HST-1/FGF-4 protects male germ cells from apoptosis under heat-stress condition.
Apoptosis plays an important role in controlling the number of male germ cells and eliminating defective germ cells during testicular development and spermatogenesis. We show here that fibroblast growth factor-4 (HST-1/FGF-4) may play a critical role as a survival factor for germ cells, protecting them from apoptosis. Testes of adult male mice that received an adenovirus carrying human HST-1/FGF-4 (AxHST-1) or a control adenovirus (AxCAwt) were exposed to mild hyperthermia, which causes germ cell apoptosis. An in situ terminal-deoxynucleotidyl transferase-mediated deoxy-UTP nick end-labeling (TUNEL) assay characterized germ cell apoptosis. The results indicated that HST-1/FGF-4 significantly reduced the apoptotic death of germ cells and prevented testicular weight loss and sperm count reduction. We also found that Hst-1/Fgf-4 present in testes is up-regulated in vivo when the testes are exposed to mild hyperthermia, and that endogenous Hst-1/Fgf-4 mRNA expression in Sertoli cells are also induced when the cells are exposed to mild hyperthermia in vitro. In addition, the MAPK cascade, which could increase an FGF-dependent survival signal, is activated by HST-1/FGF-4 stimuli in germ cells. On the other hand, upon HST-1/FGF-4 stimulation, lactate production from Sertoli cells were induced, which is indispensable nutrient for germ cell survival. These results suggest that HST-1/FGF-4 can act as an important physiological anti-apoptotic factor for male germ cells in stimulating lactate production of Sertoli cells upon heat stress, thereby promoting germ cell survival.


The nutrient removal and tolerance mechanism of a heterotrophic nitrifying bacterium Pseudomonas putida strain NP5 under metal oxide nanoparticles stress.
The occurrence of metal oxide nanoparticles (NPs) in wastewater treatment plants (WWTPs) has raised great concerns about their adverse impacts on nitrification performance. In this study, a heterotrophic nitrifying bacterium Pseudomonas putida strain NP5 showed strong resistance against TiO2 and NiO NPs. Under 5-50 mg/L NP stress, cell viability was still normal, and the final nutrient removal rates, always higher than 80%, were slightly inhibited. Correspondingly, the PO43--P removal rates were almost the same as those observed in the control test. Although the enzyme assay demonstrated ammonia monooxygenase and hydroxylamine oxidoreductase activities markedly decreased caused by increased reactive oxygen species (ROS) level under 50 mg/L NPs stress. The total antioxidant capability of NP5 could eliminate excess ROS to maintain a balance between oxidants and antioxidants. Besides, in response to the escalating burden of NPs, strain NP5 tended to secrete more extracellular polymeric substances (EPS), which could protect cell from being damaged by binding to ions and coating. Thus, the strong NP resistance of NP5 would help to overcome the vulnerability of the nitrification process in WWTPs.


Association of modifiable lifestyle with colorectal cancer incidence and mortality according to metabolic status: prospective cohort study.
Metabolic syndrome has been linked to an increased risk of colorectal cancer (CRC) incidence and mortality, but whether adopting a healthy lifestyle could attenuate the risk of CRC conferred by metabolic syndrome remains unclear. The aim of the study is to investigate the individual and joint effects of modifiable healthy lifestyle and metabolic health status on CRC incidence and mortality in the UK population. This prospective study included 328,236 individuals from the UK Biobank. An overall metabolic health status was assessed at baseline and categorized based on the presence or absence of metabolic syndrome. We estimated the association of the healthy lifestyle score (derived from 4 modifiable behaviors: smoking, alcohol consumption, diet, physical activity and categorized into "favorable," "intermediate", and "unfavorable") with CRC incidence and mortality, stratified by metabolic health status. During a median follow-up of 12.5 years, 3,852 CRC incidences and 1,076 deaths from CRC were newly identified. The risk of incident CRC and its mortality increased with the number of abnormal metabolic factors and decreased with healthy lifestyle score (P trend = 0.000). MetS was associated with greater CRC incidence (HR = 1.24, 95% CI: 1.16 - 1.33) and mortality (HR = 1.24, 95% CI: 1.08 - 1.41) when compared with those without MetS. An unfavorable lifestyle was associated with an increased risk (HR = 1.25, 95% CI: 1.15 - 1.36) and mortality (HR = 1.36, 95% CI: 1.16 - 1.59) of CRC across all metabolic health status. Participants adopting an unfavorable lifestyle with MetS had a higher risk (HR = 1.56, 95% CI: 1.38 - 1.76) and mortality (HR = 1.75, 95% CI: 1.40 - 2.20) than those adopting a favorable healthy lifestyle without MetS. This study indicated that adherence to a healthy lifestyle could substantially reduce the burden of CRC regardless of the metabolic status. Behavioral lifestyle changes should be encouraged for CRC prevention even in participants with MetS.


A rapid method for the separation of functional lymphoid cell populations of human and animal origin on PVP-silica (Percoll) density gradients.
Subclasses of lymphocytes can be separated on gradients of non-toxic polyvinylpyrrolidone-coated colloidal silica (Percoll) by virtue of differential densities. Such gradients can yield functionally active lymphocyte populations after brief centrifugation. Gradients can be generated in a discontinuous step fashion and centrifuged in standard table-top laboratory centrifuges or as self-generating gradients during ultracentrifugation. The density medium has low viscosity and can be made isotonic for virtually any use. Gradients have proved useful in both human and experimental animal studies, and high percentage yields allow for separations from small cell numbers. Methods are described for separation of whole blood and lymphoid subpopuctions. The cytoxic capability of various density fractions was evaluated for mixed lymphocyte culture-induced allogeneic killing and spontaneous, so-called "natural" killer cell activity. The lower density associated with blast transformation allows for significant enrichments of stimulated cells from in vitro cultures. Higher thymidine incorporation, restimualtion in mixed lymphocyte reactions, and greater cytotoxic capacity are associated with these "blast" fractions.


Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies.
Protein based therapeutics have successfully improved the quality of life for patients of monogenic disorders like hemophilia, Pompe and Fabry disease. However, a significant proportion of patients develop immune responses towards intravenously infused therapeutic protein, which can complicate or neutralize treatment and compromise patient safety. Strategies aimed at circumventing immune responses following therapeutic protein infusion can greatly improve therapeutic efficacy. In recent years, antigen-based oral tolerance induction has shown promising results in the prevention and treatment of autoimmune diseases, food allergies and can prevent anti-drug antibody formation to protein replacement therapies. Oral tolerance exploits regulatory mechanisms that are initiated in the gut associated lymphoid tissue (GALT) to promote active suppression of orally ingested antigen. In this review, we outline general perceptions and current knowledge about the mechanisms of oral tolerance, including tissue specific sites of tolerance induction and the cells involved, with emphasis on antigen presenting cells and regulatory T cells. We define several factors, such as cytokines and metabolites that impact the stability and expansion potential of these immune modulatory cells. We highlight preclinical studies that have been performed to induce oral tolerance to therapeutic proteins or enzymes for single gene disorders, such as hemophilia or Pompe disease. These studies mainly utilize a transgenic plant-based system for oral delivery of antigen in conjugation with fusion protein technology that favors the prevention of antigen degradation in the stomach while enhancing uptake in the small intestine by antigen presenting cells and regulatory T cell induction, thereby promoting antigen specific systemic tolerance.


Identification of the cis-elements mediating the autogenous control of ribosomal protein L2 mRNA stability in yeast.
The ribosomal protein L2 (rpL2) of Saccharomyces cerevisiae regulates the accumulation of its own mRNA by a feedback mechanism. An RNA sequence is responsible for this control, initially characterized as a 360 nucleotide-long region, localized at the 5' end of the transcript. This region, fused to an unrelated coding sequence, is able to down-regulate the accumulation of the chimeric transcript when increased levels of rpL2 are induced in the cell. The target regulatory region also responds to regulation when inserted inside an intron, demonstrating that the control process can take place inside the nucleus. Deletion analysis from the 5' and 3' borders have restricted the responsive region to approximately 200 nt. The insertion of a poly-G cassette downstream of the regulatory region allowed the identification of truncated 3' cut-off poly(A)+ RNA molecules. The parallel identification of cut-off molecules containing the 5' portion of the transcript allowed us to deduce that the truncated products originate by endonucleolytic cleavage. Altogether, these results are consistent with a mechanism by which the presence of excess amounts of rpL2 in the cell triggers its own mRNA to a degradative pathway; this involves an initial endonucleolytic cleavage that is followed by exonucleolytic trimming. Such a regulatory mechanism shows interesting analogies with the translational regulation of r-proteins in Escherichia coli.


Expression of a receptor kinase in Arabidopsis roots is stimulated by the basidiomycete Piriformospora indica and the protein accumulates in Triton X-100 insoluble plasma membrane microdomains.
Piriformospora indica, an endophytic fungus of the Sebacinaceae family, colonises the roots of a wide variety of plant species and promotes their growth, in a manner similar to mycorrhizal fungi. We demonstrate that the fungus also interacts with the non-mycorrhizal host Arabidopsis thaliana. Promotion of root growth was detectable even before noticeable root colonization, and was accompanied by a massive transfer of phosphate from the media to the aerial parts of the seedlings. During the recognition period of both organisms, the message for a receptor kinase with leucine-rich repeats is transiently upregulated. The kinase is located in Triton X-100-insoluble plasma membrane microdomains. Thus, this is one of the earliest events of a plant root in response to a fungus reported to date.


Development of a highly sensitive RT-PCR luminometric hybridization assay for human telomerase reverse-transcriptase beta-plus transcript.
Telomerase is a general diagnostic and prognostic molecular tumor marker since it is expressed in the majority of human tumors in contrast to most healthy tissues. Alternate splicing of human telomerase reverse transcriptase (hTERT) has been shown to affect telomerase activity. We have developed a hybridization assay that selectively detects the hTERT beta-plus transcript. Biotinylated PCR products were captured on streptavidin-coated microtiter wells, hybridized with digoxigenin-labeled probes and detected by a highly sensitive luminometric reaction. The method was applied in ten colorectal tumor forceps biopsies and their corresponding normal tissues. Six out of ten tumors were positive for hTERT beta plus transcript whereas none of the corresponding normal tissues were found positive. There was a complete concordance between the hybridization assay and real-time PCR. When the method was applied in peripheral blood of 20 breast cancer patients with metastatic disease and 21 healthy blood donors, 14 patients (70%) were found positive while all 21 healthy blood donors were negative. The developed hybridization assay is highly sensitive and specific for the detection of hTERT beta-plus transcript in clinical samples.


Pharmacodynamics of nine generic products of amikacin compared with the innovator in the neutropenic mouse thigh infection model.
Previously, we validated the mouse thigh infection model to test the therapeutic equivalence of generic antibiotic products. Here, our aim was to compare the in vivo efficacy of amikacin products in clinical use in Colombia using this animal model. All except one generic product had the same in vitro potency, judging by the lack of differences on MIC and MBC compared with the innovator. However, eight of nine generic products failed in the neutropenic mouse thigh infection model to achieve the innovator's maximum effect (E max ≤ 5.65 for the generics vs. 6.58 log10 CFU/g for the innovator) against Escherichia coli SIG-1, after subcutaneous treatment every 6 h with doses ranging from 1.5 to 3072 mg/kg per day. As we demonstrated previously with other antibiotics such as vancomycin, gentamicin and oxacillin, the generic products of amikacin failed the in vivo efficacy testing. The therapeutic equivalence should be assessed in vivo before clinical approval of generic products.


Sensitization to illness and the risk of death: an explanation for Sri Lanka's approach to good health for all.
Recent research has shown clearly that levels of mortality are not determined solely by income levels and the provision of modern health services. There appears to be an important sociocultural component so that the same density of health services produces lower mortality in one country than in another. Sri Lanka has achieved an expectation of life at birth of 68 years with an annual per capita income of U.S. $330 and no greater provision of health services than most countries at that income level. This paper records the investigation of how such success has been attained. A collaborative program of the University of Colombo and the Australian National University, beginning in 1985, employed both demographic and anthropological methods to study almost 11,000 persons in seven localities of southwestern Sri Lanka. It was found that the major geographical mortality differentials are no longer urban-rural but between the richer and poor areas of Colombo. The low mortality was found to be based on a great sensitivity to illness and the risk of dying. This is ancient in origin but has been heightened by a nineteenth century religious reform movement and twentieth century mass education. It has been further increased by universal death registration, the carrying out of post-mortems wherever necessary with the informing of the police if the death was unnecessary, and by the erection of a system for examining the circumstances of sudden death. This sensitivity was not sufficient to produce low death rates in conjunction with traditional medicine but only with modern medicine. Traditional medicine is still widely practiced, and exorcism is a major cause of expenditure in many families. Nevertheless, the key findings were two. First, where modern medicine can save a life, the sick person nowadays is nearly always exposed to it while there is still sufficient time for a cure. Modern medicine is now usually obtained at a shorter distance and more cheaply than traditional medicine. Second, and of central importance, is the continuing evaluation of sickness from its first appearance and the quick resort to new treatments if the present treatment does not appear to be efficacious. Because of an apprehension of an unnecessary death occurring during their treatment, healers frequently refer cases, from traditional to modern medicine and from general practitioner to hospital. Nevertheless, most changes of treatment are decided by the sick themselves and their relatives so that unsuccessful treatment is changed on average every 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)


PTHrP fragments 1-16 and 1-23 do not bind to either the ETA or the ETB endothelin receptors.
Because of some isofunctional similarities with endothelin-1 (ET-1), it has been suggested that PTHrP(1-16) and PTHrP(1-23) could interact with osteoblast cells via ETA receptors. To document this interaction, we used the thoracic rat aorta and the guinea-pig lung parenchyma paradigms as ETA and ETB models, respectively. In addition, we also performed a series of competition experiments against [125I]ET-1, using transfected cells expressing the ETA or ETB receptor. So far, no agonistic nor antagonistic activities were observed in the ETA and ETB bioassays with the PTHrP fragments. Furthermore, both fragments were unable to displace [125I]ET-1 bound to cells expressing the ETA or ETB receptor.


Pharmacogenetic tests to predict the efficacy of aspirin desensitization in patients with aspirin-exacerbated respiratory diseases; HLA-DQB302.
This study is aimed at investigating the association of HLA-DRB1, HLA-DQA1, and HLA-DQB1 variability with the response to aspirin desensitization (AD). A total of 16 patients with aspirin-exacerbated respiratory diseases (AERD, 81.3% were female) with median age of 29 ± 4.3 years were included in this study. Following 6 months, Sino-Nasal Outcome Test-22 (SNOT-22), medication, symptom scores, and forced expiratory volume in 1 s (FEV1) (all p < 0.001) improved significantly. However, only seven patients (43.7%) had clinically significant improvement in all of the medication and symptom scores and FEV1, who were considered responders to AD. Responders to AD had significantly higher symptom scores compared with non-responders at baseline (20 ± 1.18 vs 10 ± 1.27; p = 0.003). HLADQB1*0302 was significantly lower in non-responders than in responders to AD (0.12 [0.02-0.76]; p = 0.022). Sensitivity and specificity of HLA-DQB1*0302 to predict response to AD was 71.4% (95% CI: 35.8-91.7) and 81.8% (95% CI: 52.3-94.8). This study introduces HLA-DQB1*0302 as a genetic marker for favorable response to AD.


Classification of rice allergenic protein cDNAs belonging to the alpha-amylase/trypsin inhibitor gene family.
Seven cDNA clones encoding rice allergenic proteins were newly isolated. Comparison of the sequences of ten cDNA clones, including the previously isolated three clones results in their classification into four subfamilies. Homologies in the nucleotide sequences among and within subfamilies are 70-85% and above 95%, respectively. A sequence of twenty five amino-acid residues at the C-terminal proximal region is highly conserved among all clones and resembles that of plant lipid transfer proteins.


Single-walled carbon nanotubes based quenching of free FAM-aptamer for selective determination of ochratoxin A.
Ochratoxin A, a toxin produced by Aspergillus ochraceus and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins in the world. It has been classified by the International Agency for Research on Cancer (IARC) as a possible human carcinogen. In this paper, a sensitive and selective fluorescent aptasensor for ochratoxin A (OTA) detection was constructed, utilizing single-walled carbon nanotubes (SWNTs) as quencher which can quench the fluorescence of free unfolded toxin-specific aptamer attached with FAM (carboxyfluorescein). Without any coating materials as compared to graphene-oxide based sensor, we obtained the detection limit of our sensing platform based on SWNTs to be 24.1 nM with a linear detection range from 25 nM to 200 nM. This technique responded specifically to OTA without interference from other analogues (N-acetyl-L-phenylalanine, warfarin and OTB). It has also been verified for real sample application by testing 1% beer containing buffer solution spiked with a series of concentration of OTA.


Controversies in the differential diagnosis of Brown-Sequard syndrome due to cervical spinal disease from stroke: A case series.
Stroke is generally considered to be the first preliminary diagnosis in patients presenting with acute hemiparesia in the emergency department. But rarely in unexpected spontaneous neurological pathologies that may lead to hemiparesis. The data from 8 non-traumatic patients who underwent surgical treatment for brown-sequard syndrome (BSS) were reviewed retrospectively. All patients were initially misdiagnosed with strokes. Two of the patients had spinal canal stenosis, two had spinal epidural hematomas, one had an ossified herniated disc and three had soft herniated discs. None of the patients complained of significant pain at the initial presentation. All of the patients had a mild sensory deficit that was initially unrecognized. The pain of the patients began to become evident after hospitalization and, patients transferred to neurosurgery department. Cervical spinal pathologies compressing the corticospinal tract in one-half of the cervical spinal canal may present with only hemiparesis, without neck and radicular pain. If it's too late, permanent neurological damage may become inevitable while it is a correctable pathology.


Magnetic resonance guided focused ultrasound surgery. Ablation of soft tissue at bone-muscle interface in a porcine model.
Pain management treatments of patients with bone metastases have either efficacy problems or significant side effects. Percutaneous radiofrequency ablation has recently proved to be of palliative value. Magnetic resonance guided focused ultrasound surgery (MRgFUS) uses focused ultrasonic energy to non-invasively create a heat-coagulated lesion deep within the body in a controlled, accurate manner. The surgeon can monitor and control energy deposition in real time. This technology represents a potential treatment modality in oncological surgery. We investigated the ability of two MRgFUS methods to accurately and safely target and ablate soft tissue at its interface with bone. Heat-ablated lesions were created by MRgFUS at the bone-muscle interface of 15 pigs. Two different methods of energy delivery were used. Temperature rise at the target adjacent to bone was monitored by real time MR thermal images. Results were evaluated by MRI (magnetic resonance imaging), nuclear scanning and by histopathological evaluation. Soft tissue lesion sizes by both methods were in the range of 1-2 cm in diameter. Targeting the focus 'behind' the bone, achieved the same result with a single sonication only. Follow up MRI and histopathological examination of all lesions showed focal damage at its interface with bone and localized damage to the outer cortex on the side closer to the targeted tissue. There was no damage to non-targeted tissue. MRgFUS by both energy deposition methods can be used to produce controlled well-localized damage to soft tissue in close proximity to bone, with minimal collateral damage.


Studies of cervicovaginal smears for the presence of actinomycetes.
Cytologic and direct fluorescent antibody techniques were used to detect the presence of Actinomyces israelii and Arachnia propionica in cervicovaginal smears collected from 100 women, 94 of whom did not use intrauterine contraceptive devices. In no case were these organisms found. The possible significance of these results is discussed.


Expression patterns of epithelial differentiation antigens and lectin-binding sites in ameloblastomas: a comparison with basal cell carcinomas.
Whether the peripheral ameloblastoma (PA) and intraoral basal cell carcinoma (BCC) are two different clinical entities or essentially the same lesion still remains unresolved. The immunophenotypes of neoplastic cells of peripheral and intraosseous ameloblastomas, ameloblastic carcinomas, and BCCs were studied using a panel of monoclonal/polyclonal antibodies and lectins. The major cytokeratins (CKs) of neoplastic cells of ameloblastomas were CKs 5 and 14, whereas co-expression of CKs 8, 18, and 19 was observed in the cells of the stellate reticulum-like areas. Metaplastic squamous and keratinizing cells found in follicular and acanthomatous variants of ameloblastomas expressed CKs 1 and 10, involucrin, and binding sites for the lectins Ulex europeaus agglutinin I and Helix pomatia agglutinin. beta 2-Microglobulin was uniformly negative in all cases of ameloblastomas and ameloblastic carcinomas studied. Cutaneous BCCs also demonstrated similar reactive patterns with the above-mentioned antigens. The most striking feature is the presence of a peritumorous band-like peanut agglutinin staining found in both BCCs and PAs but not in intraosseous ameloblastomas. This unique peanut agglutinin staining pattern of PA may be diagnostically useful for its histopathologic distinction from an intraosseous ameloblastoma that has infiltrated the soft tissue. The neoplastic cells of ameloblastomas express markers of less-differentiated epithelial cells. Despite differences in epithelial origins, PAs are tumors analogous to cutaneous BCCs.


Extensively drug-resistant Acinetobacter baumannii in a Lebanese intensive care unit: risk factors for acquisition and determination of a colonization score.
Acinetobacter baumannii (AB) has emerged as an important nosocomial pathogen causing worldwide hospital outbreaks. It has become a prototype of extensively drug-resistant (XDR) organisms. To identify risk factors for acquisition of XDR-AB and to develop a colonization risk score in intensive care unit (ICU) patients in a Lebanese tertiary care centre where XDR-AB causes intermittent outbreaks. This retrospective study included 257 patients with baseline negative screening cultures for XDR-AB admitted to a seven-bed ICU from July 2012 to July 2013. Patients' demographic data and clinical characteristics were collected from the hospital's electronic medical records. Univariate analysis of potential risk factors was performed followed by multivariate analysis to determine parameters to be included in the colonization risk score. The rate of XDR-AB acquisition was 15.6%. Multivariate analysis identified urinary catheter placement >6 days (odds ratio: 16.98; 95% confidence interval: 3.96-49.56; P<0.0001), ICU contact pressure for >4 days (2.38; 1.48-3.57; P=0.001), presence of gastrostomy tube (5.44; 1.43-20.68; P=0.013), and previous use of carbapenems or piperacillin-tazobactam (4.20; 1.65-11.81; P=0.002) as parameters to be included in the colonization score. The risk of XDR-AB acquisition was 0, 5.6%, 17.2%, 56.8%, and 80% in the presence of a score of 0, 1, 2, 3, and 4 respectively. A score of 4 indicates high probability of XDR-AB acquisition, suggesting that patient isolation is required; zero indicates a low probability of XDR-AB acquisition. Risk factors could be used to develop a score to decide which patients need isolation to limit the spread of XDR-AB.


Prevalence, clinical characteristics, and outcomes of spontaneous portosystemic shunt in patients with hepatitis B-related cirrhosis: A multicenter study from China.
The impact of spontaneous portosystemic shunt (SPSS) on decompensated events and mortality for patients with hepatitis B-related cirrhosis remains poorly investigated. To evaluate the prevalence, clinical characteristics, and outcomes of SPSS among patients with hepatitis B-related cirrhosis. Patients who were diagnosed with hepatitis B-related cirrhosis were retrospectively recruited. All eligible patients were classified into SPSS and non-SPSS groups and their clinical characteristics and outcomes were compared and analyzed. Of the 1282 patients included in this study, SPSS was identified in 488 patients (38.1%). SPSS group had more severe liver function impairment, higher prevalence and severity of esophageal and gastric varices (EGV), and a higher prevalence of EGV bleeding (EGVB), portal vein thrombosis (PVT), hepatic encephalopathy (HE), ascites, and hepatocellular carcinoma (HCC, all P<0.05). During the follow-up period, SPSS group experienced a significantly higher incidence of EGVB, PVT, and HE (all P<0.05); however, there was no significant difference in the incidence of ascites, HCC, and mortality between the two groups (all P>0.05). With hepatitis B-related cirrhosis, SPSS was common and characterized by severe liver damage and a high prevalence of decompensated events. Moreover, patients with SPSS had higher risks of EGVB, PVT, and HE.


Ultrasound block of first branch of the lateral plantar nerve (baxter nerve): case report of a promising and effective treatment for heel chronic pain.
Chronic heel pain is a challenging diagnosis and although it is a common and disabling condition frequently mistreated. Baxter Nerve (BN) entrapment is responsible for 20% of heel pain and can be managed by an ultrasound guide nerve block, a simple, safe, and durable technique. A 67-year-old woman complained of paraesthesia on the left heel and a "stepping on glass" feeling. Various techniques were performed to manage her symptoms without any results. An ultrasound BN block was finally performed with an instant relief and satisfactory pain control for the follow-up period of six months. This clinical report highlights the success of the ultrasound BN block as an effective and lasting solution for chronic heel pain.


Effect of experimental genital mycoplasmosis on gene expression in the fetal brain.
Neurodevelopmental disorders may have their origins during intrauterine development. We used a well-defined animal model to test whether hematogenous infection with genital mycoplasma would alter the expression of genes associated with autism spectrum disorders (ASD). In a preliminary experiment, rats were exposed at 14 days gestation (GD14) to Mycoplasma pulmonis or sterile broth and sacrificed at GD18. Infection and inflammation status of the pups was ascertained by culture and cytokine ELISA. Intra-cardiac injection of 10(6)CFU M. pulmonis resulted in amniotic infection of 100% of the pups and was accompanied by higher levels of IL-1β in amniotic fluids. In a second experiment, animals were infected in a similar manner but dams and their litters were sacrificed at GD18, GD21 or postpartum day 3 (PPD3). Expression of proinflammatory cytokines and neurodevelopmental genes in the fetal brains was evaluated. M. pulmonis infection significantly increased the expression of IL-1β, TNF-α and COX-2 in fetal and neonatal brains. Expression of GFAP and CD11b, markers for activation on astrocytes and microglial cells, respectively, was also increased for infected animals. M. pulmonis significantly increased SHANK-3 gene expression at GD21 and PPD3 and PCP-2 expression at GD21. No effect of M. pulmonis infection on Reelin, PTEN, BDNF or HGF was detected. These data suggest that M. pulmonis infection at GD14 increases the expression of proinflammatory genes in the perinatal brain. Further studies with earlier time-points of infection and ones that use behavioral outcomes are needed to better understand the potential role of genital mycoplasmosis on pychopathology.


The Dependence of Isothermal ω Precipitation on the Quenching Rate in a Metastable β-Ti Alloy.
The precipitation behavior of the α strengthening phase in metastable β-Ti alloys is highly dependent on heat treatment parameters such as quenching rate, heating rate and ageing temperature. In this paper we have investigated the influence of quenching rate on the formation of isothermal ω precipitates that have been regarded as potent nucleant sites for α precipitation. The results show that the β-solutionized alloy contains a β matrix with a layer structured morphology. Regular atomic movement of the (002)β plane along the <002> direction was observed in the alloy. The increase in quenching rate refines the thickness of layers, subsequently influencing the nucleation and growth of isothermal ω precipitates after ageing treatment. The high quenching rate promotes the occurrence of ω precipitation, broadens the stage of ω precipitation and increases the number density of ω precipitates. Since the isothermal ω phase provides a heterogeneous nucleation site for α precipitates, it is inferred that the quenching rate may indirectly influence the mechanical properties of metastable β-Ti alloy.


Doxycycline Treatment of Mansonella perstans-Infected Individuals Affects Immune Cell Activation and Causes Long-term T-cell Polarization.
Doxycycline is used for treatment of Mansonella perstans infection. Immune modulatory effects of both M. perstans and doxycycline have been described but long-term implications on host immune response are not defined. Here we determined multiple immune parameters of M. perstans-infected individuals before and after doxycycline treatment to characterize doxycycline effects on host T-cell immunity. Immune characterization of doxycycline-treated M. perstans-infected individuals was performed as part of an open-label randomized clinical trial. Immune cell population phenotyping by flow cytometry and functional in vitro T-cell assays were performed at baseline, 6 months, and "long term" (18-24 months) after treatment start. Treatment efficacy, based on peripheral blood microfilaria (mf) burden, was correlated with immune parameters and effects on immune response against concomitant Mycobacterium tuberculosis infection were determined. Immune population phenotyping indicated changes in functional T-cell responses after doxycycline treatment. Constitutive and superantigen-induced T-cell activation and polarization towards T-helper type (TH) 1 phenotype at baseline declined after doxycycline treatment, whereas low proportions of TH17 and TH1* cells at baseline increased significantly at follow-up. In accordance, long-term decline in antigen-specific TH1 responses against concomitant M. tuberculosis infection was seen. Notably, only TH17 and TH1* changes after 6 months and TH17 at baseline were negatively correlated with M. perstans microfilaria burden or reduction, whereas long-term changes were not associated with treatment efficacy. We found long-term immune modulatory effects of doxycycline treatment leading to decreased constitutive T-cell activation, polarization towards TH17/TH1*, and impaired immune response against concomitant M. tuberculosis infection.


Marginal bone preservation in single-tooth replacement: a 5-year prospective clinical multicenter study.
Although this study heralded that over half the implants gained bone, this was between 1 and 5 years after placement, the amounts were trivial, and this has to be balanced with loss of bone during the first year.


ΔNp63 expression in four carcinoma cell lines and the effect on radioresistance--a siRNA knockdown model.
This study investigated the expression of ΔNp63α in carcinoma cell lines of the upper aerodigestive tract and their potential influence on radioresistance using a small interfering RNA (siRNA) knockdown approach. Four carcinoma cell lines were investigated for the expression of the ΔNp63 isoform by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (0, 24, 48 h) with and without single dose irradiation of 6 Gy. Furthermore, all cell lines were transfected with siRNA against the ΔNp63α isoform over 24 h. Knockdown effectiveness was controlled by qRT-PCR and Western blot. Apoptotic events were evaluated by terminal transferase dUTP nick end labeling (TUNEL) assay and cross-checked by a test for cell viability (WST-1, Roche) over 48 h. All cell lines presented varying expression of the ΔNp63α isoform with and without irradiation. A sufficient knockdown rate was established by siRNA transfection. Knockdown of the ΔNp63 isoform showed an effect on radiation sensitivity proven by an increase of apoptotic events detectable by immunofluorescence (TUNEL assay) and likewise a significant reduction of formazan production (WST-1 test) in three cell lines. We found overexpression of ΔNp63α with and without irradiation in three cell lines, and the knockdown of ΔNp63α led to increased apoptotic events and fewer viable cells. Thus, the overexpression of ΔNp63α might protect carcinoma cells against irradiation effects. The present work supports the hypothesis that protein 63 might serve as a negative predictor for irradiation response and survival in a clinical setting and may be a target for future therapeutic strategies.


Lower dental caries prevalence associated to chronic kidney disease: a systematic review.
The aim of this systematic review was to determine whether there is any evidence in the literature referring to a lower prevalence of dental caries in children and adolescents with chronic kidney disease (CKD) compared to healthy individuals. A search of the PubMed Medline, Ovid Medline and Cochrane Library databases was performed using the MeSH terms "dental caries" and "chronic renal failure". To be eligible for entry in our study, controlled observational studies had to present a decayed, missing and filled index for primary teeth (dmft) and/or for permanent teeth (DMFT) in children and adolescents with CKD. After evaluation of title, keywords and abstracts of the articles selected, six articles met the inclusion criteria. Three of these six articles included studies which showed susceptibility to bias and possible confounding factors. A subsequent assessment of the six studies revealed that the mean caries indices in both primary (dmf) and permanent (DMF) teeth were lower in the children and adolescents with CKD compared with healthy individuals. Data in the literature weakly support a lower prevalence of caries in children and adolescents with CKD than in their healthy counterparts. There is still a lack of well-designed studies that provide better scientific evidence in support of this conclusion.


Perception of happy and sad facial expressions in chronic schizophrenia: evidence for two evaluative systems.
Persons suffering from schizophrenia have impaired perception of emotional expressions, but it is not clear whether this is part of a generalized deficit in cognitive function. To test for existence of emotion-specific deficits by studying the effects of valence on recognition of facial emotional expressions. 24 male subjects suffering from chronic schizophrenia were examined with two tests of perception of emotion: the Penn Emotion Acuity Test (PEAT 40) and the Emotion Differentiation Task (EMODIFF). Clinical state was assessed with the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS), visual memory with the Benton Visual Retention Test (BVRT) and motor function with the finger tapping test. Identification of happy facial expressions showed significant negative correlation with age, cumulated time in hospital and length of current hospitalization; positive correlations were found with visual retention and finger tapping scores. Identification of sad facial expressions showed significant correlation only with cumulated time in hospital while identification of neutral facial expressions showed no significant correlations. Discrimination between degrees of happy but not sad facial expression showed a positive correlation with negative symptoms. Perception of happy and sad emotion relates differently to significant illness parameters. This differentiability supports the existence of an emotion-specific deficit in perception of emotions in schizophrenia and of separate channels for processing positive and negative emotions.


Multiple origins of transcription for the human placental lactogen genes.
Transcriptional activity of the three human placental lactogen (hPL) genes was compared in vitro and their relation to the hPL RNA species obtained from term placenta was analyzed. We used in vitro transcription system containing the HeLa cell crude extract as the source for RNA polymerase II and initiation factors. Gene fragments of identical length of 0.96 kilobase pair made from hPL1, hPL3, and hPL4 each contained the 5' flanking sequence of 497 base pairs, the first exon, the first intron, and a portion of the second exon. More than 90% transcripts of the hPL1 template were 470 nucleotides long, indicating that transcription was initiated at the proposed cap site. hPL3 and hPL4 genes generated heterogeneous RNA products of about 430, 470, 520, and 680 nucleotides suggesting that multiple start points were recognized for RNA synthesis in vitro. alpha-Amanitin sensitivity of transcription indicated that the DNA-dependent RNA synthesis was carried out by RNA polymerase II. These results show that hPL1, hPL3, and hPL4 genes have functional promoters and multiple initiation sites for transcription. Primer extension analysis of the 5' termini of hPL RNA isolated from term placenta shows that 82-83% of the transcripts are initiated at a region 29 base pairs downstream from a "TATA" sequence. This origin is observed in vitro for the transcript 470 nucleotides long. An additional upstream initiation region (-53) accounts for 8% of transcripts in term placenta and corresponds to the origin for the in vitro transcript of 520 nucleotides. At least three other sites 15, 23, and 39 base pairs downstream from the major cap site are functional in vivo. The initiation site at +40 is utilized preferentially for transcription from hPL3 and hPL4 genes in vitro. We have mapped the different transcription origins on hPL genes.


Genotype-phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients.
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurodegenerative disorders. Although, several genotype-phenotype studies have carried out on HSPs, the association between genotypes and clinical phenotypes remain incomplete since most studies are small in size or restricted to a few genes. Accordingly, this study provides the systematic meta-analysis of genotype-phenotype associations in HSP. We retrieved literature on genotype-phenotype associations in patients with HSP and mutated SPAST, REEP1, ATL1, SPG11, SPG15, SPG7, SPG35, SPG54, SPG5. In total, 147 studies with 13,570 HSP patients were included in our meta-analysis. The frequency of mutations in SPAST (25%) was higher than REEP1 (3%), as well as ATL1 (5%) in AD-HSP patients. As for AR-HSP patients, the rates of mutations in SPG11 (18%), SPG15 (7%) and SPG7 (13%) were higher than SPG5 (5%), as well as SPG35 (8%) and SPG54 (7%). The mean age of AD-HSP onset for ATL1 mutation-positive patients was earlier than patients with SPAST, REEP1 mutations. Also, the tendency toward younger age at AR-HSP onset for SPG35 was higher than other mutated genes. It is noteworthy that the mean age at HSP onset ranged from infancy to adulthood. As for the gender distribution, the male proportion in SPG7-HSP (90%) and REEP1-HSP (78%) was markedly high. The frequency of symptoms was varied among patients with different mutated genes. The rates of LL weakness, superficial sensory abnormalities, neuropathy, and deep sensory impairment were noticeably high in REEP1 mutations carriers. Also, in AR-HSP patients with SPG11 mutations, the presentation of symptoms including pes cavus, Neuropathy, and UL spasticity was higher. Our comprehensive genotype-phenotype assessment of available data displays that the mean age at disease onset and particular sub-phenotypes are associated with specific mutated genes which might be beneficial for a diagnostic procedure and differentiation of the specific mutated genes phenotype among diverse forms of HSP.


ADHD and infant disorganized attachment: a prospective study of children next-born after stillbirth.
To examine whether infant disorganized attachment predicts ADHD at school age. A cohort of 53 children who had been identified as having significant levels of disorganized attachment in infancy is compared to a control group. Symptoms and signs of ADHD at age 7 are evaluated together with a range of relevant maternal variables. An association is found between infant disorganized attachment scores and teacher-rated symptoms of ADHD (but not ADHD caseness). Probable ADHD caseness in the child is associated with self-rated retrospective ADHD scores in mothers. Possible ADHD caseness is associated with a measure of unresolved mourning in mothers. Mother-rated ADHD in the child was associated with low overall maternal psychosocial functioning. The finding of a link between scores for disorganized attachment at 1 year and later teacher-rated symptoms of ADHD suggests the need for further studies.


Hyperthermia-induced modulation of killing and mutation by UV and N-methyl-N'-nitro-N-nitrosoguanidine in V79 cells.
Hyperthermic exposures of V79 cells did not affect the killing by UV light, whereas it enhanced MNNG-induced killing. Such hyperthermic exposure increased the mutation induction (resistance to 6-thioguanine) by both UV and MNNG. The timing of heat exposure, before or after the treatments, had no effect on the result in cases of cytotoxicity and mutagenesis.


Transcriptional activity of the host-interaction locus and a putative pilin gene of Bdellovibrio bacteriovorus in the predatory life cycle.
Bdellovibrio bacteriovorus is a predatory bacterium that grows and replicates within the periplasm of a large variety of Gram-negative bacteria. So far, the host-interaction locus (hit locus) is the only genetic locus that is implicated in the obligate predatory lifestyle. Sequence analysis revealed that upstream of the hit locus, the genomic regions of the two obligate predatory B. bacteriovorus-type strains HD100 and HD114 encode genes for pilus formation. As pili might be involved in the invasion process, the transcriptional activity of the hit locus and of a putative pilin gene (flp1) of the pilus cluster were studied in synchronized cultures of B. bacteriovorus with Escherichia coli K-12 as prey bacteria. Stages of the life cycle were monitored with scanning electronic microscopy and transcriptional analyses were performed by quantitative reverse transcription polymerase chain reaction. Our study revealed an increased expression level of the putative hit and flp1 genes in the attack phase of B. bacteriovorus, whereas the transcriptional activity significantly decreased during the intracellular replication phase.


Early prediction of clinical deterioration using data-driven machine-learning modeling of electronic health records.
To develop and evaluate a high-dimensional, data-driven model to identify patients at high risk of clinical deterioration from routinely collected electronic health record (EHR) data. In this single-center, retrospective cohort study, 488 patients with single-ventricle and shunt-dependent congenital heart disease <6 months old were admitted to the cardiac intensive care unit before stage 2 palliation between 2014 and 2019. Using machine-learning techniques, we developed the Intensive care Warning Index (I-WIN), which systematically assessed 1028 regularly collected EHR variables (vital signs, medications, laboratory tests, and diagnoses) to identify patients in the cardiac intensive care unit at elevated risk of clinical deterioration. An ensemble of 5 extreme gradient boosting models was developed and validated on 203 cases (130 emergent endotracheal intubations, 34 cardiac arrests requiring cardiopulmonary resuscitation, 10 extracorporeal membrane oxygenation cannulations, and 29 cardiac arrests requiring cardiopulmonary resuscitation onto extracorporeal membrane oxygenation) and 378 control periods from 446 patients. At 4 hours before deterioration, the model achieved an area under the receiver operating characteristic curve of 0.92 (95% confidence interval, 0.84-0.98), 0.881 sensitivity, 0.776 positive predictive value, 0.862 specificity, and 0.571 Brier skill score. Performance remained high at 8 hours before deterioration with 0.815 (0.688-0.921) area under the receiver operating characteristic curve. I-WIN accurately predicted deterioration events in critically-ill infants with high-risk congenital heart disease up to 8 hours before deterioration, potentially allowing clinicians to target interventions. We propose a paradigm shift from conventional expert consensus-based selection of risk factors to a data-driven, machine-learning methodology for risk prediction. With the increased availability of data capture in EHRs, I-WIN can be extended to broader applications in data-rich environments in critical care.


Correlation of the exon/intron organization to the conserved domains of the mouse transcriptional corepressor TIF1beta.
TIF1beta, a member of the transcriptional intermediary factor 1 family, has been reported to function as a corepressor for the large class of KRAB domain-containing zinc finger proteins of the Krüppel type. In this study, we report the genomic organization and nucleotide sequence of the mouse TIF1beta gene. This gene comprises 17 coding exons located within 7 kb of genomic DNA. Exon sizes vary from 37 bp (exon 10) to 901 bp (exon 1), and intron sizes range from 71 bp to 1843 bp. All introns have the conserved GT and AG dinucleotides present at the donor and acceptor sites, respectively. The functional/homology regions of the TIF1beta protein are encoded by distinct exons. The amino-terminal RING finger is encoded by two exons interrupted by a small intron. The B boxes lie within individual exons. Similarly to the RING finger, the PHD finger is encoded by two exons. Three exons constitute the carboxy-terminal bromodomain, and their position correlates well with the secondary structure elements of the domain as predicted by computer modeling. Taken together, these results will facilitate the genetic manipulation of TIF1beta for future in vivo structure-function studies.


Hypothesizing that brain reward circuitry genes are genetic antecedents of pain sensitivity and critical diagnostic and pharmacogenomic treatment targets for chronic pain conditions.
While it is well established that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and in the medulla, the control and sensitivity to pain may reside in additional neurological loci, especially in the mesolimbic system of the brain (i.e., a reward center), and a number of genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. It is hypothesized that these polymorphisms associate with a predisposition to intolerance or tolerance to pain. It is further hypothesized that identification of certain gene polymorphisms provides a unique therapeutic target to assist in the treatment of pain. It is hereby proposed that pharmacogenetic testing of certain candidate genes (i.e., mu receptors, PENK etc.) will result in pharmacogenomic solutions personalized to the individual patient, with potential improvement in clinical outcomes.


High-frequency stimulation in the ventral posterolateral thalamus reverses electrophysiologic changes and hyperalgesia in a rat model of peripheral neuropathic pain.
Chronic neuropathic pain is associated with long-term changes at multiple levels of the neuroaxis, including in the brain, where electrical stimulation has been used to manage severe pain conditions. However, the clinical outcome of deep brain stimulation is often mixed, and the mechanisms are poorly understood. By means of electrophysiologic methods, we sought to characterize the changes in neuronal activity in the ventral posterolateral nucleus of the thalamus (VPL) in a rat model of peripheral neuropathic pain, and to reverse these changes with low-voltage, high-frequency stimulation (HFS) in the VPL. Extracellular single-unit neuronal activity was recorded in naive rats and in those with sciatic chronic constriction injury (CCI). Seven days after CCI, brush- and pinch-evoked firing, as well as spontaneous firing and afterdischarge, were significantly increased compared to naive rats. Spontaneous rhythmic oscillation in neuronal firing was also observed in rats with CCI. HFS decreased neuronal firing rates in rats with CCI up to ~50% except for spontaneous activity, whereas low-frequency stimulation had no effect. Compared to naive rats, burst firing properties (burst events, percentage of spikes in burst, and mean interburst time) were altered in rats with CCI, whereas these changes were reversed to near normal after HFS. Thermal hyperalgesia in rats with CCI was significantly attenuated by HFS. Therefore, this study demonstrates that electrical stimulation within the VPL can effectively modulate some nociceptive phenomena associated with peripheral neuropathic pain.


Consumption of medicinal plants by patients with heart diseases at a pharmacist-managed anticoagulation clinic in Brazil.
Medicinal plants (MP) have been used for many years with the purpose of feeding and curing. Several MP may interfere in drug response and are not always considered as potential drug-interactors in clinical practice. To investigate the consumption of MP by outpatients during a one-year follow-up. Patients with cardiopathy diagnosis and indication(s) for long-term use of warfarin were recruited at a pharmacist-managed anticoagulation clinic of a Brazilian public hospital. This research employed a descriptive method. The consumption of MP was examined regarding the type, frequency and forms of use. A total of 280 patients were studied. Most patients were female (54.6 %) with an average age of 56.8 ± 13.1 years. The consumption of MP was reported by 46 (16.4 %) patients, totalizing 59 occurrences. Lemon, lemon balm and plantain were the most common MP. The main pharmacological uses involved the digestive, urinary, and respiratory tracts. Tea was the predominant form of consumption (87 %). Twelve (33.3 %) plants presented potential herb-warfarin interactions according to the literature. We described the consumption of MP among outpatients characterized by their complex disease status, propensity for adverse events, and socioeconomic limitations. These results may guide pharmacist interventions and procedures to prevent clinical complications.


Orbital decompressive effect of endoscopic transorbital surgery for sphenoorbital meningioma.
This study was aimed at evaluating the orbital decompressive effect of endoscopic transorbital approach (TOA) in the management of sphenoorbital meningioma involving the orbit. Patients treated with TOA for this tumor from December 2016 to December 2019 were included, and the data were reviewed. Pre- and postoperative clinical and imaging findings were compared with a volumetric study. Eighteen patients (two men and 16 women) were included. Lateral wall hyperostosis (13 patients), extraconal tumor infiltration (18 patients), intraconal tumor infiltration (seven patients), and superior and lateral rectus encasement (nine patients) were found. Intraconal tumor infiltration in the posterior orbit affected compressive optic neuropathy (CON) more often than other tumor manifestations. The orbital soft tissue volume decreased to 91.18% ± 8.19% compared to that in the contralateral side preoperatively. The postoperative volume increased to 113.73% ± 12.92% compared to the preoperative volume. The average values of LogMAR visual acuity and visual field index score of ten patients with CON improved from 0.80 to 0.42 and 48.9 to 65.9%, respectively. All 17 patients with proptosis showed improvement after surgery. There were no significant complications associated with the surgery. Additional treatment, including gamma knife surgery, was applied to 12 cases for the remaining tumor. This minimally invasive surgical debulking procedure was successful in treating sphenoorbital meningioma without significant adverse events. Lateral orbital wall decompression and limited intraorbital tumor resection were effective for compressive orbitopathy from the tumor.


Very high baseline HIV viremia impairs efficacy of non-nucleoside reverse transcriptase inhibitor-based ART: a long-term observation in treatment-naïve patients.
It is not completely clear whether a very high pre-therapy viral load (≥ 500 000 copies/ml) can impair the virological response. The aim of this study was to examine the influence of very high baseline HIV-RNA levels on long-term virological responses under one type of regimen. A retrospective study was performed based on data from two multicenter cohorts in China from January to November 2009, and from May 2013 to December 2015. Untreated HIV infected adults between 18 and 65 years old were recruited before receiving non-nucleoside reverse transcriptase inhibitor-based regimen. All patients had baseline HIV-RNA levels over 500 copies/ml, good adherence, and were followed for at least 24 weeks. Virological suppression was defined as the first HIV-RNA < 50 copies/ml. Virological failure was defined as any of incomplete viral suppression (HIV-RNA ≥ 200 copies/ml without virological suppression within 24 weeks of treatment) and viral rebound (confirmed HIV-RNA level ≥ 50 copies/ml after virological suppression). Chi-square test, Kaplan-Meier analysis, Cox proportional hazards model and Logistic regression were used to compare virological response between each pretreated viral load stratum. A total of 758 treatment-naïve HIV patients in China were enlisted. Median follow-up time (IQR) was 144 (108-276) weeks. By week 48, rates of virological suppression in three groups (< 100 000, 100 000-500 000 and ≥ 500 000 copies/ml) were 94.1, 85.0, and 63.8%, respectively (P < 0.001). Very high baseline HIV viremia over 500 000 copies/ml were found to be associated with delayed virological suppression (≥ 500 000 vs < 100 000, adjusted relative hazard = 0.455, 95% CI: 0.32-0.65; P < 0.001) as well as incomplete viral suppression (≥ 500 000 vs < 100 000, adjusted odds ratio [aOR] = 6.084, 95% CI: 2.761-13.407; P < 0.001) and viral rebound (≥ 50 000 vs < 100 000, aOR = 3.671, 95% CI: 1.009-13.355, P = 0.048). Very high levels of pre-treatment HIV-RNA were related with delayed efficacy of NNRTI-based ART and increased risk of treatment failure. More potent initial regimens should be considered for those with this clinical character.


Short-Term Impacts of Pulse: An App-Based Teen Pregnancy Prevention Program for Black and Latinx Women.
Black and Latinx women aged 18-20 years have high rates of unplanned pregnancy. Furthermore, this age group is less likely than school-aged youth to be served by pregnancy prevention programs typically administered in schools. The study's purpose was to assess the effectiveness of a new app-based teen pregnancy prevention program created for this population using an online- and texting-only recruitment and evaluation approach. The study design was a randomized controlled trial with individual-level assignment of 1,304 women aged 18-20 years recruited online. Seventy-six percent of participants were black or Latinx. Women were randomized to the Pulse reproductive health app or a general health app and received regular text messages with program content and reminders to view the app. An intention-to-treat approach was used for analyses, and significance tests were adjusted to account for permuted block random assignment and multiple hypothesis testing. Linear probability models controlling for the baseline measure of each outcome, whether the participant reported ever having vaginal sex, age, and race/ethnicity, assessed program impacts for 1,124 participants 6 weeks after randomization. Participants who received the intervention were 7.6 percentage points less likely (p = .001) to report having had sex without a hormonal or long-acting contraceptive method. Intervention participants also scored 7.1 percentage points higher on contraceptive knowledge (p = .000) and were 5.7 percentage points more likely to be confident that they can use birth control during every sexual intercourse (p = .027). Impacts at 6 weeks are promising, particularly for a self-led intervention with no direct contact with study staff.


Masked "myxedema madness".
Hypothyroidism can present a wide range of psychiatric manifestations, including personality disturbance, neurotic traits and psychotic features. Psychiatric treatment techniques without recognition and correction of the endocrine root of the mental disturbance will result in a failure of treatment. However, severe hypothyroidism can exist with a poverty of classical signs and symptoms such that both internist and psychiatrist may easily overlook endocrine dysfunction as a possible etiology of the mental disorder. A case of long-standing paranoid illness whose etiology was severe myxedema with such a poverty of signs and symptoms is presented. Failure to recognize the endocrinopathy may not only produce recovery difficulties but also psychiatric and endocrine repercussions if psychotropic medications are given in such masked cases. These problems are considered with particular reference to lithium, and screening criteria to avoid this problem are discussed.


Blood flow in the foetal superior vena cava and the effect of foetal breathing movements.
The superior vena cava (SVC) drains venous blood from the upper foetal body, mainly the head. Data on the human foetus is scarce. Here we present reference values for the blood flow during the second half of pregnancy, and test the hypothesis that foetal breathing movements (FBM) enhance this flow. Based on a power calculation, 110 women with low-risk singleton pregnancies were recruited to a longitudinal study that included three sets of observations during the second half of pregnancy. Ultrasound was used to determine inner diameter, peak systolic blood velocity and time-average maximum velocities in the SVC during rest and respiratory activity. During the second half of pregnancy, SVC blood flow increased from 57.8 mL/min (95% CI 51.7-64.3) to 221.5 (204.5-239.3). Based on 558 sets of observations obtained during foetal rest and FBM, we found an overall increase in diameter from 0.41 cm (0.40-0.42) to 0.46 (0.44-0.48), peak systolic velocity from 35.9 cm/s (34.9-37.0) to 62.2 (59.1-65.5), and time-averaged maximum velocity from 20.3 cm/s (19.7-20.8) to 27.3 (26.1-28.6). This resulted in an overall 90% increase in mean SVC blood flow, from 108.1 mL/min (98.8-117.9) at rest to 205.9 (183.2-230.5) during FBM. The blood flow in the SVC increases during the second half of pregnancy and is substantially augmented during FBM. Since high-amplitude FBM additionally reduces flow in the inferior vena cava, the net effect is a prioritised venous drainage from the foetal head enhancing the washout of CO(2) in that area, which also contains the chemoreceptors.


Artificial aptamer that inhibits interleukin-23/interleukin-23 receptor interaction discovered via SELEX.
Interaction between the pro-inflammatory cytokine interleukin-23 (IL-23) and IL-23 receptor (IL-23R) is related to the development of inflammatory autoimmune diseases such as psoriasis, inflammatory bowel disease, and Crohn's disease. In this study, we conducted systematic evolution of ligands by exponential enrichment (SELEX) for in vitro selection against human IL-23 and observed RNA sequence enrichment in the final SELEX round. IL-23-pull-down assay by chemiluminescence detection and fluorescence imaging demonstrated that SELEX-enriched RNA clone bound to IL-23. Quantitative polymerase chain reaction-based pull-down assay using the IL-23 alpha (IL-23A) subunit, a component of the IL-23 heterodimer, indicated that the RNA clone bound to IL-23A, which is favorable for autoimmune disease treatment. We also observed that the novel IL-23-binding RNA aptamer inhibited interaction between IL-23 and IL-23R. Thus, the novel IL-23-binding RNA aptamer can be used for IL-23 studies and has potential to be used for IL-23 diagnosis and IL-23-related inflammatory autoimmune disease treatment.


The field-dependence of the solid-state photo-CIDNP effect in two states of heliobacterial reaction centers.
The solid-state photo-CIDNP (photochemically induced dynamic nuclear polarization) effect is studied in photosynthetic reaction centers of Heliobacillus mobilis at different magnetic fields by (13)C MAS (magic-angle spinning) NMR spectroscopy. Two active states of heliobacterial reaction centers are probed: an anaerobic preparation of heliochromatophores ("Braunstoff", German for "brown substance") as well as a preparation of cells after exposure to oxygen ("Grünstoff", "green substance"). Braunstoff shows significant increase of enhanced absorptive (positive) signals toward lower magnetic fields, which is interpreted in terms of an enhanced differential relaxation (DR) mechanism. In Grünstoff, the signals remain emissive (negative) at two fields, confirming that the influence of the DR mechanism is comparably low.


The Silverman Andersen respiratory severity score in the delivery room predicts subsequent intubation in very preterm neonates.
Treatment with mechanical ventilation is associated with chronic lung disease and poor neurologic outcomes in very premature neonates. Surfactant replacement in patients with respiratory distress syndrome reduces need for mechanical ventilation and may be most beneficial when performed early.


Surgical treatment of carotid paragangliomas presenting unusual technical difficulties. The value of preoperative embolization.
Although the application of reconstructive vascular surgical procedures to the treatment of carotid paragangliomas has made their resection the method of choice and has produced excellent cure rates, it has not obviated some of the technical problems presented by excessively vascular, adherent, or bulky lesions. Our experience with preoperative trans-catheter embolization for the reduction of the vascularity in six cases of this group of lesions is presented and the conclusion is made that preoperative embolization greatly reduced operative technical difficulties.


Electronic Patient-reported Outcomes During Breast Cancer Adjuvant Radiotherapy.
Patient-reported outcomes (PROs) have become extremely important in following patients' health-related quality of life during cancer treatments. The aim of this study was to assess the usefulness of electronic PROs (ePROs) during adjuvant radiotherapy (RT) in patients with early breast cancer. A registry trial was conducted with a total of 253 patients with breast cancer receiving RT. Adverse event data were collected from 9 items on the ePRO questionnaires that were administered before RT (N = 253), at the end of RT (± 3 days; N = 234), 1 month after RT (N = 230), and 3 months (N = 225) after RT. The patient characteristics and treatment details were collected from the medical records. The patients have started actively using the ePRO system, and the response rates were high (82.6%). During RT, 39.3% of the ePRO responses were about symptoms, and 60.7% were about treatment-related questions or advice. Patients treated with hypofractionated RT reported fewer local adverse events such as skin symptoms (P = .001) and pain (P = .002) than those who received conventional RT. One of the main findings of this study was that tiredness, fatigue, and anxiety were commonly reported on the patients' ePRO questionnaires, but they were rarely recorded in the medical records. Patients were motivated to use the ePRO system, and the response rates were high. Additionally, patients seemed to find that the ePRO system was an easy way to contact their own health care professionals. More attention should be paid to mental well-being during visits to the clinic.


Candidate human papillomavirus (HPV) type 27b: nucleotide sequence and heterogeneity with HPV 27.
More than 100 human papillomavirus (HPV) types have been reported as tumorigenic agents. HPV types 2 and 27 were identified in benign tumors and classified closely according to the sequence homology. An HPV type 2 related sequence was identified previously in an oral papilloma. However, the correct typing and sequencing was impossible at that time. A candidate HPV was cloned by the long-PCR technique from an oral papilloma and characterized by nucleotide sequence. This virus was basically HPV type 27, but there was some heterogeneity in comparison with the prototype. Most differences were nucleotide-sequence variations. Two of four-nucleotide insertions were frame shift, resulting in longer L1 protein than that of HPV 27.


Effects of a vertical console position on operator muscular stress during ultrasonic diagnosis.
Ultrasound examinations tend to put sonographers in unnatural postures, which may lead to musculoskeletal disorders. In this study, we focused on the height of the operation panel of the diagnostic ultrasound system to quantitatively assess the effects of panel height (work plane height) on musculoskeletal stress during scanning in a sitting position. Eight subjects were asked to perform a simulated scanning task that involved touching nine points on the operation panel at four different panel heights. Electromyogram, left wrist joint angle, and subjective evaluation on ease of manipulation, etc., indicated that the optimum height of the operation panel during scanning in a sitting position is elbow height.


Spatial-temporal dynamics and time series prediction of HFRS in mainland China: A long-term retrospective study.
Hemorrhagic fever with renal syndrome (HFRS) is highly endemic in mainland China. The current study aims to characterize the spatial-temporal dynamics of HFRS in mainland China during a long-term period (1950-2018). A total of 1 665 431 cases of HFRS were reported with an average annual incidence of 54.22 cases/100 000 individuals during 1950-2018. The joint regression model was used to define the global trend of the HFRS cases with an increasing-decreasing-slightly increasing-decreasing-slightly increasing trend during the 68 years. Then spatial correlation analysis and wavelet cluster analysis were used to identify four types of clusters of HFRS cases located in central and northeastern China. Lastly, the prophet model outperforms auto-regressive integrated moving average model in the HFRS modeling. Our findings will help reduce the knowledge gap on the transmission dynamics and distribution patterns of the HFRS in mainland China and facilitate to take effective preventive and control measures for the high-risk epidemic area.


The effect of long-term spaceflight on drug potency and the risk of medication failure.
Pharmaceuticals selected for exploration space missions must remain stable and effective throughout mission timeframes. Although there have been six spaceflight drug stability studies, there has not been a comprehensive analytical analysis of these data. We sought to use these studies to quantify the rate of spaceflight drug degradation and the time-dependent probability of drug failure resulting from the loss of active pharmaceutical ingredient (API). Additionally, existing spaceflight drug stability studies were reviewed to identify research gaps to be addressed prior to exploration missions. Data were extracted from the six spaceflight studies to quantify API loss for 36 drug products with long-duration exposure to spaceflight. Medications stored for up to 2.4 years in low Earth orbit (LEO) exhibit a small increase in the rate of API loss with a corresponding increase in risk of product failure. Overall, the potency for all spaceflight-exposed medications remains within 10% of terrestrial lot-matched control with a ~1.5 increase in degradation rate. All existing studies of spaceflight drug stability have focused primarily on repackaged solid oral medications, which is important because non-protective repackaging is a well-established factor contributing to loss of drug potency. The factor most detrimental to drug stability appears to be nonprotective drug repackaging, based on premature failure of drug products in the terrestrial control group. The result of this study supports a critical need to evaluate the effects of current repackaging processes on drug shelf life, and to develop and validate suitable protective repackaging strategies that help assure the stability of medications throughout the full duration of exploration space missions.


Double knockout of β-lactamase and cephalosporin acetyl esterase genes from Escherichia coli reduces cephalosporin C decomposition.
The phenomenon of CPC decomposition occurs in Escherichia coli JM105/pMKC-sCPCacy during the one-step enzymatic conversion of cephalosporin C (CPC) into 7-aminocephalosporanic acid (7-ACA) by CPC acylase (sCPCAcy) for synthesis of cephalosporin antibiotics. E. coli JM105/pMKC-sCPCacy can constitutively produce sCPCacy as a fusion protein with maltose binding protein (MBP). Control experiments verified that the cell lysis solution from the host E. coli JM105 resulted in CPC decomposition by approximately 15%. Two miscellaneous enzymes, β-lactamase (AmpC) and cephalosporin acetyl esterase (Aes), are believed to play a major role in the degradation of CPC. Using the Red recombination system, the genes ampC, aes or both ampC and aes were knocked out from the chromosome of E. coli JM105 to generate the engineers: E. coli JM105(ΔampC), E. coli JM105(Δaes) and E. coli JM105(ΔampC, Δaes). The CPC decomposition was reduced to 12.2% in E. coli JM105(Δaes), 1.3% in E. coli JM105(ΔampC), and even undetectable in ampC-aes double knockout cells of E. coli JM105(ΔampC, Δaes). When catalyzed by crude MBP-sCPCAcy isolated from E. coli JM105(ΔampC, Δaes)/pMKC-sCPCacy (3377U·l(-1)), the CPC utilization efficiency increased to 98.4% from the original 88.7%. Similar results were obtained for the ampC-aes double knockout host derived from E. coli JM109(DE3) and the CPC utilization efficiency enhanced to 99.3% in the catalysis of crude sCPCAcy harvested from E. coli JM109(DE3, ΔampC, Δaes)/pET28-sCPCacy.


Self-practice/self-reflection as an alternative to personal training-therapy in cognitive behavioural therapy training: A qualitative analysis.
The study examined the qualitative impact and credibility of self-practice/self-reflection (SP/SR). Nineteen participants reflected on the self-practice of cognitive behavioural therapy techniques. Written reflections were analysed using inductive thematic analysis. Two superordinate themes (a) Personal-self and (b) Therapist-self, with themes and subthemes emerged. The themes found equivalents in existing goals of traditional therapists' training-therapy. Though brief, SP/SR may be a credible alternative/adjunctive training-therapy.


Experimental and numerical assessment of two reconstructive techniques for the fragility fractures of the pelvis type Ia.
Anterior pelvic ring fractures are common in geriatric patients. The Supraacetabular External Fixator (SEF) is a relatively simple and effective surgical procedure. On the other hand, there is the option of a Subcutaneous Iliopubic Plate (SIP) osteosynthesis. Only limited comparative biomechanical data of these two devices are available. Therefore, this biomechanical study's objective was to compare the stabilizing effect of the SEF versus the SIP in a model of Fragility Fractures of the Pelvis (FFP) type Ia. A test stand for pelvic biomechanics testing that emulates the gait loading cycle with physiological relevance was used. The osteotomy on the right pelvic ring was stabilized either with the SEF or the SIP. Strain gauges were used to measure strain in the pelvic ring. The osteotomy's spatial interfragmentary displacement (SID) was monitored using a 3D digital image correlation system. The SEF stabilization reduced the SID by approximately 10%, whereas the locking SIP could reduce displacement by about 62%. Additionally, the SIP reduced the stress/strain levels by 67% in the posterior pelvic ring. We could demonstrate that the SIP is superior to SEF in treating FFP type Ia as it significantly reduced the osteotomy's SID and the strain in the posterior pelvic ring.


Both the shell of the nucleus accumbens and the central nucleus of the amygdala support amphetamine self-administration in rats.
Intracranial self-administration of drugs offers the opportunity to localize the neuronal substrates mediating the rewarding effects of drugs. The purpose of the present study was to explore whether the nucleus accumbens shell and the central nucleus of the amygdala, two components of the "extended amygdala," would support self-administration of the psychostimulant amphetamine. Male Wistar rats were trained to lever press under a Fixed Ratio 1 schedule of reinforcement for D-amphetamine injections (0, 1.0, 1.5, 2.0 and 3.0 microg/microl/inj) into either the nucleus accumbens shell or the central nucleus of the amygdala. An ascending limb dose-response function with peak responding at the 2.0 microg/microl/inj dose was obtained for self-administration at both brain sites. These results indicate that monoaminergic transmission in both the nucleus accumbens shell and the central nucleus of the amygdala mediates the rewarding effects of amphetamine. Further, the present study provides additional evidence about the functional homogeneity of the forebrain continuum called the "extended amygdala."


The interactions between a low molecular weight protease inhibitor of bronchial mucus and chymotrypsin-like cationic proteins of granulocytes.
The proteolytic activity of the chymotrypsin-like cationic proteins of human granulocytes is inhibited by complex formation with the acid-stable low molecular weight protease inhibitor of human bronchial mucus (Ki = 1.0 x 10(7)M). The molar combining ratio is 1:1.


An algorithm to differentiate diabetic respondents in the Canadian Community Health Survey.
This article describes an algorithm to classify respondents to cycle 1.1 (2000/2001) of the Canadian Community Health Survey (CCHS) according to whether they have type 1, type 2 or gestational diabetes. The data are from the chronic disease module and the drug module of cycle 1.1 of the CCHS. A total of 6,361 respondents to cycle 1.1 of the CCHS reported that a health care professional had diagnosed them as having diabetes. The Ng-Dasgupta-Johnson algorithm classifies this group according to whether they have type 1, type 2 or gestational diabetes, based on their answers to CCHS questions about diabetes during pregnancy, use of oral medications to control diabetes, use of insulin, timing of initiation of insulin treatment, and age at diagnosis. Application of an earlier algorithm to CCHS cycle 1.1 results in a 10%-90% split for type 1 and type 2 diabetes. By contrast, the Ng-Dasgupta-Johnson algorithm yields a 5%-95% split. This is not unreasonable, given the rapid rise in obesity, a major risk factor for type 2 diabetes, in Canada.


MPT51 and MPT64-based antigen detection assay for the diagnosis of extrapulmonary tuberculosis from urine samples.
In view of WHO's "End-TB" strategy, we developed a non-invasive, urine-based ELISA, targeting 2 Mycobacterium tuberculosis antigens namely MPT51 and MPT64 for extrapulmonary TB (EPTB) diagnosis. Suspected EPTB patients (n = 137) [Pleural TB, Abdominal TB and Tuberculous meningitis] were categorized in "Definite" EPTB (n = 10) [Xpert-MTB/RIF and/or culture-positive], "Probable" EPTB (n = 77) and "Non-EPTB" (n = 50) groups using defined composite reference standards. ROC-curves were generated using ELISA results of "Definite" EPTB and "Non-EPTB" groups for both antigens independently and cut-off values were selected to provide 86.3% (95%CI:73.3-94.2) specificity for MPT51 and 92% (95%CI:80.8-97.8) for MPT64. The sensitivity of MPT51-ELISA and MPT64-ELISA was 70% (95%CI:34.7-93.3) and 90% (95%CI:55.5-99.7) for "Definite" EPTB group and 32.5% (95%CI:22.2-44.1) and 30.8% (95%CI:20.8-42.2) for "Probable" EPTB group, respectively. Combining the results of both ELISAs showed a 100% (95%CI:69.1-100) sensitivity in "Definite" EPTB group and 41.6% (95%CI:30.4-53.4) in "Probable" EPTB group, with an 80% (95%CI:66.3-89.9) specificity. The results demonstrated the potential of urine-based ELISAs as screening tests for EPTB diagnosis.


Churg-Strauss syndrome associated with third nerve palsy and mononeuritis multiplex of the legs.
We present the rare case of a 62-year-old woman with Churg-Strauss syndrome associated with a left third nerve palsy and a mononeuritis multiplex. Cranial nerve palsies are unusual in patients with Churg-Strauss syndrome, and the most frequent cranial nerve lesion observed is an ischemic optic neuritis. Third nerve involvement secondary to vasculitis-induced ischemia is extremely rare in this disorder.


Dot-immunobinding assay as an accurate and versatile technique for the quantification of human IgG subclasses.
A dot-immunobinding assay on nitrocellulose membranes has been developed for the quantification of human IgG subclasses using subclass-specific monoclonal antibodies. The advantages of this technique can be summarized as follows: (1) possibility of rapid semi-quantitative evaluation and/or precise quantitation from the same dot-pattern; (2) simple procedure with very good reproducibility; (3) sensitivity for nanogram concentrations of individual subclasses, therefore applicable not only to serum but also to other body fluids with a low content of IgG; (4) very small amounts of test material needed; (5) very good correlation of results with other techniques (ELISA, radial immunodiffusion) but without some of the inherent problems of the latter methods.


Effects of an intravenous ketamine infusion on inflammatory cytokine levels in male and female Sprague-Dawley rats.
Ketamine, a multimodal dissociative anesthetic drug, is widely used as an analgesic following traumatic injury. Although ketamine may produce anti-inflammatory effects when administered after injury, the immunomodulatory properties of intravenous (IV) ketamine in a non-inflammatory condition are unclear. In addition, most preclinical studies use an intraperitoneal (IP) injection of ketamine, which limits its clinical translation as patients usually receive an IV ketamine infusion after injury. Here, we administered sub-anesthetic doses of a single IV ketamine infusion (0, 10, or 40 mg/kg) to male and female Sprague-Dawley rats over a 2-h period. We collected blood samples at 2- and 4-h post-ketamine infusion to determine plasma inflammatory cytokine levels using multiplex immunoassays. The 10 mg/kg ketamine infusion reduced spontaneous locomotor activity in male and female rats, while the 40 mg/kg infusion stimulated activity in female, but not male, rats. The IV ketamine infusion produced dose-dependent and sex-specific effects on plasma inflammatory cytokine levels. A ketamine infusion reduced KC/GRO and tumor necrosis factor alpha (TNF-α) levels in both male and female rats, interleukin-6 (IL-6) levels in female rats, and interleukin-10 (IL-10) levels in male rats. However, most cytokine levels returned to control levels at 4-h post-infusion, except for IL-6 levels in male rats and TNF-α levels in female rats, indicating a different trajectory of certain cytokine changes over time following ketamine administration. The current findings suggest that sub-anesthetic doses of an IV ketamine infusion may produce sex-related differences in the effects on peripheral inflammatory markers in rodents, and further research is warranted to determine potential therapeutic effects of an IV ketamine infusion in an inflammatory condition.


Effects of changes in the shape of the intracellular action potential on the peak-to-peak ratio of single muscle fibre potentials.
In situ recording of the intracellular action potential (IAP) of human muscle fibres is not yet feasible, and consequently, knowledge about certain IAP characteristics of these IAPs is still limited. The ratio between the amplitudes of the second and first phases (the so-called peak-to-peak ratio, PPR) of a single fibre action potential (SFAP) is known to be closely related to the IAP profile. The PPR of experimentally recorded SFAPs has been found to be largely independent of changes in the fibre-to-electrode (radial) distance. The main goal of this paper is to analyze the effect of changes in different aspects of the IAP spike on the relationship between PPR and radial distance. Based on this analysis, we hypothesize about the characteristics of IAPs obtained experimentally. It was found that the sensitivity of the SFAP PPR to changes in radial distance is essentially governed by the duration of the IAP spike. Assuming that, for mammals, the duration of the IAP rising phase lies within the range 0.2-0.4ms, we tentatively suggest that the duration of the IAP spike should be over approximately 0.75ms, with the shape of the spike strongly asymmetric. These IAP characteristics broadly coincide with those observed in mammal IAPs.


[Evaluation of dark field microscopic techniques and correlation between DFM data and clinical periodontal parameters].
Two subgingival sampling methods (curette and washing) used in DFM were compared. The effect of repeated washing sampling to subgingival microflora were also evaluated. These results demonstrated that washing techniques and curette could be used alternatively. No significant change of subgingival flora were observed after repeated washing sampling were used. 204 bacterial samples obtained from different periodontal status were analysed by DFM. The data showed that there was significant positive correlation between spirochete%, motile rods % and P1I. BI. PD, both incross-sectioned and longitudinal analysis (22 samples DFM assessed before and after periodontal treatment). Also, our data suggested that it was impossible to establish a threshold level of microorganism to diagnose periodontal diseases only by DFM analysis.


Carcinogenesis induced by black pepper (Piper nigrum) and modulated by vitamin A.
Painting and feeding of mice with 2mg of an extract from black pepper on 3 days a week for 3 months results in a significant increase of the number of tumor-bearing mice. Tumor incidence is reduced in those groups of experimental animals receiving 5 or 10mg Vitamin A-palmitate twice weekly for 3 months by feeding or painting during and subsequent to application of pepper extract. Feeding of mice with powder of black pepper in diet (50g/3kg food) has no impact on carcinogenesis.


Cytomegalovirus infection in immunocompetent adults: Is observation still the best strategy?
Cytomegalovirus (CMV) infection in immunocompetent patients generally resolves with few sequelae. However, it can cause severe and relapsing symptoms that can last for several weeks. Due to the self-limiting nature of CMV disease in immunocompetent individuals, criteria for specific antiviral therapy in this cohort are not well established. Additionally the adverse effect profile of currently available anti-CMV therapy limits its use in specific patient populations .We describe 3 immunocompetent adults who developed symptomatic CMV infection and were ill for several weeks. All patients had positive CMV viral assays and ultimately received anti-CMV therapy with significant improvement in symptoms within a few days of starting therapy. Choosing appropriate candidates for anti-CMV therapy, among mmunocompetent individuals, requires further research.


Lung cancer in never smokers: Distinct population-based patterns by age, sex, and race/ethnicity.
Epidemiological patterns for lung cancer among never smokers (LCNS) are largely unknown, even though LCNS cases comprise 15% of lung cancers. Past studies were based on epidemiologic or health system cohorts, and not fully representative of the underlying population. The objective was to analyze rates (and trends) of LCNS by sex, age group, and race and ethnicity based on all-inclusive truly population-based sources. Individual-level data from 2014 to 2018 on smoking status among microscopically-confirmed lung cancer cases from Florida's cancer registry were combined with population denominators adjusted with NHIS data on smoking prevalence to compute population-based LCNS incidence rates and rate ratios. Incidence rates and proportional mortality were ranked against other cancers. Joinpoint regression analyses examined trends. Proportions of LCNS ranged from 9% among White men to 83% among Chinese women. Overall, LCNS was 13% (IRR 1.13, 95%CI 1.08-1.17) more common among men than women, but variation occurred by age group, with female rates exceeding male in younger ages. Age-adjusted rates per 100,000 were highest among Asian/Pacific Islander (API) men and women (15.3 and 13.5, respectively) and Black populations (14.6, 12.9), intermediate for White (13.2, 11.8) and lowest among the Hispanic population (12.1, 10.6). Among API women, LCNS was the second leading cause of cancer death, surpassed only by breast cancer. LCNS trends were stable over time. LCNS is the 11th most frequently occurring cancer in men and 8th in women. LCNS differences by race/ethnicity are small, within a 15% range of the White population's rates. Surprisingly, API men and women have the highest LCNS rates and proportional mortality. As smoking prevalence decreases in the US, LCNS cases will inevitably increase, warranting inquiry into risk factors across the lifespan.


Predicting the risk of death following coronary artery bypass graft made simple: a retrospective study using the American College of Surgeons National Surgical Quality Improvement Program database.
Risk models to predict 30-day mortality following isolated coronary artery bypass graft is an active area of research. Simple risk predictors are particularly important for cardiothoracic surgeons who are coming under increased scrutiny since these physicians typically care for higher risk patients and thus expect worse outcomes. The objective of this study was to develop a 30-day postoperative mortality risk model for patients undergoing CABG using the American College of Surgeons National Surgical Quality Improvement Program database. Data was extracted and analyzed from the American College of Surgeons National Surgical Quality Improvement Program Participant Use Files (2005-2010). Patients that had ischemic heart disease (ICD9 410-414) undergoing one to four vessel CABG (CPT 33533-33536) were selected. To select for acquired heart disease, only patients age 40 and older were included. Multivariate logistic regression analysis was used to create a risk model. The C-statistic and the Hosmer-Lemeshow goodness-of-fit test were used to evaluate the model. Bootstrap-validated C-statistic was calculated. A total of 2254 cases met selection criteria. Forty-nine patients (2.2%) died within 30 days. Six independent risk factors predictive of short-term mortality were identified including age, preoperative sodium, preoperative blood urea nitrogen, previous percutaneous coronary intervention, dyspnea at rest, and history of prior myocardial infarction. The C-statistic for this model was 0.773 while the bootstrap-validated C-statistic was 0.750. The Hosmer-Lemeshow test had a p-value of 0.675, suggesting the model does not overfit the data. The American College of Surgeons National Surgical Quality Improvement Program risk model has good discrimination for 30-day mortality following coronary artery bypass graft surgery. The model employs six independent variables, making it easy to use in the clinical setting.


Impact of drug screening in suspected overdose.
We studied how emergency qualitative drug screens were ordered and used during the evaluation of 405 consecutive adult patients presenting to a metropolitan emergency department with suspected drug intoxication. Physicians completed a two-part questionnaire outlining diagnosis, diagnostic certainty, suspected drug(s), and management plans immediately following initial evaluation and again at the time of ED disposition. Screen results were reviewed prior to ED disposition in 361 (89%) cases. We found that qualitative drug screens were associated with substantial changes in diagnostic certainty, as measured by changes in probability estimates and changes in absolute mean log-likelihood ratios. In 196 cases for which all data were recorded prospectively, drug screens excluded a diagnosis of drug intoxication or specifically suspected drugs in 81 cases (41%), but identified previously unsuspected drugs in only 21 cases (11%, P less than .001). Management changes followed qualitative drug screen results in 16 of 361 cases overall (4.4%), but seven of these were also associated with diagnostic quantitative serum drug levels. Potentially critical interventions were begun in two cases following positive screens but delayed in another due to a falsely negative screen. Guidelines for more efficient test utilization are proposed.


In vivo quantitative analysis of Talin turnover in response to force.
Cell adhesion to the extracellular matrix (ECM) allows cells to form and maintain three-dimensional tissue architecture. Cell-ECM adhesions are stabilized upon exposure to mechanical force. In this study, we used quantitative imaging and mathematical modeling to gain mechanistic insight into how integrin-based adhesions respond to increased and decreased mechanical forces. A critical means of regulating integrin-based adhesion is provided by modulating the turnover of integrin and its adhesion complex (integrin adhesion complex [IAC]). The turnover of the IAC component Talin, a known mechanosensor, was analyzed using fluorescence recovery after photobleaching. Experiments were carried out in live, intact flies in genetic backgrounds that increased or decreased the force applied on sites of adhesion. This analysis showed that when force is elevated, the rate of assembly of new adhesions increases such that cell-ECM adhesion is stabilized. Moreover, under conditions of decreased force, the overall rate of turnover, but not the proportion of adhesion complex components undergoing turnover, increases. Using point mutations, we identify the key functional domains of Talin that mediate its response to force. Finally, by fitting a mathematical model to the data, we uncover the mechanisms that mediate the stabilization of ECM-based adhesion during development.


Safety and clinical outcomes of computed tomography-guided percutaneous microwave ablation in patients aged 80 years and older with early-stage non-small cell lung cancer: A multicenter retrospective study.
Previous studies have documented the therapeutic value of computed tomography (CT)-guided percutaneous microwave ablation (MWA) for early-stage non-small cell lung cancer (NSCLC). However, few studies have focused on patients aged 80 years and older. This retrospective study aimed to evaluate the safety and clinical outcomes of CT-guided percutaneous MWA in patients aged 80 years and older with early-stage peripheral NSCLC. A retrospective analysis of 63 patients aged 80 years and older with cT1a-2bN0M0 peripheral NSCLC who underwent CT-guided percutaneous MWA was performed between January 2008 and January 2018 at 11 hospitals in Shandong Province, China. The median follow-up time was 21.0 months. The overall median survival time was 50 months. The cancer-specific median survival time was not reached in five years. The one-, two-, three-, four-, and five-year overall survival rates were 97.1%, 92.6%, 63.4%, 54.4%, and 32.6%, respectively. The one-, two-, and three-year cancer-specific survival (CSS) rates were 97.9%, 97.9%, and 69.4%, respectively. The four- and five-year CSS rates were not achieved. A total of 14 patients (22.2%) had local progression. The one-, two-, three-, four-, and five-year local control rates were 88.8%, 78.8%, 70.3%, 63.9%, and 63.9%, respectively. The mortality rate was 0% within 30 days after the procedure. Major complications included pneumothorax requiring drainage (21.1%), pulmonary infection (4.2%), and pleural effusions requiring drainage (2.8%). CT-guided percutaneous MWA is a safe and effective modality for treating patients aged 80 years and older with early-stage peripheral NSCLC.


Multivariable analysis of clinical and laboratory data manifestations predicting severity and mortality risk in patients with Coronavirus disease 2019 in the mountainous west of Iran: a retrospective single-center study.
Few reports have addressed the clinical and laboratory features of patients with coronavirus disease-2019 (COVID-19) in mountainous areas, especially in Iran. To report the clinical and laboratory data and manifestations predicting mortality of patients with COVID-19 in the west of Iran. We conducted a retrospective cohort study of 286 patients hospitalized with COVID-19 between 25 February 2020 and 12 May 2020 to describe their clinical symptoms and laboratory test findings when they were admitted at the Hajar Hospital affiliated with the Shahrekord University of Medical Sciences, and a multivariable analysis of factors that predict their disease severity and mortality. After hospital admission, 18 patients died and 268 were discharged. Older age [odds ratio (OR) = 1.02, 95% confidence interval (CI) = 1.01-1.04, P = 0.001], presence of underlying diseases (OR = 1.86, 95% CI = 1.01-3.45, P = 0.04), elevated hematocrit (OR = 1.08, 95% CI = 1.03-1.13, P = 0.002), and increase in red blood cell distribution width (RDW) coefficient of variation (OR = 1.18, 95% CI = 1.02-1.36, P = 0.02) were significantly associated with disease severity. Older age (OR = 1.00, 95% CI = 1.00-1.07, P = 0.03), hypocalcemia (OR = 0.20, 95% CI = 0.09-0.58, P = 0.002), hypophosphatemia (OR = 0.50, 95% CI = 0.26-1.02, P = 0.04), and increase in platelet-larger cell ratio (P-LCR; OR = 1.10, 95% CI = 1.00-1.15, P = 0.04) were significantly associated with mortality. The areas under the receiver operating characteristic curves were as follows: calcium 0.759; lactate dehydrogenase (LDH) 0.731; phosphorus 0.725; bilirubin 0.689; C-reactive protein 0.679; and RDW - standard deviation (RDW-SD) 0.624. Those who did not survive tended to be elderly and had a greater incidence of comorbidities. Elevated LDH, decreased levels of calcium and phosphorus, and anemia at diagnosis were associated with greater risk of death for these Iranian patients hospitalized with COVID-19. Regular assessment of these markers would help to manage patients with COVID-19.