FM group vs. 1 in the MD group, p = 0.32). The massage device shows promise as an adjunctive tool in the postoperative management of trabeculectomies.


Evaluation of costs associated with fertility treatment leading to a live birth after one fresh transfer: A global perspective.
Considerable costs are associated with infertility treatment, but little evidence is available on the main drivers of treatment costs. This cost analysis investigated key costs for treatment with assisted reproductive technology (ART) and the proportion of costs attributed to the acquisition of recombinant human follicle-stimulating hormone (r-hFSH) alfa originator for one fresh embryo transfer (ET) leading to a live birth in Spain, Norway, the UK, Germany, Denmark, South Korea, Australia, and New Zealand. The total costs for one ART cycle with a fresh ET leading to a live birth varied between countries (€4108-€12,314). Costs for pregnancy and live birth were the major contributors in European countries, and the costs of oocyte retrieval, monitoring during ovarian stimulation, pregnancy, and live birth were the top contributors in the Asia-Pacific countries, included in this analysis. Acquisition costs for r-hFSH alfa originator contributed to only 5%-17% of the total costs of one ART cycle with one fresh ET leading to a live birth.


Efficacy and safety of erythropoietin in patients with traumatic brain injury: A systematic review and meta-analysis.
The purpose of this study was to evaluate the effects of erythropoietin (EPO) on mortality and neurological outcomes in patients with traumatic brain injury (TBI). Electronic databases of studies published up to January 5, 2017 were searched to retrieve relevant investigations comparing the outcomes of EPO-treated patients and untreated patients following TBI. We calculated the relative risk (RR) of mortality, neurologic outcomes, and deep vein thrombosis (DVT) with corresponding 95% confidence interval (CI) using meta-analysis. Six randomized controlled clinical trials met the eligibility criteria. In total, 1041 patients were included among the studies. EPO was found to significantly reduce the occurrence of mortality (RR 0.68 [95% CI 0.50-0.95]; P = 0.02), but did not significantly reduce poor functional outcome (RR 1.22 [95% CI 0.82-1.81]; P = 0.33). There were no significant differences in the occurrence of complications, such as DVT, between the treatment groups (RR -0.02 [95% CI -0.06-0.02]; P = 0.81). Results of the present meta-analysis suggest that the use of EPO may prevent death following TBI without causing adverse events, such as deep vein thrombosis. However, the role of EPO in improving neurological outcome(s) remains unclear. Further well-designed, randomized controlled trials using modified protocols and involving specific patient populations are required to clarify this issue, and to verify the findings.


3H-substance P binding to guinea-pig ileum longitudinal smooth muscle membranes.
Specific binding of 3H-substance P was studied in guinea-pig ileum longitudinal smooth muscle membranes. A single population of non-interacting sites with an apparent dissociation constant of 1.8 nM was observed. The relative potencies of some structural analogues of substance P, notably eledoisin and substance P (5-11), in competing for 3H-substance P binding sites, however, had little resemblance to their potencies in contracting the intact muscle or in eliciting the breakdown of inositol phospholipids in this tissue. The results are discussed in the light of other binding studies for substance P.


Developing and testing the patient-centred innovation questionnaire for hospital nurses.
Develop the patient-centred innovation questionnaire for hospital nurses and establish its validity and reliability. Patient-centred care has been adopted by health care managers in their efforts to improve health care quality. It is regarded as a core concept for developing innovation. A cross-sectional study was employed to collect data from hospital nurses in Taiwan. This study was divided into two stages: pilot study and main study. In the main study, 596 valid responses were collected. This study adopted reliability analysis, exploratory factor analysis, confirmatory factor analysis and selected nurse innovation scale as a criterion to test criterion-related validity. Five-dimension patient-centred innovation questionnaire was proposed: access and practicability, co-ordination and communication, sharing power and responsibility, care continuity, family and person focus. Each dimension demonstrated a reliability of 0.89-0.98. All dimensions had acceptable convergent and discriminate validity. The patient-centred innovation questionnaire and nurse innovation scale exhibited a significantly positive correlation. Patient-centred innovation questionnaire not only had a good theoretical basis but also had sufficient reliability and construct validity, and criterion-related validity. Patient-centred innovation questionnaire could give a measure for evaluating the implementation of patient-centred care and could be used as a management tool during the process of nurse innovation.


Ependymoma in children: molecular considerations and therapeutic insights.
A multi-modality approach that encompasses maximal surgical resection in combination with adjuvant therapy is critical for achieving optimal disease control in children with ependymoma. In view of its complex biology and variable response to therapy, ependymoma remains a challenge for clinicians involved in the care of these patients. Meanwhile, translation of molecular findings can characterize unique features of childhood ependymoma and their natural history. Furthermore, understanding the biology of pediatric ependymoma serves as a platform for development of future targeted therapies. In line with these goals, we review the molecular basis of pediatric ependymoma and its prognostic implications, as well as novel therapeutic advances in the management of ependymoma in children.


Continuous negative extrathoracic pressure combined with high-frequency oscillation improves oxygenation with less impact on blood pressure than high-frequency oscillation alone in a rabbit model of surfactant depletion.
Negative air pressure ventilation has been used to maintain adequate functional residual capacity in patients with chronic muscular disease and to decrease transpulmonary pressure and improve cardiac output during right heart surgery. High-frequency oscillation (HFO) exerts beneficial effects on gas exchange in neonates with acute respiratory failure. We examined whether continuous negative extrathoracic pressure (CNEP) combined with HFO would be effective for treating acute respiratory failure in an animal model. The effects of CNEP combined with HFO on pulmonary gas exchange and circulation were examined in a surfactant-depleted rabbit model. After induction of severe lung injury by repeated saline lung lavage, 18 adult white Japanese rabbits were randomly assigned to 3 groups: Group 1, CNEP (extra thoracic negative pressure, -10 cmH2O) with HFO (mean airway pressure (MAP), 10 cmH2O); Group 2, HFO (MAP, 10 cmH2O); and Group 3, HFO (MAP, 15 cmH2O). Physiological and blood gas data were compared among groups using analysis of variance. Group 1 showed significantly higher oxygenation than Group 2, and the same oxygenation with significantly higher mean blood pressure compared to Group 3. Adequate CNEP combined with HFO improves oxygenation with less impact on blood pressure than high-frequency oscillation alone in an animal model of respiratory failure.


Association of salivary cortisol and psychological burden in patients with oral cancer and oral potentially malignant disorders: A prospective study.
This study aimed to find an association between psychological burden (in terms of depression, anxiety, and stress) and salivary cortisol among oral cancer (OC) and oral potentially malignant disorder (OPMD) patients at various time frames. In total, 50 patients with OC and OPMD were studied after their informed consent along with 30 healthy controls. Depression, anxiety, and stress scale-21 (DASS-21) was administered and saliva was collected (non-invasively) at different stages including the time of diagnosis, one and three months after intervention (medical or surgical). To avoid diurnal variation, saliva was collected twice (morning and evening). To assess the linear relationship between depression, anxiety, and stress with salivary cortisol, a partial correlation was calculated. Comparison of salivary cortisol levels among control, OC, and OPMD groups showed a statistically significant difference in both morning and evening values at different point of time intervals. Higher values of salivary cortisol were observed in OC patients (both morning and evening) in comparison to the OPMD or control group. A positive correlation was discerned between stress and salivary cortisol in both OPMD and OC patients, while no association was found for depression and anxiety domains. The measurement of salivary cortisol effectively demonstrates raised stress levels in OPMD as well as OC patients. Therefore, it is recommended to institute stress management interventions in the patients as part of the treatment of OPMD and OC.


Stabilisation of tri-valent ions with a vacant coordination site at a corrole-metal interface.
By exploiting an established on-surface metallation strategy, we address the ability of the corrolic macrocycle to stabilise transition metal ions in high-valent (III) oxidation states in metal-supported molecular layers. This approach offers a route to engineer adsorbed metal complexes that cannot be easily fabricated by organic synthesis methods and bear a vacant axial coordination site for catalytic conversions.