Evaluating Both Partner and Patient Satisfaction With Postmastectomy Breast Reconstruction.
Few studies have looked in-depth at the relationship between patient and partner satisfaction with postmastectomy breast reconstruction. The studies that do exist suggest that perceived partner satisfaction is an important predictor of patient satisfaction in postmastectomy breast reconstruction. We created a novel survey designed to look at reconstruction outcomes from a partner's perspective. Patients with a history of mastectomy-alone or mastectomy with reconstruction at our institution from January 2011 through December 2020 were contacted electronically to complete a demographic form and the BREAST-Q, while partners completed our novel partner survey. Sixteen mastectomy-only and 76 mastectomy with reconstruction couples completed surveys. The mean Breast-Q and partner survey scores were 87 and 87 (maximum possible = 100), respectively, for mastectomy with reconstruction. There was a correlation of 0.57 between patient and partner overall satisfaction. There was no difference in overall satisfaction between patients who underwent reconstruction and those who did not (P = 0.19). There was a relationship between satisfaction with preoperative counseling and overall satisfaction in both patients and partners. The partner survey was found to have high internal consistency for measuring various areas of partner satisfaction. There is a relationship between patient and partner satisfaction with postmastectomy breast reconstruction. Our data may support the positive impact of social support on recovery after breast cancer treatment, as satisfaction was high in both groups. We therefore encourage partners to attend and participate in preoperative consultations. Finally, our novel partner survey is a reliable tool to assess partner satisfaction with postmastectomy breast reconstruction.


Management of warfarin anticoagulation in patients with fractured neck of femur.
Background. Most orthopaedic units do not have a policy for reversal of anticoagulation in patients with hip fractures. The aim of this study was to examine the current practice in a district general hospital and determine difference in the time to surgery, if any, with cessation of warfarin versus cessation and treatment with vitamin K. Methods. A retrospective review of the case notes between January 2005 and December 2008 identified 1797 patients with fracture neck of femur. Fifty seven (3.2%) patients were on warfarin at the time of admission. Patients were divided into 2 groups (A and B). Group A patients (16/57; 28%) were treated with cessation of warfarin only and group B patients (41; 72%) received pharmacological therapy in addition to stopping warfarin. Time to surgery between the two groups was compared. Results. The mean INR on admission was 2.9 (range 1.7-6.5) and prior to surgery 1.4 (range 1.0-2.1). Thirty eight patients received vitamin K only and 3 patients received fresh frozen plasma and vitamin K. The average time to surgery was 4.4 days in group A and 2.4 days in group B. The difference was statistically significant (P < .01). Conclusion. Reversal of high INR is important to avoid significant delay in surgery. There is a need for a national policy for reversing warfarin anticoagulation in patients with hip fractures requiring surgery. Vitamin K is safe and effective for anticoagulation reversal in hip fracture patients.


Falling films on flexible inclines.
The nonlinear stability and dynamic behavior of falling fluid films is studied for flow over a flexible substrate. We use asymptotic methods to deduce governing equations valid in various limits. Long-wave theory is used to derive Benney-like coupled equations for the film thickness and substrate deflection. Weakly nonlinear equations are then derived from these equations that, in the limit of large wall damping and/or large wall tension, reduce to the Kuramoto-Sivashinsky equation. These models break down when inertia becomes more significant, so we also use a long-wave approximation in conjunction with integral theory to derive three strongly coupled nonlinear evolution equations for the film thickness, substrate deflection, and film volumetric flow rate valid at higher Reynolds numbers. These equations, accounting for inertia, capillary, viscous, wall tension, and damping effects, are solved over a wide range of parameters. Our results suggest that decreasing wall damping and/or wall tension can promote the development of chaos in the weakly nonlinear regime and lead to severe substrate deformations in the strongly nonlinear regime; these can give rise to situations in which the free surface and underlying substrate come into contact in finite time.


Fitting hearing aids with the Articulation Index: impact on hearing aid effectiveness.
Although most clinical tests focus on how much a particular hearing aid improves speech audibility under controlled conditions, it is unclear how these measures relate to hearing aid effectiveness, or the benefit perceived by the patient under everyday conditions. In this study, the relationship between audibility and hearing aid effectiveness was examined in a cohort of patients who obtained hearing aids through the Veteran's Administration. The measure of audibility was the Articulation Index, a common index of speech audibility. Measures of effectiveness included two hearing-specific surveys and self-reported ratings of global satisfaction and hearing aid use adherence. Results indicated that there were no systematic relationships between measurements of improved audibility and patient ratings of communication ability. Additionally, improved audibility was not related to overall satisfaction with the amplification characteristics of the hearing aid (fitting). However, improved audibility is related to hearing aid use adherence, with patients who achieve better audibility reporting that they use their hearing aids more frequently.


Small and sick newborn care during the COVID-19 pandemic: global survey and thematic analysis of healthcare providers' voices and experiences.
The COVID-19 pandemic is disrupting health systems globally. Maternity care disruptions have been surveyed, but not those related to vulnerable small newborns. We aimed to survey reported disruptions to small and sick newborn care worldwide and undertake thematic analysis of healthcare providers' experiences and proposed mitigation strategies. Using a widely disseminated online survey in three languages, we reached out to neonatal healthcare providers. We collected data on COVID-19 preparedness, effects on health personnel and on newborn care services, including kangaroo mother care (KMC), as well as disruptors and solutions. We analysed 1120 responses from 62 countries, mainly low and middle-income countries (LMICs). Preparedness for COVID-19 was suboptimal in terms of guidelines and availability of personal protective equipment. One-third reported routine testing of all pregnant women, but 13% had no testing capacity at all. More than 85% of health personnel feared for their own health and 89% had increased stress. Newborn care practices were disrupted both due to reduced care-seeking and a compromised workforce. More than half reported that evidence-based interventions such as KMC were discontinued or discouraged. Separation of the mother-baby dyad was reported for both COVID-positive mothers (50%) and those with unknown status (16%). Follow-up care was disrupted primarily due to families' fear of visiting hospitals (~73%). Newborn care providers are stressed and there is lack clarity and guidelines regarding care of small newborns during the pandemic. There is an urgent need to protect life-saving interventions, such as KMC, threatened by the pandemic, and to be ready to recover and build back better.


Nosocomial influenza: new concepts and practice.
Nosocomial influenza constitutes a serious risk among patients with underlying diseases and those of extreme age, and is associated with excess health-care costs. This article will review recent literature on this area. Despite longstanding recommendations and the fact that influenza vaccination of health-care workers improves patient and employee safety, vaccine coverage among health-care workers remains low worldwide. The Centers for Disease Prevention and Control recommends the use of signed declination forms for those health-care workers who refuse vaccination. Rapid antigen detection tests may accurately diagnose influenza at the point of care, and their use has been associated with reduced antibiotic use, diagnostic tests, and costs. Multiplex molecular methods may simultaneously detect several respiratory viruses and might prove advantageous for surveillance within hospitals. The beginning of the 2007-2008 influenza season was marked by the detection of a significant proportion of influenza A/H1N1 viruses resistant to oseltamivir in Europe. Given the prohibiting rates of resistance to adamantanes worldwide, our means for containing outbreaks within health-care facilities may narrow. Provision of influenza vaccine at no cost and at the work site, education to promote vaccination, and switch to a mandatory influenza vaccination policy should be implemented in order to achieve high and sustained vaccine coverage among health-care workers. Surveillance to monitor antiviral resistance in influenza viruses should be enhanced. Development of new antivirals is needed.


Cardiac tissue inhibitor of matrix metalloprotease 4 dictates cardiomyocyte contractility and differentiation of embryonic stem cells into cardiomyocytes: Road to therapy.
TIMP4 (Tissue Inhibitors of Matrix Metalloprotease 4), goes down in failing hearts and mice lacking TIMP4 show poor regeneration capacity after myocardial infarction (MI). This study is based on our previous observation that administration of cardiac inhibitor of metalloproteinase (~TIMP4) attenuates oxidative stress and remodeling in failing hearts. Therefore, we hypothesize that TIMP4 helps in cardiac regeneration by augmenting contractility and inducing the differentiation of cardiac progenitor cells into cardiomyocytes. To validate this hypothesis, we transfected mouse cardiomyocytes with TIMP4 and TIMP4-siRNA and performed contractility studies in the TIMP4 transfected cardiomyocytes as compared to siRNA-TIMP4 transfected cardiomyocytes. We evaluated the calcium channel gene serca2a (sarcoplasmic reticulum calcium ATPase2a) and mir122a which tightly regulates serca2a to explain the changes in contractility. We treated mouse embryonic stem cells with cardiac extract and cardiac extract minus TIMP4 (using TIMP4 monoclonal antibody) to examine the effect of TIMP4 on differentiation of cardiac progenitor cells. Contractility was augmented in the TIMP4 transfected cardiomyocytes as compared to siRNA-TIMP4 transfected cardiomyocytes. There was elevated expression of serca2a in the TIMP4 transformed myocytes and down regulation of mir122a. The cells treated with cardiac extract containing TIMP4 showed cardiac phenotype in terms of Ckit+, GATA4+ and Nkx2.5 expression. This is a novel report suggesting that TIMP4 augments contractility and induces differentiation of progenitor cells into cardiac phenotype. In view of the failure of MMP9 inhibitors for cardiac therapy, TIMP4 provides an alternative approach, being an indigenous molecule and a natural inhibitor of MMP9.


Clinical and laboratory characteristics of adolescents with platelet function disorders and heavy menstrual bleeding.
Platelet function disorders (PFDs) have emerged as an important etiology of heavy menstrual bleeding (HMB) in adolescents. However, neither clinical nor laboratory data have been methodically analyzed in this population subset. The objective of this study was to evaluate these parameters in order to distinguish characteristics of the disorder that in turn will lead to earlier diagnosis and therapy initiation. Retrospective review of medical records from postmenarcheal adolescents with documented PFDs referred to a hemophilia treatment center and university faculty practices for bleeding diatheses with their clinical and laboratory data evaluated. Of 63 teens with documented PFDs, HMB was the most common clinical manifestation of PFD (43; 68.3%). Of these, 37 (86%) were diagnosed with PFD either at or after menarche with the diagnosis based on HMB symptoms alone. Only 6 (14%) were diagnosed with a PFD prior to menarche, based on associated bleeding, i.e., epistaxis, ecchymosis, and all developed HMB after menstruation onset. Interestingly, 20 girls were diagnosed with a PFD prior to menarche and of these, only 6 (30%) went on to develop HMB after pubertal transition, while the majority (14; 70%) did not. The average age-at-PFD diagnosis was 14.5yrs, significantly differing from the 10.9yrs average age-at-PFD diagnosis in their counterparts that, after menarche, did not develop HMB (P<.01) Blood type O occurred significantly more frequently (76%) than national norms (P <.037). Incidence of δ-Storage Pool deficiency (δ-SPD) was significantly higher (74%) than their non-HMB cohorts (45%) (P <.007). Coagulation and von Willebrand factor studies were all normal. Abnormal closure times and aggregation studies were observed in 42% and 60%, respectively, of tested girls. In 25.6% for whom standard platelet studies were normal, electron microscopy detected reduced platelet δ-granules numbers (δ-SPD). Adolescents with PFDs and HMB appear to be clinically distinct from their non-HMB counterparts. This group of girls is characterized by HMB the major bleeding symptom, significantly high incidences of blood group O and the δ-SPD with a PFD diagnosed well after menarche. High false negative standard platelet function study results indicate additional diagnostic strategies, particularly for δ-SPD, should be considered.


Genetic and environmental contributions to the association between ADHD and affective problems in early childhood-A Swedish population-based twin study.
Few twin studies have explored the relative contribution of genetic and environmental factors to the association between attention deficit hyperactivity disorder (ADHD) and affective problems, and no study has focused on preschool children. We used the classical twin design to explore the genetic and environmental overlap between ADHD symptoms and affective problems in preschool children, based on 879 five-year-old twin pairs born in Sweden 2004-2005. Questionnaire-based parent-ratings were used to measure ADHD symptoms and affective problems. A bivariate twin design was used to decompose variance in ADHD and affective problems into genetic and environmental components, and to test the degree to which these components overlapped across the two traits. Our results showed that there was a significant correlation of 0.34 (95% Confidence Interval [CI] 0.29-0.38) between ADHD and affective problems. This correlation was mostly explained by additive genetic factors (64%, 95%CI 37-93%), and to a lesser extent by shared environmental factors (35%, 95%CI 10-59%). Nonshared environmental factors did not contribute to the correlation between ADHD and affective problems (0%, 95%CI -9 to 10%). These findings show that there is a significant association between ADHD and affective problems in preschool children that is mostly explained by genetic influences. This adds important knowledge about the etiology of both ADHD and affective problems by indicating that these phenotypes are linked from as early as preschool years. This also needs to be taken into consideration when diagnosing young children and clinicians should consider assessing both affective problems and ADHD if one is present.


Heterosexual transmission of HIV-1 associated with the use of smokable freebase cocaine (crack).
A study of risk factors for HIV-1 infection was conducted at a sexually transmitted disease clinic in an area of New York City where the cumulative incidence of AIDS in adults through mid-1990 was 9.1 per 1000 of the population and where the use of illicit drugs, including smokable freebase cocaine (crack), is common. The overall seroprevalence among volunteers was 12% (369 out of 3084), with 80% of those who were seropositive reporting risk behavior associated with HIV-1 infection, including male-to-male sexual contact, intravenous drug use and heterosexual contact with an intravenous drug user. The seroprevalence in individuals denying these risks was 3.6% (50 out of 1389) and 4.2% (22 out of 522) in men and women, respectively. Among these individuals, the behaviors significantly associated with infection were use of crack and prostitution in women, and history of syphilis and crack use in men. These results suggest that in areas where the level of HIV-1 infection in heterosexual intravenous drug users is high and the use of crack is common, increased sexual activity (including the exchange of drugs or money for sex) may result in increased heterosexual transmission of HIV-1.


Pimecrolimus 1% cream for anogenital lichen sclerosus in childhood.
Lichen sclerosus is a chronic inflammatory disease with a predilection of the anogenital region. Because of the potential side effects of repeated local application of potent glucocorticosteroids, equally-effective, safer therapeutic options are required, especially in the treatment of children. We report on the efficacy of twice-daily application of pimecrolimus 1% cream in four prepubertal girls (range of age: 4 to 9 years) who suffered from anogenital lichen sclerosus. After three to four-month treatment, all patients had almost complete clinical remission including relief from itch, pain and inflammation. Only minor improvement was observed for the white sclerotic lesions. No significant side effects have been observed. Topical pimecrolimus appears to be an effective and safe treatment for children with anogenital lichen sclerosus. The clinical benefits observed in the four patient presented particularly include relief of pruritus, pain and inflammation. Vehicle-controlled studies on a larger number of patients are now warranted to substantiate our promising findings, and to investigate long-term efficacy and safety of topical pimecrolimus in anogenital lichen sclerosus.


Simple sequence repeat marker development and genetic mapping in quinoa (Chenopodium quinoa Willd.).
Quinoa is a regionally important grain crop in the Andean region of South America. Recently quinoa has gained international attention for its high nutritional value and tolerances of extreme abiotic stresses. DNA markers and linkage maps are important tools for germplasm conservation and crop improvement programmes. Here we report the development of 216 new polymorphic SSR (simple sequence repeats) markers from libraries enriched for GA, CAA and AAT repeats, as well as 6 SSR markers developed from bacterial artificial chromosome-end sequences (BES-SSRs). Heterozygosity (H) values of the SSR markers ranges from 0.12 to 0.90, with an average value of 0.57. A linkage map was constructed for a newly developed recombinant inbred lines (RIL) population using these SSR markers. Additional markers, including amplified fragment length polymorphisms (AFLPs), two 11S seed storage protein loci, and the nucleolar organizing region (NOR), were also placed on the linkage map. The linkage map presented here is the first SSR-based map in quinoa and contains 275 markers, including 200 SSR. The map consists of 38 linkage groups (LGs) covering 913 cM. Segregation distortion was observed in the mapping population for several marker loci, indicating possible chromosomal regions associated with selection or gametophytic lethality. As this map is based primarily on simple and easily-transferable SSR markers, it will be particularly valuable for research in laboratories in Andean regions of South America.


Application of the navigation guide systematic review methodology to evaluate prenatal exposure to particulate matter air pollution and infant birth weight.
Low birth weight is an important risk factor for many co-morbidities both in early life as well as in adulthood. Numerous studies report associations between prenatal exposure to particulate matter (PM) air pollution and low birth weight. Previous systematic reviews and meta-analyses report varying effect sizes and significant heterogeneity between studies, but did not systematically evaluate the quality of individual studies or the overall body of evidence. We conducted a new systematic review to determine how prenatal exposure to PM2.5, PM10, and coarse PM (PM2.5-10) by trimester and across pregnancy affects infant birth weight. Using the Navigation Guide methodology, we developed and applied a systematic review protocol [CRD42017058805] that included a comprehensive search of the epidemiological literature, risk of bias (ROB) determination, meta-analysis, and evidence evaluation, all using pre-established criteria. In total, 53 studies met our inclusion criteria, which included evaluation of birth weight as a continuous variable. For PM2.5 and PM10, we restricted meta-analyses to studies determined overall as "low" or "probably low" ROB; none of the studies evaluating coarse PM were rated as "low" or "probably low" risk of bias, so all studies were used. For PM2.5, we observed that for every 10 µg/m3 increase in exposure to PM2.5 in the 2nd or 3rd trimester, respectively, there was an associated 5.69 g decrease (I2: 68%, 95% CI: -10.58, -0.79) or 10.67 g decrease in birth weight (I2: 84%, 95% CI: -20.91, -0.43). Over the entire pregnancy, for every 10 µg/m3 increase in PM2.5 exposure, there was an associated 27.55 g decrease in birth weight (I2: 94%, 95% CI: -48.45, -6.65). However, the quality of evidence for PM2.5 was rated as "low" due to imprecision and/or unexplained heterogeneity among different studies. For PM10, we observed that for every 10 µg/m3 increase in exposure in the 3rd trimester or the entire pregnancy, there was a 6.57 g decrease (I2: 0%, 95% CI: -10.66, -2.48) or 8.65 g decrease in birth weight (I2: 84%, 95% CI: -16.83, -0.48), respectively. The quality of evidence for PM10 was rated as "moderate," as heterogeneity was either absent or could be explained. The quality of evidence for coarse PM was rated as very low/low (for risk of bias and imprecision). Overall, while evidence for PM2.5 and course PM was inadequate primarily due to heterogeneity and risk of bias, respectively, our results support the existence of an inverse association between prenatal PM10 exposure and low birth weight.


The binding of cationic detergent to insulin, zinc-insulin and iso-insulin.
Insulin, zinc-insulin and iso-insulin were precipitated by cetyltrimethylammonium bromide when the detergent/protein molar ratio was less than 10:1, whereas no precipitation was observed at ratios greater than 10:1. It is concluded that the detergent binds as a dimer at each binding site at ratios greater than 10:1. U.v. difference spectra indicated that the tyrosine residues were perturbed by detergent binding.


Transient thermal conductivity and colloidal stability measurements of nanofluids by using the 3omega method.
Nanofluid is a mixture of nanoscale particles of metal, metal oxide or carbon nanotube and heat transfer fluids such as water and ethylene glycol. This work presents the application of the 3-omega (3omega) method for measuring the colloidal stability and the transient thermal conductivity of multi-wall carbon nanotube (MWCNT), Al2O3 and TiO2 nanoparticles suspended in water or ethylene glycol. The microfabricated 3omega device is verified by comparing the measured thermal conductivities of pure fluids with the table values. After the validation, the transient thermal responses of the nanofluids are measured to evaluate the colloidal stability. All of Al2O3 nanofluid samples show a clear sign of sedimentation while the acid-treated MWCNT (tMWCNT) nanofluid and a couple of TiO2 nanofluids with pH control or surfactant addition are found to have excellent colloidal stability. The thermal conductivities of tMWCNT nanofluids in the de-ionized water and ethylene glycol are measured, which are found to be in good agreement with previous data.


Association of Patient Age With Progression of Low-risk Papillary Thyroid Carcinoma Under Active Surveillance: A Systematic Review and Meta-analysis.
Active surveillance is sometimes considered as a disease management option for individuals with small, low-risk papillary thyroid carcinoma. To assess whether patient age is associated with progression of low-risk papillary thyroid carcinoma (tumor growth or incident metastatic disease) in adults under active surveillance. Eight electronic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Emcare, PsycINFO, Web of Science, and ClincalTrials.gov) were searched from inception to March 2019, supplemented with a hand search. Two investigators independently screened citations, reviewed full-text articles, and abstracted data. Additional data were sought from authors. Random-effects meta-analyses were performed using incidence data (statistically adjusted for confounders and crude rates). A total of 1658 unique citations were screened, and 62 full-text articles were reviewed, including 5 studies. Three studies included exclusively microcarcinomas and 2 included tumors up to 2 cm in maximal diameter. The mean age of participants was 51.0 to 55.2 years in 4 studies reporting this value. The mean or median follow-up was 5 years or more in 3 studies and approximately 2 years in 2 studies. The pooled risk ratio for tumor growth of 3 mm or more in maximal diameter in individuals aged 40 to 50 years compared with younger individuals was 0.51 when adjusted for confounders (95% CI, 0.29-0.89; 1619 patients, 2 studies), and the unadjusted risk ratio of this outcome for individuals 40 years or older was 0.55 (95% CI, 0.36-0.82; 2097 patients, 4 studies). In adults aged 40 to 45 years, the unadjusted risk ratio for any tumor volume increase compared with younger individuals was 0.65 (95% CI, 0.51-0.83; 1232 patients, 4 studies). The pooled risk ratio for incident nodal metastases in individuals 40 years or older was 0.22 (95% CI, 0.10-0.47; 1806 patients, 3 studies); however, in a secondary analysis, the risk difference was not significantly different. There was no statistically significant heterogeneity in any of the meta-analyses. There were no thyroid cancer-related deaths nor incident distant metastases. This study suggests that older age may be associated with a reduced risk of primary papillary thyroid carcinoma tumor growth under active surveillance. Incident metastatic disease is uncommon during active surveillance.


Longitudinal performance of a vestibular prosthesis as assessed by electrically evoked compound action potential recording.
Electrical stimulation of the vestibular end organ with a vestibular prosthesis may provide an effective treatment for vestibular loss if the stimulation remains effective over a significant period of time after implantation of the device. To assess efficacy of electrical stimulation in an animal model, we implanted 3 rhesus monkeys with a vestibular prosthesis based on a cochlear implant. We then recorded vestibular electrically evoked compound action potentials (vECAPs) longitudinally in each of the implanted canals to see how the amplitude of the response changed over time. The results suggest that vECAPs, and therefore electrical activation of vestibular afferent fibers, can remain largely stable over time following implantation.


A novel endonuclease that may be responsible for damaged DNA base repair in Pyrococcus furiosus.
DNA is constantly damaged by endogenous and environmental influences. Deaminated adenine (hypoxanthine) tends to pair with cytosine and leads to the A:T→G:C transition mutation during DNA replication. Endonuclease V (EndoV) hydrolyzes the second phosphodiester bond 3' from deoxyinosine in the DNA strand, and was considered to be responsible for hypoxanthine excision repair. However, the downstream pathway after EndoV cleavage remained unclear. The activity to cleave the phosphodiester bond 5' from deoxyinosine was detected in a Pyrococcus furiosus cell extract. The protein encoded by PF1551, obtained from the mass spectrometry analysis of the purified fraction, exhibited the corresponding cleavage activity. A putative homolog from Thermococcus kodakarensis (TK0887) showed the same activity. Further biochemical analyses revealed that the purified PF1551 and TK0887 proteins recognize uracil, xanthine and the AP site, in addition to hypoxanthine. We named this endonuclease Endonuclease Q (EndoQ), as it may be involved in damaged base repair in the Thermococcals of Archaea.


Providing Health Sciences Services in a Joint-Use Distributed Learning Library System: An Organizational Case Study.
The purpose of this organizational case study is to describe the complexities librarians face when serving a multi-campus institution that supports both a joint-use library and expanding health sciences academic partnerships. In a system without a centralized health science library administration, liaison librarians are identifying dispersed programs and user groups and collaborating to define their unique service and outreach needs within a larger land-grant university. Using a team-based approach, health sciences librarians are communicating to integrate research and teaching support, systems differences across dispersed campuses, and future needs of a new community-based medical program.


Clinical Application of a Graphene Oxide-Based Surface Plasmon Resonance Biosensor to Measure First-Trimester Serum Pregnancy-Associated Plasma Protein-A/A2 Ratio to Predict Preeclampsia.
Preeclampsia, a major cause of adverse pregnancy outcomes, involves metalloproteinases pregnancy-associated plasma protein (PAPP)-A and PAPP-A2 from placental trophoblasts. The graphene oxide (GO)-based surface plasmon resonance (SPR) biosensor has higher sensitivity, affinity, and selective ability than the traditional SPR biosensor. The aim of this study was to explore the feasibility of measuring first-trimester serum PAPP-A/PAPP-A2 ratio as a novel predictor of preeclampsia using the GO-SPR biosensor. This prospective case-control study of pregnant women was conducted at MacKay Memorial Hospital, Taipei, Taiwan between January 2018 and June 2020. The SPR angle shifts of first-trimester serum PAPP-A, PAPP-A2, and PAPP-A/PAPP-A2 ratio measured using the GO-SPR biosensor were compared between preeclampsia and control groups. Serum samples from 185 pregnant women were collected, of whom 30 had preeclampsia (5 early-onset; 25 late-onset). The response time between the antibody-antigen association and dissociation only took about 200 seconds. The SPR angle shift of PAPP-A in the preeclampsia group was significantly smaller than that in the control group (median (interquartile range): 5.33 (4.55) versus 6.89 (4.10) millidegrees (mDeg), P = 0.008). Conversely, the SPR angle shift of PAPP-A2 in the preeclampsia group was significantly larger than that in the control group (5.70 (3.81) versus 3.63 (2.38) mDeg, P < 0.001). Receiver operating characteristic (ROC) curve analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict all preeclampsia of ≤ 0.76, with an area under the ROC curve (AUC) of 0.79 (95% CI 0.73-0.85, P < 0.001). Sub-group analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict early-onset preeclampsia of ≤ 0.53 (AUC 0.99, 95% CI 0.96-1.00, P < 0.001), and ≤ 0.73 to predict late-onset preeclampsia (AUC 0.75, 95% CI 0.68-0.81, P < 0.001). Measuring first-trimester serum PAPP-A/PAPP-A2 ratio using the GO-SPR biosensor could be a valuable method for early prediction of preeclampsia.


Sexual Functioning and Opioid Maintenance Treatment in Women. Results From a Large Multicentre Study.
Opioid maintenance treatment (OMT) is the most widespread therapy for both females and males opioid addicts. While many studies have evaluated the OMT impact on men's sexuality, the data collected about the change in women's sexual functioning is still limited despite the fact that it is now well-known that opioids - both endogenous and exogenous - affect the endocrine system and play an important role in sexual functioning. The present study aims to determine how OMT with buprenorphine (BUP) or methadone (MTD) affects sexual health in women; examining also any possible emerging correlation between sexual dysfunction (SD), type of opioid and patients' mental health. This multi-center study case recruited 258 female volunteers attending Italian public Addiction Outpatients Centers that were stabilized with OMT for at least 3 months. SD was assessed with the Arizona Sexual Experience Scale. The twelve-item General Health Questionnaire was used to assess participants' mental health conditions. The results show that 56.6% of women receiving OMT for at least 3 months presented SD without significant differences between MTD e BUP groups. The majority of the subjects with SD have a poorer quality of intimate relationships and worse mental health than the average. To the best of our knowledge, the present study is the largest report on the presence of SDs in women as a side effects of MTD and BUP used in OMT. Since SDs cause difficulties in intimate relationships, lower patients' quality of life and interfere with OMT beneficial outcomes, we recommend that women undertaking an opioid therapy have routine screening for SD and we highlight the importance to better examine opioid-endocrine interactions in future studies in order to provide alternative potential treatments such as the choice of opioid, opioid dose reduction and hormone supplementation.


Effect of Omega-3 Supplementation on Lipocalin 2 and Retinol-Binding Protein 4 in Type 2 Diabetic Patients.
Serum levels of lipocalin 2 (LCN 2) and retinol-binding protein-4 (RBP 4), increase in type 2 diabetes mellitus (T2DM). We sought to determine whether serum LCN 2 and RBP 4 change after an intervention with omega-3 fatty acids supplementation in diabetic patients. Forty-five type 2 diabetic patients from Iranian Diabetic Association in Tehran, Iran in 2013 were randomly recruited into two groups: one group received 4 g/d omega-3 for 10 wk; and the control group received placebo. Blood samples, food intake records, anthropometric measurements were obtained from all participants at the beginning and end of the study. Fasting RBP 4 plasma levels significantly changed after 10 wk supplementation (P = 0.01). The LCN 2 concentrations decreased in omega-3 group, but the changes were not statistically significant. Omega-3 supplementation had no noticeable effect on anthropometric factors. These findings provide a rationale for omega-3 supplements aimed at lowering serum RBP 4 levels in T2DM.


Glomus tumor of the thenar eminence in neurofibromatosis type 1: case report and literature review.
Neurofibromatosis type 1 (NF1) is a disease characterized by increased tumorigenesis susceptibility, caused by mutations of the oncosuppressor gene NF1. The glomus tumor (GT) is a rare, very painful mesenchymal neoplasm, arising from the glomus body. In recent years, it has been highlighted the association between NF1 and GT. We report a case of a man aged 65 years, suffering from NF1, with intense pain at the thenar eminence of the right hand, successfully treated with the excision of the mass.


Evaluation of the role of two conserved active-site residues in beta class glutathione S-transferases.
Glutathione S-transferases (GSTs) normally use hydroxy-group-containing residues in the N-terminal domain of the enzyme for stabilizing the activated form of the co-substrate, glutathione. However, previous mutagenesis studies have shown that this is not true for Beta class GSTs and thus the origin of the stabilization remains a mystery. The recently determined crystal structure of Proteus mirabilis GST B1-1 (PmGST B1-1) suggested that the stabilizing role might be fulfilled in Beta class GSTs by one or more residues in the C-terminal domain of the enzyme. To test this hypothesis we mutated His(106) and Lys(107) of PmGST B1-1 to investigate their possible role in the enzyme's catalytic activity. His(106) was mutated to Ala, Asn and Phe, and Lys(107) to Ala and Arg. The effects of the replacement on the activity, thermal stability and antibiotic-binding capacity of the enzyme were examined. The results are consistent with the involvement of His(106) and Lys(107) in interacting with glutathione at the active site but these residues do not contribute significantly to catalysis, folding or antibiotic binding.


Multiuse trail intersection safety analysis: A crowdsourced data perspective.
Real and perceived concerns about cycling safety are a barrier to increased ridership in many cities. Many people prefer to bike on facilities separated from motor vehicles, such as multiuse trails. However, due to underreporting, cities lack data on bike collisions, especially along greenways and multiuse paths. We used a crowdsourced cycling incident dataset (2005-2016) from BikeMaps.org for the Capital Regional District (CRD), BC, Canada. Our goal was to identify design characteristics associated with unsafe intersections between multiuse trails and roads. 92.8% of mapped incidents occurred between 2014 and 2016. We extracted both collision and near miss incidents at intersections from BikeMaps.org. We conducted site observations at 32 intersections where a major multiuse trail intersected with roads. We compared attributes of reported incidents at multiuse trail-road intersections to those at road-road intersections. We then used negative binomial regression to model the relationship between the number of incidents and the infrastructure characteristics at multiuse trail-road intersections. We found a higher proportion of collisions (38%, or 17/45 total reports) at multiuse trail-road intersections compared to road-road intersections (23%, or 62/268 total reports). A higher proportion of incidents resulted in an injury at multiuse trail-road intersections compared to road-road intersections (33% versus 15%). Cycling volumes, vehicle volumes, and trail sight distance were all associated with incident frequency at multiuse trail-road intersections. Supplementing traditional crash records with crowdsourced cycling incident data provides valuable evidence on cycling safety at intersections between multiuse trails and roads, and more generally, when conflicts occur between diverse transportation modes.


Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling.
Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.


[Clinico-immunological and bronchological characteristics of the late onset asthma].
Clinicoimmunological and bronchological examination was performed in 452 patients with bronchial asthma (BA) which were divided into two groups: 286 patients with late BA (onset at the age of 40 and older) and 166 patients with BA onset at the age under 40. Late BA develops because of non-allergic factors, especially persistent bronchopulmonary infection. Bad pulmonary background contributes to development of rapidly progressing respiratory obstruction with irreversible component. Cytological tests of the bronchoalveolar lavage revealed subnormal cytosis and viability of the cells, high counts of eosinophils and neutrophils, cells of bronchial epithelium with signs of dystrophy, low count of alveolar macrophages. Immunological tests in late BA patients evidence for suppression of local bronchopulmonary defense, low levels of both T-helper and T-suppressor cells, deficiency of C3 and C4, high serum IgG. The above changes are determined for the most part by immunosuppression induced by concomitant and past respiratory diseases.


HISTOPATHOLOGIC FINDINGS IN FREE-RANGING CALIFORNIA HUMMINGBIRDS, 1996-2017.
A histopathologic study of free-ranging hummingbirds found in California, US was performed to identify mortality trends. Tissues from 61 wild hummingbirds representing five native California species collected by the San Diego Zoo from 1996 to 2016 or the Lindsay Wildlife Experience from 2015 to 2017 were histologically examined. Birds were either found dead or moribund at the time of submission or were euthanized due to unresolvable health issues. Long-term rehabilitated birds were excluded from this study. Lesions were sorted by organ, etiology, and gender. The most commonly affected organs were the lung (68%, 40/59), followed by the ingluvies (67%, 34/51) and the liver (54%, 33/61). While some birds had minimal or nonspecific lesions, 23% (14/61) had lesions primarily attributable to trauma, 16% (10/61) had lesions associated with bacteria, fungi, or viruses, 11% (7/61) had parasitic lesions, and 13% (8/61) had multifactorial concurrent processes. Infectious disease lesions included those associated with avian poxvirus, intestinal adenovirus, disseminated aspergillosis, bacterial septicemia, malaria ( Haemoproteus spp.), and mycobacteriosis. The most commonly identified parasitic infection was intestinal cestodiasis, for which there was no significant associated intestinal damage, although the large size of these cestodes may have affected digestion. The incidence of traumatic lesions did not vary significantly by sex, age, species, or sampling location. Other significant findings not related to disease or trauma, but not previously documented, were histologic evidence of a gallbladder and the presence of aortic ossification. Our study reported mortality trends at a population level for free-ranging hummingbirds found in California and identified the presence of intestinal adenovirus and two anatomic structures not previously described.


High frequency atomic tunneling yields ultralow and glass-like thermal conductivity in chalcogenide single crystals.
Crystalline solids exhibiting glass-like thermal conductivity have attracted substantial attention both for fundamental interest and applications such as thermoelectrics. In most crystals, the competition of phonon scattering by anharmonic interactions and crystalline imperfections leads to a non-monotonic trend of thermal conductivity with temperature. Defect-free crystals that exhibit the glassy trend of low thermal conductivity with a monotonic increase with temperature are desirable because they are intrinsically thermally insulating while retaining useful properties of perfect crystals. However, this behavior is rare, and its microscopic origin remains unclear. Here, we report the observation of ultralow and glass-like thermal conductivity in a hexagonal perovskite chalcogenide single crystal, BaTiS3, despite its highly symmetric and simple primitive cell. Elastic and inelastic scattering measurements reveal the quantum mechanical origin of this unusual trend. A two-level atomic tunneling system exists in a shallow double-well potential of the Ti atom and is of sufficiently high frequency to scatter heat-carrying phonons up to room temperature. While atomic tunneling has been invoked to explain the low-temperature thermal conductivity of solids for decades, our study establishes the presence of sub-THz frequency tunneling systems even in high-quality, electrically insulating single crystals, leading to anomalous transport properties well above cryogenic temperatures.


Health of vermiculite miners exposed to trace amounts of fibrous tremolite.
A small cohort of 194 men with low exposure to fibrous tremolite (mean 0.75 f/ml y) in the mining and milling of vermiculite in South Carolina experienced 51 deaths 15 years or more from first employment. The SMR (all causes) was 1.17 reflecting excess deaths from circulatory disease. There were four deaths from lung cancer and 3.31 expected (SMR 1.21, 95% CI 0.33-3.09). Three of the four deaths were in the lowest exposure category (less than 1 f/ml y); no death was attributed to mesothelioma or pneumoconiosis. These findings contrast with those in Montana where the vermiculite ore was heavily contaminated with fibrous tremolite. A radiographic survey of 86 current and recent South Carolina employees found four with small parenchymal opacities (greater than or equal to 1/0) and seven with pleural thickening. These proportions were not higher than in a non-exposed group and much lower than had been observed in Montana. Examination of sputum from 76 current employees showed that only two specimens contained typical ferruginous bodies, confirming low cumulative fibre exposure. Any possible adverse effects of work with vermiculite, minimally contaminated with fibrous or non-fibrous tremolite, were thus beyond the limits of detection in this workforce.


Drivers of Vaginal Drug Delivery System Acceptability from Internet-Based Conjoint Analysis.
Vaginal microbicides potentially empower women to protect themselves from HIV and other sexually transmitted infections (STIs), especially when culture, religion, or social status may prevent them from negotiating condom use. The open literature contains minimal information on factors that drive user acceptability of women's health products or vaginal drug delivery systems. By understanding what women find to be most important with regard to sensory properties and product functionality, developers can iteratively formulate a more desirable product. Conjoint analysis is a technique widely used in market research to determine what combination of elements influence a consumer's willingness to try or use a product. We applied conjoint analysis here to better understand what sexually-active woman want in a microbicide, toward our goal of formulating a product that is highly acceptable to women. Both sensory and non-sensory attributes were tested, including shape, color, wait time, partner awareness, messiness/leakage, duration of protection, and functionality. Heterosexually active women between 18 and 35 years of age in the United States (n = 302) completed an anonymous online conjoint survey using IdeaMap software. Attributes (product elements) were systematically presented in various combinations; women rated these combinations of a 9-point willingness-to-try scale. By coupling systematic combinations and regression modeling, we can estimate the unique appeal of each element. In this population, a multifunctional product (i.e., broad spectrum STI protection, coupled with conception) is far more desirable than a microbicide targeted solely for HIV protection; we also found partner awareness and leakage are potentially strong barriers to use.


Detection based on rainbow refractometry of droplet sphericity in liquid-liquid systems.
The shape of droplets in liquid-liquid systems influences their mass and momentum transfer processes. The deviation from sphericity of rising droplets in liquid-liquid systems was investigated for different droplet sizes. Rainbow refractometry permits one to test, in this case, whether the use of laser-optical particle sizing will be correct or faulty. Since the assumption of spherical particle geometry is a general basis of laser-optical particle-sizing techniques such as rainbow refractometry or phase Doppler anemometry, deviation from the spherical shape results in a measuring error. A sphericity check based on rainbow refractometry is introduced.


Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma.
Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly acquire resistance and present with enhanced tumor progression and invasion, demanding alternative treatment options. We show 2nd generation hexameric TRAIL-receptor-agonist IZI1551 (IZI) to effectively induce apoptosis in MM cells irrespective of the intrinsic BRAF/NRAS mutation status. Conditioning to the EC50 dose of IZI converted the phenotype of IZI-sensitive parental MM cells into a fast proliferating and invasive, IZI-resistant metastasis. Mechanistically, we identified focal adhesion kinase (FAK) to play a dual role in phenotype-switching. In the cytosol, activated FAK triggers survival pathways in a PI3K- and MAPK-dependent manner. In the nucleus, the FERM domain of FAK prevents activation of wtp53, as being expressed in the majority of MM, and consequently intrinsic apoptosis. Caspase-8-mediated cleavage of FAK as well as FAK knockdown, and pharmacological inhibition, respectively, reverted the metastatic phenotype-switch and restored IZI responsiveness. FAK inhibition also re-sensitized MM cells isolated from patient metastasis that had relapsed from targeted kinase inhibition to cell death, irrespective of the intrinsic BRAF/NRAS mutation status. Hence, FAK-inhibition alone or in combination with 2nd generation TRAIL-receptor agonists may be recommended for treatment of initially resistant and relapsed MM, respectively.


Peripheral nerve regeneration and NGF-dependent neurite outgrowth of adult sensory neurons converge on STAT3 phosphorylation downstream of neuropoietic cytokine receptor gp130.
After nerve injury, adult sensory neurons can regenerate peripheral axons and reconnect with their target tissue. Initiation of outgrowth, as well as elongation of neurites over long distances, depends on the signaling of receptors for neurotrophic growth factors. Here, we investigated the importance of gp130, the signaling subunit of neuropoietic cytokine receptors in peripheral nerve regeneration. After sciatic nerve crush, functional recovery in vivo was retarded in SNS-gp130(-/-) mice, which specifically lack gp130 in sensory neurons. Correspondingly, a significantly reduced number of free nerve endings was detected in glabrous skin from SNS-gp130(-/-) compared with control mice after nerve crush. Neurite outgrowth and STAT3 activation in vitro were severely reduced in cultures in gp130-deficient cultured neurons. Surprisingly, in neurons obtained from SNS-gp130(-/-) mice the increase in neurite length was reduced not only in response to neuropoietic cytokine ligands of gp130 but also to nerve growth factor (NGF), which does not bind to gp130-containing receptors. Neurite outgrowth in the absence of neurotrophic factors was partially rescued in gp130-deficient neurons by leptin, which activates STAT3 downstream of leptic receptor and independent of gp130. The neurite outgrowth response of gp130-deficient neurons to NGF was fully restored in the presence of leptin. Based on these findings, gp130 signaling via STAT3 activation is suggested not only to be an important regulator of peripheral nerve regeneration in vitro and in vivo, but as determining factor for the growth promoting action of NGF in adult sensory neurons.


MAPL1: q-space reconstruction using ℓ1 -regularized mean apparent propagator.
To improve the quality of mean apparent propagator (MAP) reconstruction from a limited number of q-space samples. We implement an ℓ1 -regularised MAP (MAPL1) to consider higher order basis functions and to improve the fit without increasing the number of q-space samples. We compare MAPL1 with the least-squares optimization subject to non-negativity (MAP), and the Laplacian-regularized MAP (MAPL). We use simulations of crossing fibers and compute the normalized mean squared error (NMSE) and the Pearson's correlation coefficient to evaluate the reconstruction quality in q-space. We also compare coefficient-based diffusion indices in the simulations and in in vivo data. Results indicate that MAPL1 improves NMSE in 1 to 3% when compared to MAP or MAPL in a high undersampling regime. Additionally, MAPL1 produces more reproducible and accurate results for all sampling rates when there are enough basis functions to meet the sparsity criterion for the regularizer. These improved reconstructions also produce better coefficient-based diffusion indices for in vivo data. Adding an ℓ1 regularizer to MAP allows the use of more basis functions and a better fit without increasing the number of q-space samples. The impact of our research is that a complete diffusion spectrum can be reconstructed from an acquisition time very similar to a diffusion tensor imaging protocol.


Development of an Assessment Method for Building Materials Under Euratom Scope.
In 2013, the European Commission published its basic safety standards for protection against the dangers arising from exposure to ionizing radiation (Council Directive 2013/59/Euratom)-also known as EU-BSS. As a result, the use of raw materials with potentially elevated activity concentrations such as fly ash, phosphogypsum, and slags will now fall under EU-BSS scope when applied in building materials. In light of this new policy, a variety of tools are available to assess compliance with the 1-mSv y reference level for building materials. At the heart of these tools is a gamma-spectrometric determination of the naturally occurring radionuclides Ra, Th, and K in the material of concern. As a large number of construction products contain a certain amount of the raw material that falls under the scope of the EU regulation, this policy will lead to substantial measurement of building materials that pose little radiation risk. For this reason, a method is developed to enable assessment against the 1-mSv value not on the basis of gamma-spectrometric analysis but rather based on the product's material composition. The proposed method prescribes a maximum permitted content of raw materials with potentially elevated activity concentrations in terms of a weight percentage of the end product, where the raw materials of concern are defined as those listed in Annex XIII of the EU-BSS. The permitted content is a function of the product's surface density. Therefore, a product with a low surface density of up to 25 kg m can consist of nearly 100% raw materials with potentially elevated activity concentrations, and this percentage drops to around 15% for products with a surface density of around 500 kg m. Building materials that comply with these requirements on product composition are exempt from testing, while products that do not comply must perform regular gamma-spectrometric analysis. A full validation and testing of the method is provided. In addition, the paper discusses issues relevant for regulatory implementation.


Absorption, pharmacokinetics and disposition of biodegradable nanoscale preparations.
Nowadays, biodegradable nanoscale preparations such as liposomes, micelles, nanoparticles (NPs), and solid lipid nanoparticles (SLN) have attracted increasing attention from major researchers. This article aims to review the absorption, pharmacokinetics, distribution properties and toxicity of the above-mentioned nanoscale preparations and the relative methodology. It may be significant for successful use of more nanoscale preparations in clinical practice.


Co-ordinate decrease in the expression of the mitochondrial genome and nuclear genes for mitochondrial proteins in the lactation-induced mitochondrial hypotrophy of rat brown fat.
The relative abundance of the mitochondrial-encoded mRNAs for cytochrome c oxidase subunit II and NADH dehydrogenase subunit I was lower in brown adipose tissue (BAT) from lactating rats than in virgin controls. This decrease was in parallel with a significant decrease in mitochondrial 16 S rRNA levels and in the relative content of mitochondrial DNA in the tissue. BAT from lactating rats showed lowered mRNA expression of the nuclear-encoded genes for the mitochondrial uncoupling protein, subunit IV of cytochrome c oxidase and the adenine nucleotide translocase isoforms ANT1 and ANT2, whereas mRNA levels for the ATP synthase beta-subunit were unchanged. However, the relative content of this last protein was lower in BAT mitochondria from lactating rats than in virgin controls. It is concluded that lactation-induced mitochondrial hypotrophy in BAT is associated with a co-ordinate decrease in the expression of the mitochondrial genome and nuclear genes for mitochondrial proteins. This decrease is caused by regulatory events acting at different levels, including pre- and post-transcriptional regulation. BAT appears to be a useful model with which to investigate the molecular mechanisms involved in the co-ordination of the expression of the mitochondrial and nuclear genomes during mitochondrial biogenesis.


Uncemented and cemented primary total hip arthroplasty in the Swedish Hip Arthroplasty Register.
Since the introduction of total hip arthroplasty (THA) in Sweden, both components have most commonly been cemented. A decade ago the frequency of uncemented fixation started to increase, and this change in practice has continued. We therefore analyzed implant survival of cemented and uncemented THA, and whether the modes of failure differ between the two methods of fixation. All patients registered in the Swedish Hip Arthroplasty Register between 1992 and 2007 who received either totally cemented or totally uncemented THA were identified (n = 170,413). Kaplan-Meier survival analysis with revision of any component, and for any reason, as the endpoints was performed. Cox regression models were used to calculate risk ratios (RRs) for revision for various reasons, adjusted for sex, age, and primary diagnosis. Revision-free 10-year survival of uncemented THA was lower than that of cemented THA (85% vs. 94%, p < 0.001). No age or diagnosis groups benefited from the use of uncemented fixation. Cox regression analysis confirmed that uncemented THA had a higher risk of revision for any reason (RR = 1.5, 95% CI: 1.4-1.6) and for aseptic loosening (RR = 1.5, CI: 1.3-1.6). Uncemented cup components had a higher risk of cup revision due to aseptic loosening (RR = 1.8, CI: 1.6-2.0), whereas uncemented stem components had a lower risk of stem revision due to aseptic loosening (RR = 0.4, CI: 0.3-0.5) when compared to cemented components. Uncemented stems were more frequently revised due to periprosthetic fracture during the first 2 postoperative years than cemented stems (RR = 8, CI: 5-14). The 5 most common uncemented cups had no increased risk of revision for any reason when compared with the 5 most commonly used cemented cups (RR = 0.9, CI: 0.6-1.1). There was no significant difference in the risk of revision due to infection between cemented and uncemented THA. Survival of uncemented THA is inferior to that of cemented THA, and this appears to be mainly related to poorer performance of uncemented cups. Uncemented stems perform better than cemented stems; however, unrecognized intraoperative femoral fractures may be an important reason for early failure of uncemented stems. The risk of revision of the most common uncemented cup designs is similar to that of cemented cups, indicating that some of the problems with uncemented cup fixation may have been solved.


A dynamic population of prophase CENP-C is required for meiotic chromosome segregation.
The centromere is an epigenetic mark that is a loading site for the kinetochore during meiosis and mitosis. This mark is characterized by the H3 variant CENP-A, known as CID in Drosophila. In Drosophila, CENP-C is critical for maintaining CID at the centromeres and directly recruits outer kinetochore proteins after nuclear envelope break down. These two functions, however, happen at different times in the cell cycle. Furthermore, in Drosophila and many other metazoan oocytes, centromere maintenance and kinetochore assembly are separated by an extended prophase. We have investigated the dynamics of function of CENP-C during the extended meiotic prophase of Drosophila oocytes and found that maintaining high levels of CENP-C for metaphase I requires expression during prophase. In contrast, CID is relatively stable and does not need to be expressed during prophase to remain at high levels in metaphase I of meiosis. Expression of CID during prophase can even be deleterious, causing ectopic localization to non-centromeric chromatin, abnormal meiosis and sterility. CENP-C prophase loading is required for multiple meiotic functions. In early meiotic prophase, CENP-C loading is required for sister centromere cohesion and centromere clustering. In late meiotic prophase, CENP-C loading is required to recruit kinetochore proteins. CENP-C is one of the few proteins identified in which expression during prophase is required for meiotic chromosome segregation. An implication of these results is that the failure to maintain recruitment of CENP-C during the extended prophase in oocytes would result in chromosome segregation errors in oocytes.


Cannabinoid CB(2) receptor activation prevents bronchoconstriction and airway oedema in a model of gastro-oesophageal reflux.
Cannabinoids have been shown to inhibit sensory nerve activation in guinea-pigs and humans. Their effects are mediated by specific activation of two types of receptors, named CB(1) and CB(2). The purpose of this study was to investigate the effects of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone, a non selective agonist of cannabinoid receptors, and JWH 133, (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran a selective cannabinoid CB(2) receptor agonist, on the sensory nerve component of intraoesophageal (i.oe.) HCl-induced airway microvascular leakage and bronchoconstriction in guinea-pigs. We also tested the effect of WIN 55,212-2 on substance P-induced plasma extravasation and bronchoconstriction. Airway microvascular leakage and bronchoconstriction induced by i.oe. HCl was inhibited by the cannabinoid CB(1)/CB(2) agonist WIN 55,212-2 (0.3-3 mg/kg i.p.) in a dose-dependent manner (maximal inhibition at the dose of 3 mg kg(-1), P<0.01). The effect of WIN 55,212-2 was inhibited by a cannabinoid CB(2) receptor antagonist SR 144528, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1] heptan-2yl]-5-(-4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide], but not by a CB(1) receptor antagonist, SR 141716, [N-(piperidin-1yl)-5-(-4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride]. The cannabinoid CB(2) agonist JWH 133 (0.3-3 mg/kg i.p.) mimicked the inhibitory effect of WIN 55,212-2 on HCl-induced microvascular leakage. Under similar conditions, WIN 55,212-2 (1 mg kg (-1) i.p.) was unable to counteract the airway microvascular leakage and bronchoconstriction induced by substance P. These results suggest that inhibition by WIN 55,212-2 of airway plasma extravasation and bronchoconstriction induced by i.oe. HCl instillation in guinea-pigs is mediated through cannabinoid CB(2) receptor activation.


Absorbing-active transition in a multi-cellular system regulated by a dynamic force network.
Collective cell migration in 3D extracellular matrix (ECM) is crucial to many physiological and pathological processes. Migrating cells can generate active pulling forces via actin filament contraction, which are transmitted to the ECM fibers and lead to a dynamically evolving force network in the system. Here, we elucidate the role of this force network in regulating collective cell behaviors using a minimal active-particle-on-network (APN) model, in which active particles can pull the fibers and hop between neighboring nodes of the network following local durotaxis. Our model reveals a dynamic transition as the particle number density approaches a critical value, from an "absorbing" state containing isolated stationary small particle clusters, to an "active" state containing a single large cluster undergoing constant dynamic reorganization. This reorganization is dominated by a subset of highly dynamic "radical" particles in the cluster, whose number also exhibits a transition at the same critical density. The transition is underlaid by the percolation of "influence spheres" due to the particle pulling forces. Our results suggest a robust mechanism based on ECM-mediated mechanical coupling for collective cell behaviors in 3D ECM.


Color tunable emission from Eu3+ and Tm3+ co-doped CsPbBr3 quantum dot glass nanocomposites.
Cesium lead bromide (CsPbBr3) quantum dots (QDs) have shown great potential in the field of luminescent materials owing to their superior optical and electrical properties. However, instability and lack of multicolor emissions resulting from the intrinsic nature of CsPbBr3 QDs are still the major challenge for their commercialization. Herein, Eu3+ and Tm3+ co-doped CsPbBr3 QD glass nanocomposites (GNCs) are successfully synthesized via traditional melt-quenching followed by a heat-treatment route to obtain tunable emission in a durable host material. Tm3+ ions are doped to blue-shift the main emission peak of CsPbBr3 QDs, while Eu3+ ions are incorporated to compensate for the red deficiency. Accordingly, a tunable color emission spanning the entire visible spectrum is achieved from GNCs with a fixed composition. The incorporation of Eu3+ and Tm3+ ions promotes the crystallization of CsPbBr3 QDs in the glass host resulting in ∼100% photoluminescence quantum yield (PLQY) using a dilution method. The selected glass host has also been proven to effectively protect CsPbBr3 QDs against chemical, thermal and photo degradation. Interestingly, the selected Eu3+/Tm3+ co-doped CsPbBr3 QD GNC shows warm-white light with a low color temperature of 3692 K without utilizing any commercial phosphors. This indicates that the produced GNCs have the potential to be used as light convertor materials in multi-color LED or warm white LED applications due to their robust stability and extremely pure and tunable emission colors.


India's tryst with salt: Dandi march to low sodium salts.
Salt plays a critical role in India's past as well as its present, from Dandi March to its role as a vehicle for micronutrient fortification. However, excess salt intake is a risk factor for high blood pressure and cardiovascular diseases (CVDs). Indians consume double the World Health Organization recommended daily salt (<5 g). India has committed to a 30 per cent reduction in sodium intake by 2025. Evidence based strategies for population sodium intake reduction require a moderate reduction in salt in - home cooked foods, packaged foods and outside-home foods. Reducing the sodium content in packaged food includes policy driven interventions such as front-of-package warning labels, food reformulation, marketing restrictions and taxation on high sodium foods. For foods outside of the home, setting standards for foods purchased and served by schemes like mid-day meals can have a moderate impact. For home cooked foods (the major source of sodium), strategies include advocacy for reducing salt intake. In addition to mass media campaigns for awareness generation, substituting regular salt with low sodium salt (LSS) has the potential to reduce salt intake even in the absence of a major shift in consumer behaviour. LSS substitution effectively lowers blood pressure and thus reduces the risk of CVDs. Further research is required on the effect of LSS substitutes on patients with chronic kidney disease. India needs an integrated approach to sodium reduction that uses evidence based strategies and can be implemented sustainably at scale. This will be possible only through scientific research, governmental leadership and a responsive evidence-to-action approach through a multi-stakeholder coalition.


Ablation of Dicer from murine Schwann cells increases their proliferation while blocking myelination.
The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer(-/-) Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was markedly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 microRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism.


Spontaneous resolution of soft-tissue interposition after closed reduction of hip endoprosthesis dislocation.
Over a 5-year period at a single institution, 164 endoprostheses were used for the treatment of displaced femoral neck fractures. Soft-tissue restraint preservation and repair (hip capsule and labrum) is recommended to enhance stability after endoprosthesis placement. When dislocation does occur, however, this soft tissue may become interposed after closed reduction. This occurred in 2 of the dislocations reported here. In these 2 dislocations, despite the widened joint space, the range of motion was stable. Neither of these cases had a subsequent dislocation, and after 1 month, both had spontaneously narrowed their joint space back to the immediate postoperative state.


[Heparin in the treatment and secondary prevention of myocardial infarction. A critical review of the main trials].
The aim of this article is to assess the therapeutic value of standard heparin in the acute phase and secondary prevention of myocardial infarction. Only clinical trials with an adequate methodology have been analysed. In patients having undergone thrombolytic therapy associated with aspirin, heparin slightly reduces the mortality but only during the period of its administration. In a metaanalysis of approximately twenty clinical trials of patients not receiving thrombolytic or aspirin therapy, heparin was associated with a significant reduction of deep vein thrombosis, pulmonary embolism, recurrent myocardial infarction and cerebrovascular accidents. In the context of secondary prevention of myocardial infarction, the administration of a moderate dose of subcutaneous heparin resulted in a beneficial effect on morbidity and mortality in one published trial. The use of low molecular weight heparins for the prevention of coronary thrombosis merits attention because of the pharmacological and pharmacokinetic properties of these products.


[Genetic control of plasmid recombination in the cotransformation of Saccharomyces cerevisiae: the role of RAD52 and FLP genes].
In our earlier works we observed high frequency of recombination between two chimeric plasmids of different types, when they were introduced into yeast cells via cotransformation. Incapability of one of these plasmids to replicate autonomously in yeast cell is the necessary condition for such recombination. The high efficiency of this process point to the differences between interplasmid recombination and other types of yeast recombination. In this work, we studied the participation of two genes in the control of interplasmid exchanges. These are RAD52 responsible for normal processes of meiotic and mitotic recombination and highly specific gene FLP located on 2 mkm DNA which specifies site-specific recombination in the region of inverted sequences of this plasmid. The mutation rad52 in the recipient strain was shown to sharply decrease the efficiency of recombination between integrative and episome plasmids during cotransformation. The absence of FLP gene in the recipient strain (cirO) has no influence on this process.


Suboptimal prescribing in older inpatients and outpatients.
Investigators searched Medline and HealthSTAR databases from January 1, 1985 through June 30, 1999 to identify articles on suboptimal prescribing in those age 65 years and older. A manual search of the reference lists from identified articles and the authors' article files, book chapters, and recent reviews was conducted to identify additional articles. The definitions for various types of suboptimal prescribing (polypharmacy, inappropriate, and underutilization) are numerous, and measurement varies from study to study. The literature suggests that suboptimal prescribing is common in older outpatients and inpatients. Moreover, there is significant morbidity and mortality associated with suboptimal prescribing for these older patients. Evidence from well-controlled studies suggests that multidisciplinary teams and clinical pharmacy interventions can modify suboptimal drug use in older people. Future research is necessary to measure and test other methods for tackling this major public health problem facing older people.


Implementing Caregiver Support Programs in a Regional Stroke System.
Background and Purpose- Family caregivers play a central role in the recovery of people with stroke. They need support to optimize the care they provide and their own health and well-being. Despite support from the literature and best practice recommendations, healthcare systems are not formally adopting caregiver programs. This study aimed to describe system-level facilitators and barriers to caregiver support program implementation in a regional stroke system. Methods- Using a qualitative descriptive study design, focus groups were conducted with regional rehabilitation specialists, education coordinators, community and long-term care specialists, and regional/district program directors. Semi-structured interviews were conducted with regional medical directors, health professionals providing stroke care in acute care, rehabilitation and community settings, regional health executives, and primary care leaders. Data were analyzed using inductive thematic analysis. Results- Four focus groups (n=43) and 29 interviews were conducted. We identified 4 themes related to caregiver program implementation: (1) establishing the need for caregiver education and support in an integrated healthcare system; (2) incorporating caregiver programs into the system of care across the care continuum; (3) uncertainty regarding ownership and responsibility for implementation; and (4) addressing regional variations related to access, availability, and culture. Conclusions- This study provides a comprehensive understanding of organization and system-level considerations for implementing caregiver programs in a regional stroke system. Program implementation requires evidence to establish the need for caregiver programs, practical strategies, and establishing ownership to incorporate programs into existing healthcare systems, and consideration of regional variations across healthcare systems. Ultimately, adopting programs to support caregivers will improve recovery in people with stroke and caregiver well-being.


Programmable Design and Performance of Modular Magnetic Microswimmers.
Synthetic biomimetic microswimmers are promising agents for in vivo healthcare and important frameworks to advance the understanding of locomotion strategies and collective motion at the microscopic scale. Nevertheless, constructing these devices with design flexibility and in large numbers remains a challenge. Here, a step toward meeting this challenge is taken by assembling such swimmers via the programmed shape and arrangement of superparamagnetic micromodules. The method's capacity for design flexibility is demonstrated through the assembly of a variety of swimmer architectures. On their actuation, strokes characterized by a balance of viscous and magnetic forces are found in all cases, but swimmers formed from a series of size-graded triangular modules swim quicker than more traditional designs comprising a circular "head" and a slender tail. Linking performance to design, rules are extracted informing the construction of a second-generation swimmer with a short tail and an elongated head optimized for speed. Its fast locomotion is attributed to a stroke that better breaks beating symmetry and an ability to beat fully with flex at high frequencies. Finally, production at scale is demonstrated through the assembly and swimming of a flock of the triangle-based architectures to reveal four types of swimmer couplings.


Coherent switching with decay of mixing: an improved treatment of electronic coherence for non-Born-Oppenheimer trajectories.
The self-consistent decay-of-mixing (SCDM) semiclassical trajectory method for electronically nonadiabatic dynamics is improved by modifying the switching probability that determines the instantaneous electronic state toward which the system decoheres. This method is called coherent switching with decay of mixing (CSDM), and it differs from the previously presented SCDM method in that the electronic amplitudes controlling the switching of the decoherent state are treated fully coherently in the electronic equations of motion for each complete passage through a strong interaction region. It is tested against accurate quantum mechanical calculations for 12 atom-diatom scattering test cases. Also tested are the SCDM method and the trajectory surface hopping method of Parlant and Gislason that requires coherent passages through each strong interaction region, and which we call the "exact complete passage" trajectory surface hopping (ECP-TSH) method. The results are compared with previously presented results for the fewest switches with time uncertainty and Tully's fewest switches (TFS) surface hopping methods and the semiclassical Ehrenfest method. We find that the CSDM method is the most accurate of the semiclassical trajectory methods tested. Including coherent passages improves the accuracy of the SCDM method (i.e., the CSDM method is more accurate than the SCDM method) but not of the trajectory surface hopping method (i.e., the ECP-TSH method is not more accurate on average than the TFS method).


Proton beam therapy: a fad or a new standard of care.
Newer methods and advances in radiation therapy promise to reduce the risk of complications in children who require irradiation. They have secured the role of radiation therapy in the treatment of a variety of pediatric central nervous system and solid tumors and for young patients enrolled on clinical trials. Proton therapy is the latest advancement in radiation therapy. Its availability is increasing as new centers are built throughout the United States. Pediatric specialists should understand that proton therapy is in its pioneering stage of development and that advantages have not been quantitatively demonstrated. Proton therapy clearly reduces collateral radiation dose to normal tissue when compared with photon (X-ray)-based methods of irradiation and has the potential to selectively and safely escalate dose to high-risk tumors; however, research results are lacking in both of these areas, leading to some confusion among pediatric specialists with regard to indications and the need to refer patients for this limited resource and expensive form of radiation therapy. This review highlights a number of issues surrounding proton therapy in children and supports the use of proton therapy in clinical trials.


High spontaneous mutation rate of Rous sarcoma virus demonstrated by direct sequencing of the RNA genome.
Direct and extensive sequencing of RSV RNA genome is reported. More than 10,000 nt of the T1 RNase resistant RSV RNA fragments (1) have been sequenced and shown to cover 3900 nt of RSV genome. The frequent sequence variations found indicate that RSV supports a very high incidence of spontaneous mutations in the course of replication, one very probable cause of the genetic diversity among the avian retroviruses. Sequences of the structured RSV RNAs allowed us also to precisely characterize the structured domains of the retroviral genome and show that the src gene is not structured.


Vitrectomy for the Treatment of Expulsive Hemorrhage.
Purpose: An evaluation of surgical outcome of vitrectomy in the treatment of expulsive hemorrhage associated with intraocular surgery.Methods: We reviewed 12 eyes from 12 patients with expulsive hemorrhage, occurring after or during cataract extraction (4 eyes), phacoemulsification (2 eyes), glaucoma filtering surgery (4 eyes), or vitrectomy (2 eyes). Mean follow-up period was 21 months.Results: The retina was reattached in 6 eyes (50%) after the initial surgery and ultimately in 9 eyes (75%). Three eyes, which failed to achieve retinal reattachment, resulted in phthisis bulbi. Final visual acuity was 0.1 or better in 4 eyes and 0.01 to 0.09 in 4 eyes. The incidence of expulsive hemorrhage was 0% for cataract surgery, 0.57% for trabeculectomy, and 0.09% for vitrectomy at Toho University Sakura Hospital.Conclusion: In the treatment of expulsive hemorrhage, vitrectomy is an effective surgical procedure to improve the visual function.


Optical coherence tomographic hyperreflective foci in early stages of diabetic retinopathy.
To analyze the presence of hyperreflective foci in Type 1 and Type 2 diabetic patients, separately, without clinically significant diabetic macular edema and visual impairment. Noninvasive, observational prospective study. Seventeen and 19 consecutive Type 1 and Type 2 diabetic patients (33 and 38 eyes), respectively, were recruited. All patients had no clinically significant diabetic macular edema or visual impairment. Two age- and sex-matched control groups were also included. Patients underwent an ophthalmologic examination including spectral domain optical coherence tomography. Hyperreflective foci were counted considering horizontal B-scan passing through the fovea. On spectral domain optical coherence tomography, patients affected by Type 1 and Type 2 diabetes had a mean of 7.5 ± 4.6 and 9.9 ± 4.5 hyperreflective foci, respectively. Subjects of control groups had a mean of 0.9 ± 0.8 and 1.7 ± 1.5 hyperreflective foci, respectively. Hyperreflective foci amount was statistically different between Type 1 and Type 2 diabetic groups (P = 0.032) and significantly higher in diabetic patients than in controls (P < 0.001). Hyperreflective foci amount was significantly higher in diabetic patients with a poor quality glycometabolic control (P < 0.001 and P = 0.016) or affected by hypertension (P = 0.008). We reported the presence of hyperreflective foci in diabetic patients without diabetic macular edema and visual impairment. This spectral domain optical coherence tomography finding might be a useful marker for the diagnosis and the follow-up in the early stage of diabetic retinopathy.


Impact of the COVID-19 pandemic on adolescent vaccinations: projected time to reverse deficits in routine adolescent vaccination in the United States.
The COVID-19 pandemic has led to significant reductions in the administration of routinely recommended vaccines among adolescents in the US including tetanus, diphtheria, and acellular pertussis (Tdap); meningococcal (ACWY); and human papillomavirus (HPV) vaccines. The extent to which these deficits could persist in 2021 and beyond is unclear. To address this knowledge gap, this study estimated the cumulative deficits of routine vaccine doses among US adolescents during the COVID-19 pandemic and estimated the time and effort needed to recover from those deficits. Monthly reductions in Tdap, meningococcal, and HPV doses administered to US adolescents during the COVID-19 pandemic were quantified using MarketScan Commercial Claims and Encounters data. The time and effort required to reverse the vaccination deficit under various catch-up scenarios were estimated. Annual doses administered of Tdap, meningococcus, and HPV vaccines decreased by 21.2%, 20.8%, and 24.0%, respectively, in 2020 compared to 2019. For 2021, the reduction in doses administered is projected to be 6%-21% compared to 2019 under different scenarios. The projected deficit of missed doses is expected to be cleared between winter 2023 and fall 2031. Administration rates of routine vaccines decreased significantly among US adolescents during COVID-19. Reversing these deficits to mitigate long-term health and economic consequences will require a sustained increase in vaccination rates over multiple years.


Exclusion of male mitochondria and plastids during syngamy in barley as a basis for maternal inheritance.
It is known from genetic analyses that maternal inheritance of cytoplasmic organelles is the rule among plants and animals. Although recognized as one of several possible mechanisms for strictly maternal cytoplasmic inheritance, exclusion of sperm cytoplasm at the time of gametic fusion has remained poorly documented for the flowering plants. In the present investigation, enucleated, cytoplasmic bodies approximately the size of intact, prefusion sperm cells have been observed within degenerated synergids and adjacent to recently fertilized egg cells. A complete series of ultrathin sections (68 sections) through such a cytoplasmic body revealed 59 mitochondria, 3 plastids, 7 dictyosomes, and a large vacuole with no limiting membrane. This structure is interpreted as the entire male cytoplasm that was left outside the egg during fusion between egg and sperm. The observation of only one cytoplasmic body per embryo sac may indicate a preliminary fusion between sperm cells or, more likely, the existence of a fundamentally different mechanism of fertilization between the second sperm and the central cell.


Usefulness of microspheres composed of gelatin with various cross-linking density.
The release rate of insulin, as a model peptide, from gelatin microspheres (GM) prepared with gelatin having various cross-linking densities in vitro was examined. The release of insulin from GM showed the burst effect, followed by a slow release phase regardless of the cross-linking density of gelatin. The total amount of insulin released in 2 weeks decreased with increasing cross-linking density of gelatin. The release rate of insulin within 6 h was well correlated with the cross-linking density of gelatin. The remaining amounts of both insulin and GM after injection of insulin incorporated in GM to mice femoral muscle tissue were also examined in vivo. Both insulin and GM rapidly disappeared from the injection site within 1 day, and thereafter slowly disappeared over 14 days. The time courses of the remaining amounts were fairly similar to each other. Furthermore, the remaining amount of insulin 1 day after administration was well correlated with the cross-linking density of gelatin. These data suggest that insulin was released from GM with the degradation of GM in mice muscular tissue and that the release rate of insulin can be controlled by modifying the cross-linking density of gelatin. In conclusion, the control of the release rate of insulin from GM can be achieved under both in vitro and in vivo conditions by gelatin through the alteration of cross-linking conditions.


Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats.
Irinotecan hydrochloride (CPT-11), an antitumor camptothecin derivative, causes severe forms of diarrhea clinically. We characterized CPT-11-induced diarrhea histologically and enzymologically and assessed the relationships between intestinal toxicity and the activity of the enzymes that play a key role in the major metabolic pathway of CPT-11 in rats. CPT-11 (60 mg/kg i.v. for 4 days) induced intestinal toxicity characterized by severe chronic diarrhea, loss of body weight, and anorexia. Histological damage was most severe in the cecum. The segmental difference in the degree of the damage showed good correlation with the beta-glucuronidase activity in the contents of the lumen in each case, but not with the intestinal tissue carboxylesterase activity, which converts CPT-11 to its active form (7-ethyl-10-hydroxycamptothecin). Inhibition of the beta-glucuronidase activity in the intestinal microflora by antibiotics (1 mg penicillin and 2 mg streptomycin per ml of drinking water) markedly ameliorated the diarrhea and reduced cecal damage. Analysis of CPT-11 and its metabolites in the feces indicated that antibiotics completely inhibited the deconjugation of the glucuronic conjugate of 7-ethyl-10-hydroxycamptothecin by beta-glucuronidase. It is suggested that CPT-11-induced diarrhea would be attributable to the damage to the cecum, and that the inhibition of the beta-glucuronidase activity in the intestinal microflora is a major protective effect of antibiotics.


Reflections on clinician leadership and management in mental health.
To review the role of clinician leadership in the management of mental health services. The literature suggests that clinician leadership is increasingly regarded as an essential element in the effective introduction of innovation and improved quality of clinical care by those who manage mental health services. Psychiatrist leaders have a role to play in ensuring that service change and innovation is based on sound clinical values, is developed in partnership with clinicians and is understood and supported by psychiatrist colleagues. Clinician leaders require clear vision, commitment and courage. The support of their colleagues is essential if the psychiatric profession is to have influence on future development of mental health services.


Experimental observation of dark solitons on the surface of water.
We present the first ever observation of dark solitons on the surface of water. It takes the form of an amplitude drop of the carrier wave which does not change shape in propagation. The shape and width of the soliton depend on the water depth, carrier frequency, and the amplitude of the background wave. The experimental data taken in a water tank show an excellent agreement with the theory. These results may improve our understanding of the nonlinear dynamics of water waves at finite depths.


Hypoxic stimulus alters hypothalamic AMP-activated protein kinase phosphorylation concomitant to hypophagia.
Acute exposure to hypobaric hypoxia is known to decrease food intake, but the molecular mechanisms of such alteration in feeding behavior remain unknown. We tested the hypothesis that hypothalamic AMP-activated protein kinase (AMPK) phosphorylation is affected by acute exposure to hypobaric hypoxia and thus would be involved in initial anorexia. To address this issue, male rats weighing 255-270 g were either submitted to hypobaric hypoxia (H, equivalent altitude of 5,500 m), maintained under local barometric pressure conditions (N), or pair-fed an equivalent quantity of food to that consumed by H rats (PF), for 6, 24, or 48 h. Daily food intake dropped by 73% during the first day of hypoxia (P<0.01) and remained by 46% lower than in N rats thereafter (P<0.01). Hypoxia per se, as estimated by comparing experimental data between the H and PF groups, increased ob gene transcription and plasma leptin concentration. A transient increase in glucose availability occurred in the H group compared with PF animals (P<0.05). The hypoxic stimulus led to an early and transient decrease in hypothalamic AMPK and acetyl-CoA carboxylase (ACC) phosphorylation, concomitant with hypophagia and associated alterations in nutrients and hormones. An increase in NPY mRNA levels occurred from day 1, similarly in H and PF rats, and thus mainly related to food restriction alone (P<0.05). In conclusion, the present study demonstrates that hypoxia per se inhibited AMPK and ACC phosphorylation in the hypothalamus, concomitant with profound anorexia. A powerful counterregulation occurs rapidly, mediated by NPY and devoted to avoid prolonged anorexia.


The ChEMBL Database in 2023: a drug discovery platform spanning multiple bioactivity data types and time periods.
ChEMBL (https://www.ebi.ac.uk/chembl/) is a manually curated, high-quality, large-scale, open, FAIR and Global Core Biodata Resource of bioactive molecules with drug-like properties, previously described in the 2012, 2014, 2017 and 2019 Nucleic Acids Research Database Issues. Since its introduction in 2009, ChEMBL's content has changed dramatically in size and diversity of data types. Through incorporation of multiple new datasets from depositors since the 2019 update, ChEMBL now contains slightly more bioactivity data from deposited data vs data extracted from literature. In collaboration with the EUbOPEN consortium, chemical probe data is now regularly deposited into ChEMBL. Release 27 made curated data available for compounds screened for potential anti-SARS-CoV-2 activity from several large-scale drug repurposing screens. In addition, new patent bioactivity data have been added to the latest ChEMBL releases, and various new features have been incorporated, including a Natural Product likeness score, updated flags for Natural Products, a new flag for Chemical Probes, and the initial annotation of the action type for ∼270 000 bioactivity measurements.


Post-fledging movements of white-tailed eagles: Conservation implications for wind-energy development.
The presence of poorly sited wind farms raises concerns for wildlife, including birds of prey. Therefore, there is a need to extend the knowledge of the potential human-wildlife conflicts associated with wind energy. Here, we report on the movements and habitat use of post-fledging satellite-tagged white-tailed eagles in Finland, where wind-energy development is expected to increase in the near future. In particular, we examine the probability of a fledgling approaching a hypothetical turbine that is placed at different distances from the nest. We found that this probability is high at short distances but considerably decreases with increasing distances to the nest. A utilisation-availability analysis showed that the coast was the preferred habitat. We argue that avoiding construction between active nests and the shoreline, as well as adopting the currently 2-km buffer zone for turbine deployment, can avoid or minimise potential impacts on post-fledging white-tailed eagles.


Ultrasensitive detection of cancer biomarkers by nickel-based isolation of polydisperse extracellular vesicles from blood.
Extracellular vesicles (EVs) are secreted membranous particles intensively studied for their potential cargo of diagnostic markers. Efficient and cost-effective isolation methods need to be established for the reproducible and high-throughput study of EVs in the clinical practice. We designed the nickel-based isolation (NBI) to rapidly isolate EVs and combined it with newly-designed amplified luminescent proximity homogeneous assay or digital PCR to detect biomarkers of clinical utility. From plasma of 46 healthy donors, we systematically recovered small EV (~250 nm of mean diameter; ~3 × 1010/ml) and large EV (~560 nm of mean diameter; ~5 × 108/ml) lineages ranging from 50 to 700 nm, which displayed hematopoietic/endothelial cell markers that were also used in spike-in experiments using EVs from tumor cell lines. In retrospective studies, we detected picomolar concentrations of prostate-specific membrane antigen (PSMA) in fractions of EVs isolated from the plasma of prostate cancer patients, discriminating them from control subjects. Directly from oil-encapsulated EVs for digital PCR, we identified somatic BRAF and KRAS mutations circulating in the plasma of metastatic colorectal cancer (CRC) patients, matching 100% of concordance with tissue diagnostics. Importantly, with higher sensitivity and specificity compared with immuno-isolated EVs, we revealed additional somatic alterations in 7% of wild-type CRC cases that were subsequently validated by further inspections in the matched tissue biopsies. We propose NBI-combined approaches as simple, fast, and robust strategies to probe the tumor heterogeneity and contribute to the development of EV-based liquid biopsy studies. FUND: Associazione Italiana per la Ricerca sul Cancro (AIRC), Fondazione Cassa di Risparmio Trento e Rovereto (CARITRO), and the Italian Ministero Istruzione, Università e Ricerca (Miur).


A micro-CT analysis of murine lung recruitment in bleomycin-induced lung injury.
The effects of lung injury on pulmonary recruitment are incompletely understood. X-ray computed tomography (CT) has been a valuable tool in assessing changes in recruitment during lung injury. With the development of preclinical CT scanners designed for thoracic imaging in rodents, it is possible to acquire high-resolution images during the evolution of a pulmonary injury in living mice. We quantitatively assessed changes in recruitment caused by intratracheal bleomycin at 1 and 3 wk after administration using micro-CT in 129S6/SvEvTac mice. Twenty female mice were administered 2.5 U of bleomycin or saline and imaged with micro-CT at end inspiration and end expiration. Mice were extubated and allowed to recover from anesthesia and then reevaluated in vivo for quasi-static compliance measurements, followed by harvesting of the lungs for collagen analysis and histology. CT images were converted to histograms and analyzed for mean lung attenuation (MLA). MLA was significantly greater for bleomycin-exposed mice at week 1 for both inspiration (P<0.0047) and exhalation (P<0.0377) but was not significantly different for week 3 bleomycin-exposed mice. However, week 3 bleomycin-exposed mice did display significant increases in MLA shift from expiration to inspiration compared with either group of control mice (P<0.005), suggesting increased lung recruitment at this time point. Week 1 bleomycin-exposed mice displayed normal shifts in MLA with inspiration, suggesting normal lung recruitment despite significant radiographic and histological changes. Lung alveolar recruitment is preserved in a mouse model of bleomycin-induced parenchymal injury despite significant changes in radiographic and physiological parameters.