Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia.

BACKGROUND: Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non-high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)-mediated inhibition of lipoprotein lipase. METHODS: We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24. RESULTS: A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of -49.8 percentage points (95% confidence interval [CI], -59.0 to -40.6) with the 10-mg-quarterly dose, -56.0 percentage points (95% CI, -65.1 to -46.8) with the 25-mg-quarterly dose, -62.4 percentage points (95% CI, -71.5 to -53.2) with the 50-mg-quarterly dose, and -44.2 percentage points (95% CI, -53.4 to -35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose. CONCLUSIONS: In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.).

Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia.

BACKGROUND: Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver. METHODS: We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24. RESULTS: A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran. CONCLUSIONS: In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.).

Room temperature synthesis of a chiral covalent organic framework core-shell composite for high-performance liquid chromatography enantioseparation.

In this article, chiral covalent organic framework core-shell composite CCOF-TpPa-Py@SiO2 was facilely synthesized by induction at room temperature. The CCOF-TpPa-Py@SiO2 core-shell composite was used as a chiral stationary phase for the separation of the racemates by high-performance liquid chromatography, which exhibits good separation performance for chiral compounds including ketones, alcohols, esters, epoxides, carboxylic acids, amides, and amines. The effects of analyte injection mass on the enantioseparation were studied. The reproducibility and stability of the CCOF-TpPa-Py@SiO2 chiral column were explored. The intra-day (n = 5), inter-day (n = 5), and inter-column (n = 3) relative standard deviations for the migration times and resolution of benzoin were 0.32%-0.54%, 0.45%-0.61%, and 1.21%-1.53%, respectively. In addition, the chiral separation ability of the CCOF-TpPa-Py@SiO2 chiral column (column A) was compared with that of the MDI-ß-CD-Modified COF@SiO2 (column B) as well as a commercial chiral column (Chiralpak AD-H). The chiral recognition ability of column A is complementary to that of column B and AD-H column. The resolution mechanism of CCOF-TpPa-Py@SiO2 stationary phase towards chiral analyte was explored. Hence, the synthesis of CCOF-TpPa-Py@SiO2 core-shell composite by induction at room temperature as chiral stationary phases for chromatographic separation has important research potential and application prospects.

Asymmetric catalytic synthesis of chiral covalent organic framework composite (S)-DTP-COF@SiO2 for HPLC enantioseparations by normal-phase and reversed-phase chromatographic modes.

A novel CCOF core-shell composite material (S)-DTP-COF@SiO2 was prepared via asymmetric catalytic and in situ growth strategy. The prepared (S)-DTP-COF@SiO2 was utilized as separation medium for HPLC enantioseparation using normal-phase and reversed-phase chromatographic modes, which displays excellent chiral separation performance for alcohols, esters, ketones, and epoxides, etc. Compared with chiral commercial chromatographic columns (Chiralpak AD-H and Chiralcel OD-H columns) and some previously reported chiral CCOF@SiO2 (CC-MP CCTF@SiO2 and MDI-ß-CD-modified COF@SiO2)-packed columns, there are 4, 3, 13, and 15 tested racemic compounds that could not be resolved on the Chiralpak AD-H column, Chiralcel OD-H column, CC-MP CCTF@SiO2 column, and MDI-ß-CD-modified COF@SiO2 column, respectively, which indicates that the resolution effect of (S)-DTP-COF@SiO2-packed column can be complementary to the other ones. The effects of the analyte mass, column temperature, and mobile phase composition on the enantiomeric separation were investigated. The chiral column exhibits good reproducibility after multiple consecutive injections. The RSDs (n = 5) of the peak area and retention time were less than 1.5% for repetitive separation of 2-methoxy-2-phenylethanol and 1-phenyl-1-pentanol. The chiral core-shell composite (S)-DTP-COF@SiO2 exhibited good enantiomeric separation performance, which not only demonstrates its potential as a novel CSP material in HPLC but also expands the range of applications for chiral COFs.

A qualitative exploration of goals-of-care discussions with seriously ill patients in Jordan.

OBJECTIVES: This study aims to explore seriously ill patients' experiences during goals-of-care discussions and perspectives of end-of-life (EOL) decision-making in the Middle Eastern country of Jordan. METHODS: This is a qualitative descriptive study with semi-structured, one-on-one interviews. Settings were 2 large hospitals in Jordan. Patients were a purposeful sample of 14 Arabic-speaking adults who were seriously ill and hospitalized with palliative care needs. RESULTS: Conventional content analysis identified 4 main themes: perceived suffering during serious illness, attitudes toward discussing EOL decision-making, goals of care and preferences for EOL, and actions to enhance EOL decision-making. Disease and treatment burdens and concerns about life, family, and death were sources of suffering during serious illness. What matters most to patients at EOL were alleviating suffering and getting support from family, friends, and care providers. Although patients expressed reluctance and inaction toward EOL decision-making due to uncertainties, lacking awareness, and assumptions of fear, their potential goals of care were to live longer, be with their families, and die with dignity. SIGNIFICANCE OF RESULTS: Jordanians and culturally similar Arabs could benefit from goals-of-care discussions. The proper, culturally sensitive implementation of goals-of-care discussions in Arab populations with similar cultural norms requires raising public awareness and clarifying the legitimacy of goals-of-care discussions, preparing patients and their families for the discussions, and considering individual variations in handling the discussions.

Tonsillectomy: Post-Operative Hemorrhage Reduction Strategy in Jos, North Central Nigeria.

BACKGROUND: Post-tonsillectomy hemorrhage (PTH) is one of the more life-threatening /lethal complications and the leading malpractice claims/convictions in Oto-laryngological practice. OBJECTIVE: A Study on PTH reduction strategy in Jos, North Central Nigeria. STUDY DESIGN: Prospective Cohort Study. METHODS: Participants who met the criteria under GA had dissection Tonsillectomy ± Adenoidectomy between August 1, 2017-July 31, 2019 at the Jos University Teaching Hospital, Nigeria, were enrolled. Data analysis was by SPSS version 21.0 Chicago, IL, USA. RESULTS: We studied 96 participants with a M:F = 1.7:1. Age range was 9months-51years with a Median = 3.0years. Snoring-83(86.5%), Nasal obstruction - 71(74.0%), Mouth breathing -18(18.8), OSA(S) - 17(17.7%) were main features. Seventy-Eight (81.2%) were Grade III & IV and 71(75.0%) had Adenoid Nasopharyngeal Ratio >0.5. Mean INR was 1.22 ± 0.24 where 28(29.2%) were abnormal. Post-operative blood loss was 10ml - 250ml with Median = 35ml. There was a correlations between the Brodsky's grading with Tonsil volume and between Tonsil grade with volume of blood loss. An estimated 76.0% had the surgery within 60mins. We practice 'awake' extubation. Incidence of Primary PTH of 3.1% with no secondary PTH or mortality. CONCLUSION: We established that blood loss was directly proportional to the tonsil size which brings new insights in PTH prevention. Our use of specific agents for GA, technique/ expertise, pillar infiltration with Lignocaine, 'awake extubation, liberal post-operative analgesia with systemic antibiotics may be responsible for the low incidence of PTH in this series.

CONTEXTE: L'hémorragie post-amygdalectomie (HPT) est l'une des complications les plus mortelles et l'une des principales réclamations/convictions pour faute professionnelle dans la pratique de l'oto-laryngologie. OBJECTIF: Étude de la stratégie de réduction des hémorragies pulmonaires à Jos, dans le centre-nord du Nigeria. PLAN DE L'ÉTUDE: Étude de cohorte prospective. MÉTHODES: Les participants qui répondaient aux critères de l'AG ont subi une amygdalectomie ± adénoïdectomie par dissection entre le 1er août 2017 et le 31 juillet 2019 à l'hôpital universitaire de Jos, au Nigeria, ont été inscrits. L'analyse des données a été effectuée par SPSS version 21.0 Chicago, IL, USA. RÉSULTATS: Nous avons étudié 96 participants avec un rapport M:F = 1,7:1. La fourchette d'âge était de 9 mois à 51 ans avec une médiane de 3,0 ans. Le ronflement - 83 (86,5%), l'obstruction nasale - 71 (74,0%), la respiration buccale - 18 (18,8), le SAOS(S) - 17 (17,7%) étaient les principales caractéristiques. Soixante-dix-huit (81,2%) étaient de grade III et IV et 71 (75,0 %) avaient un rapport adénoïdenasopharyngé >0,5. L'INR moyen était de 1,22 ± 0,24 et 28 (29,2%) étaient anormaux. La perte de sang postopératoire était de 10ml -250ml avec une médiane de 35ml. Il y avait une corrélation entre le classement de Brodsky et le volume de l'amygdale et entre le classement de l'amygdale et le volume de la perte de sang. Environ 76,0% des patients ont été opérés dans les 60 minutes. Nous pratiquons l'extubation "éveillée". Incidence de l'HTP primaire de 3,1% sans HTP secondaire ni mortalité. CONCLUSION: Nous avons établi que la perte de sang était directement proportionnelle à la taille de l'amygdale, ce qui apporte de nouvelles perspectives dans la prévention de l'HTP. Notre utilisation d'agents spécifiques pour l'AG, notre technique/expertise, l'infiltration des piliers avec de la lignocaïne, l'extubation éveillée, l'analgésie postopératoire libérale avec des antibiotiques systémiques peuvent être responsables de la faible incidence d'HTP dans cette série. Mots-clés: Dissection de l'amygdalectomie, Perte de sang, Stratégie de réduction, Résultat.

Upgrading Octane Number of Naphtha by a Robust and Easily Attainable Metal-Organic Framework through Selective Molecular Sieving of Alkane Isomers.

The separation of alkanes, particularly monobranched and dibranched isomers, is of paramount importance in the petrochemical industry for optimizing the feedstock of ethylene production as well as for upgrading the octane number of gasoline. Here, we report the full separation of linear/monobranched alkanes from their dibranched isomers by a robust and easily scalable metal-organic framework material, Co3 (HCOO)6 . The compound completely excludes dibranched alkanes but adsorbs their linear and monobranched isomers, as evidenced by single-component and multicomponent adsorption measurements. More importantly, the material exhibits excellent performance in separating naphtha and is capable of providing high quality feedstock for the production of ethylene and gasoline components with high octane number, making it a promising candidate for naphtha separation in petrochemical industry.

Evaluation of Rapid IgG4 Test for Diagnosis of Gnathostomiasis.

Human gnathostomiasis is a parasitic disease caused by Gnathostoma nematode infection. A rapid, reliable, and practical immunoassay, named dot immuno-gold filtration assay (DIGFA), was developed to supporting clinical diagnosis of gnathostomiasis. The practical tool detected anti-Gnathostoma-specific IgG4 in human serum using crude extract of third-stage larvae as antigen. The result of the test was shown by anti-human IgG4 monoclonal antibody conjugated colloidal gold. The sensitivity and specificity of the test were both 100% for detection in human sera from patients with gnathostomiasis (13/13) and from healthy negative controls (50/50), respectively. Cross-reactivity with heterogonous serum samples from patients with other helminthiases ranged from 0 (trichinosis, paragonimiasis, clonorchiasis, schistosomiasis, and cysticercosis) to 25.0% (sparganosis), with an average of 6.3% (7/112). Moreover, specific IgG4 antibodies diminished at 6 months after treatment. This study showed that DIGFA for the detection of specific IgG4 in human sera could be a promising tool for the diagnosis of gnathostomiasis and useful for evaluating therapeutic effects.

Targeting the Ca2+/Calmodulin-dependent protein kinase II by Tetrandrine in human liver cancer cells.

Hepatocellular carcinoma (HCC) is the most prevalent malignancy in liver and a leading cause of cancer-related deaths. Despite the pressing need for treatment options, patients with HCC develop significant resistance and adverse side effects to current approved drugs that becomes a major barrier to effective treatment. A natural product Tetrandrine (TET) is a potential alternative treatment option for HCC, with demonstrated effectiveness and low toxicity. However, the mechanisms by which Tetrandrine inhibits HCC are unclear. In the current study, we identify Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) as a potential TET drug target through structural modeling. Screening of a panel of HCC cell lines reveal differential sensitivities toward TET treatment. Interestingly, IC50 of TET inhibition of HCC cell proliferation is positively correlated with CaMKIIδ expression level in these distinct HCC cells. Furthermore, TET treatment resulted in a marked reduction of CaMKIIδ phosphorylation level, and knockdown of CaMKIIδ reduced the sensitivity of HCC cells to TET. Most importantly, CaMKIIδ protein levels in high-grade human HCC samples were significantly elevated as compared to normal liver tissues. Taken together, our studies demonstrate that the natural compound TET targets CaMKIIδ in HCC cells, and that CaMKIIδ level is a potential biomarker to identify HCC patient populations sensitive to Tetrandrine treatment.

Discovery of a ferroelastic topological insulator in a two-dimensional tetragonal lattice.

Ferroelasticity and band topology are two intriguing yet distinct quantum states of condensed matter materials. Their coexistence in a single two-dimensional (2D) lattice, however, has never been observed. Here, we found that the 2D tetragonal HfC monolayer allowed simultaneous presence of ferroelastic and topological orders. By using first-principles calculations, we found that it could allow a low switching barrier with reversible strain of 17.4%, indicating that the anisotropic properties are achievable experimentally for a 2D tetragonal lattice. More interestingly, the tuning of topological behaviors with strain led to spin-separated and gapless edge states, that is, the quantum spin Hall effect. These findings from the coupling of two quantum orders offer insights into ferroelastic control over topological edge states for achieving multifunctional properties in next-generation 2D nanodevices.

Identification of the UBA2-WTIP fusion gene in acute myeloid leukemia.

Identifying and targeting oncogenic fusion genes have revolutionized the treatment of leukemia, such as PML-RARα fusion gene in acute promyelocytic leukemia. Here we identified an intrachromosomal fusion gene located on chromosome 19q.13 between UBA2 and WTIP gene in a case of acute myeloid leukemia. The UBA2-WTIP fusion gene contains the N-terminal E1_enzyme_family, VAE_Ubl domains of UBA2, and the C-terminal LIM domains of WTIP. The UBA2-WTIP fusion was detected by reverse transcriptase polymerase chain reaction and Sanger sequencing in 19 of 56 acute myeloid leukemia samples (33.9%). Ectopic expression of the UBA2-WTIP fusion in human acute myeloid leukemia KG-1a cells showed enhanced cell proliferation both in vitro and in vivo. The UBA2-WTIP fusion induced phosphorylation of STAT3, STAT5 and ERK1/2, and abrogates WTIP-mediated mammalian processing body formation. Finally, triptolide displayed selective cytotoxicity against KG-1a cells harboring the UBA2-WTIP fusion. Collectively, our findings suggest that the UBA2-WTIP fusion is an oncogenic fusion gene, as well as a promising therapeutic target for the treatment of acute myeloid leukemia.

Human Development Index and its association with staff spiritual care provision: a Middle Eastern oncology study.

BACKGROUND: Although staff spiritual care provision plays a key role in patient-centered care, there is insufficient information on international variance in attitudes toward spiritual care and its actual provision. METHODS: A cross-sectional survey of the attitudes of Middle Eastern oncology physicians and nurses toward eight examples of staff provision of spiritual care: two questionnaire items concerned prayer, while six items related to applied information gathering, such as spiritual history taking, referrals, and encouraging patients in their spirituality. In addition, respondents reported on spiritual care provision for their last three advanced cancer patients. RESULTS: Seven hundred seventy responses were received from 14 countries (25% from countries with very high Human Development Index (HDI), 41% high, 29% medium, 5% low). Over 63% of respondents positively viewed the six applied information gathering items, while significantly more, over 76%, did so among respondents from very high HDI countries (p value range, p < 0.001 to p = 0.01). Even though only 42-45% overall were positively inclined toward praying with patients, respondents in lower HDI countries expressed more positive views (p < 0.001). In interaction analysis, HDI proved to be the single strongest factor associated with five of eight spiritual care examples (p < 0.001 for all). Significantly, the Middle Eastern respondents in our study actually provided actual spiritual care to 47% of their most recent advanced cancer patients, compared to only 27% in a parallel American study, with the key difference identified being HDI. CONCLUSIONS: A country's development level is a key factor influencing attitudes toward spiritual care and its actual provision. Respondents from lower ranking HDI countries proved relatively more likely to provide spiritual care and to have positive attitudes toward praying with patients. In contrast, respondents from countries with higher HDI levels had relatively more positive attitudes toward spiritual care interventions that involved gathering information applicable to patient care.

Correction to: Human Development Index and its association with staff spiritual care provision: a Middle Eastern oncology study.

Incorrect family name of Layth Mula-Hussain.

Training for awareness of one's own spirituality: A key factor in overcoming barriers to the provision of spiritual care to advanced cancer patients by doctors and nurses.

OBJECTIVE: When patients feel spiritually supported by staff, we find increased use of hospice and reduced use of aggressive treatments at end of life, yet substantial barriers to staff spiritual care provision still exist. We aimed to study these barriers in a new cultural context and analyzed a new subgroup with "unrealized potential" for improved spiritual care provision: those who are positively inclined toward spiritual care yet do not themselves provide it. METHOD: We distributed the Religion and Spirituality in Cancer Care Study via the Middle East Cancer Consortium to physicians and nurses caring for advanced cancer patients. Survey items included how often spiritual care should be provided, how often respondents themselves provide it, and perceived barriers to spiritual care provision.ResultWe had 770 respondents (40% physicians, 60% nurses) from 14 Middle Eastern countries. The results showed that 82% of respondents think staff should provide spiritual care at least occasionally, but 44% provide spiritual care less often than they think they should. In multivariable analysis of respondents who valued spiritual care yet did not themselves provide it to their most recent patients, predictors included low personal sense of being spiritual (p < 0.001) and not having received training (p = 0.02; only 22% received training). How "developed" a country is negatively predicted spiritual care provision (p < 0.001). Self-perceived barriers were quite similar across cultures.Significance of resultsDespite relatively high levels of spiritual care provision, we see a gap between desirability and actual provision. Seeing oneself as not spiritual or only slightly spiritual is a key factor demonstrably associated with not providing spiritual care. Efforts to increase spiritual care provision should target those in favor of spiritual care provision, promoting training that helps participants consider their own spirituality and the role that it plays in their personal and professional lives.

Safety and efficacy of dehydrated ethanol soaking of the operative field in the treatment of spontaneous hepatocellular carcinoma rupture.

BACKGROUND: The aim of our study was to evaluate the clinical safety and value of ethanol surgical field infiltration (ESFI), combined with distilled water peritoneal lavage (DWPL), after hepatectomy in patients with hepatocellular carcinoma (HCC) rupture. METHODS: Rat liver tissue samples were soaked in dehydrated ethanol for different soaking times, and 18 rats were assigned to three groups that underwent different soaking methods of the hepatectomy cut surface. We retrospectively reviewed 45 patients who underwent hepatectomy for treatment of ruptured HCC. Among these, EFSI combined with DWPL was used in 21 patients (DAW group), with only DWPL used in the other 24 patients (DW group). Clinical outcomes were compared between the two groups. RESULTS: For in vitro experiments, the depth of coagulation degeneration and necrosis increased with the duration of soaking. For in vivo experiments, rats in all three groups survived until postoperative day 7 without significant postoperative complication. In patients, the rate of post-operation complication was comparable between the two groups (P = 0.398), with no between-group differences in liver function levels. The incidence of peritoneal dissemination was significantly higher for DW than DAW group (P = 0.037). Kaplan-Meier test identified dehydrated ethanol treatment as a significant factor of disease-free survival (DFS) (P = 0.036). On univariate analysis, dehydrated ethanol treatment was associated with better prognostic outcomes, although it was not retained as an independent factor of patient outcome. CONCLUSIONS: Dehydrated ethanol soaking of the cut surface of the hepatectomy could potentially lower the risk of metastasis and improve the effect of hepatectomy for ruptured HCC as well as showed potential therapeutic value for intraoperative iatrogenic rupture of HCC.

Cake Compressibility Analysis of BPOME from a Hybrid Adsorption-Microfiltration Process.

This study investigates the utility of a hybrid adsorption-membrane process for cake compressibility evaluation of biotreated palm oil mill effluent (BPOME). A low-cost empty fruit bunch (EFB) based powdered activated carbon (PAC) was employed for the upstream adsorption process with operation conditions of 60 g/L PAC dose, 68 min mixing time, and 200 rpm mixing speed to reduce the feed-water strength and alleviate probable fouling of the membranes. Two polyethersulfone microfiltration (MF) membranes of 0.1 and 0.2 µm pore sizes were investigated under constant transmembrane pressures (TMP) of 40, 80, and 120 kPa. The compressibility factors (z), which was obtained from the slopes of power plots (function of specific cake resistance (α) and pressure gradient) were evaluated. The z values of 0.32 and 0.52, respectively obtained, for the 0.1 and 0.2 µm MF membranes provided compressible and stable z values as observed from their power plots. Besides, these membranes were found suitable for the measurement of z since the results are in consonance with the established principle of cake compressibility. Moreover, the upstream adsorption mitigated the clogging of the membranes which ultimately led to moderate resistances and cake compressibility. These are indications that with the secondary cake filtration, a sustainable flux can be achieved during BPOME filtration. The membranes exhibited close to 100% restoration after cleaning.

Sequence analysis of four vitamin D family genes (VDR, CYP24A1, CYP27B1 and CYP2R1) in Vogt-Koyanagi-Harada (VKH) patients: identification of a potentially pathogenic variant in CYP2R1.

BACKGROUND: VKH is a rare autoimmune disease. Decreased level of vitamin D has recently been found to be involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. This study was designed to screen the vitamin D pathway genes for pathogenic mutations, if any, in VKH patients. METHODS: Genomic DNA was extracted from blood samples collected from patients with VKH disease and healthy controls. Entire coding region, exon-intron junctions of four genes were sequenced in DNA from 39 Saudi VKH patients and 50 ethnically matched healthy individuals. All patients and controls were unrelated. RESULTS: Vitamin D levels in VKH patients were found either insufficient (21-29 ng/mL) or deficient (<20 ng/mL). Sequencing analysis of the VDR, CYP24A1, CYP27B1 and CYP2R1 detected twelve nucleotide changes in these genes in our cohort of 39 patients; 4 of which were non-coding, 6 were synonymous coding and 2 were non-synonymous coding sequence changes. All synonymous coding variants were benign polymorphisms with no apparent clinical significance. A non-synonymous coding sequence variant (c.2 T > C; p.1Met?) found in VDR is an initiation coding change and was detected in control individuals as well, while another variant (c.852G > A; p.284 M > I) found in CYP2R1 is predicted to be disease causing by mutationtaster software. This potentially pathogenic variant was found in 17 out of 39 VKH patients. CONCLUSIONS: Screening of four Vitamin D pathway genes in 39 VKH patients shows that a potentially pathogenic sequence variant in CYP2R1 may cause VKH in a subset of patients. These findings support the previous observation that low vitamin D levels might play a role in VKH pathogenesis and mutations in genes involved in vitamin D anabolism and catabolism might be of importance in VKH pathobiology.

A telehealth program for CPAP adherence reduces labor and yields similar adherence and efficacy when compared to standard of care.

PURPOSE: This study evaluated the effectiveness and coaching labor requirements of a web-based automated telehealth (TH) messaging program compared with standard of care (SOC) in newly diagnosed patients with obstructive sleep apnea (OSA). METHODS: In this non-blinded, multicenter, prospective study, all patients were started on continuous positive airway pressure (CPAP) with heated humidification and a wireless modem. They all received standardized CPAP education and setup. Patients in the TH group (n = 58) received an automated series of text messages and/or e-mails that were triggered by preset conditions. Patients in the SOC group (n = 64) received scheduled calls on days 1, 7, 14, and 30. Additional contacts were allowed for patients in both groups as deemed clinically necessary. Coaching labor was calculated by totaling the number and type of patient contacts and assigning historical time values. RESULTS: One hundred twenty-two patients were included in the final analysis. There were no statistically significant differences between the TH and SOC groups for Medicare adherence (83 vs. 73 %), daily CPAP usage (5.1 ± 1.9 h vs. 4.7 ± 2.1 h), CPAP efficacy (mean residual apnea-hypopnea index (3.0 ± 4.1/h vs. 2.8 ± 3.8/h), or change in Epworth Sleepiness Scale score (-5.8 ± 5.5 vs. -5.1 ± 5.9), although all trends favored the TH group. There was, however, a significant reduction in the number of minutes coaching required per patient in the TH vs. SOC group (23.9 ± 26 vs. 58.3 ± 25, 59 % reduction; p < 0.0001). CONCLUSIONS: Use of a web-based telehealth program for CPAP adherence coaching significantly reduced the coaching labor requirement compared with SOC, while maintaining similar adherence and effectiveness.

Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor.

BI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3'-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 µM. BI 224436 also has a low, ∼2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC95 values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials.

Polymerase chain reaction-based assays for the diagnosis of human brucellosis.

Polymerase chain reaction (PCR) is an in vitro technique for the nucleic acid amplification, which is commonly used to diagnose infectious diseases. The use of PCR for pathogens detection, genotyping and quantification has some advantages, such as high sensitivity, high specificity, reproducibility and technical ease. Brucellosis is a common zoonosis caused by Brucella spp., which still remains as a major health problem in many developing countries around the world. The direct culture and immunohistochemistry can be used for detecting infection with Brucella spp. However, PCR has the potential to address limitations of these methods. PCR are now one of the most useful assays for the diagnosis in human brucellosis. The aim of this review was to summarize the main PCR techniques and their applications for diagnosis and follow-up of patients with brucellosis. Moreover, advantages or limitation of the different PCR methods as well as the evaluation of PCR results for treatment and follow-up of human brucellosis were also discussed.