Role of probiotics in chronic rhinosinusitis: a systematic review of randomised, controlled trials.

OBJECTIVE: This review evaluated the safety profile and efficacy of probiotics in chronic rhinosinusitis and was registered with Prospero (Centre for Reviews and Dissemination number: 42020193529). METHOD: Literature databases were searched through inception to August 2022. Randomised, controlled trials exploring adjunctive probiotics in adult chronic rhinosinusitis patients were included. From 948 records screened, 4 randomised, controlled trials were included. RESULTS: Probiotics-associated adverse effects comprised epistaxis and abdominal pain. No reduction in Sino-Nasal Outcome Test values before 4 weeks (p = 0.58) or beyond 8 weeks (p = 0.08) of treatment or reduction of severe symptom frequency (p = 0.75) was observed. Symptom relapse in probiotic-treated patients was significantly lower across all timepoints (p = 0.045). Lower sinusitis relapse risks during treatment (risk ratio = 0.49; p = 0.019) and 8 months post-treatment (risk ratio = 0.56, p = 0.013) were observed. Probiotics demonstrated potential in improving Sino-Nasal Outcome Test symptom subscales, including sleep, psychological and rhinology subscales. CONCLUSION: The optimal mode of probiotic administration, treatment duration and target patient subgroups requires further study to evaluate the utility of probiotics.

Should mild obstructive sleep apnoea be treated? A systematic review from the standpoint of disease progression.

OBJECTIVE: This study was a systematic review to investigate the progression of untreated obstructive sleep apnoea in order to evaluate whether mild obstructive sleep apnoea should be treated from the standpoint of disease progression. METHOD: The database search study outcomes that were collected included Apnea Hypopnea Index and Respiratory Disturbance Index. A meta-analysis of obstructive sleep apnoea severity over time intervals was performed. RESULTS: A total of 17 longitudinal studies and 1 randomised, controlled trial were included for review. For patients with mild obstructive sleep apnoea, mean pre-study and post-study Apnea Hypopnea Index was 5.21 and 8.03, respectively, over a median interval of 53.1 months. In patients with moderate to severe obstructive sleep apnoea, mean pre-study and post-study Apnea Hypopnea Index was 28.9 and 30.3, respectively, over a median interval of 57.8 months. Predictors for disease progression in mild obstructive sleep apnoea are patients aged less than 60 years and those with a baseline body mass index less than 25. CONCLUSION: Mild obstructive sleep apnoea progression is observed, but it does not appear to reach any clinically significant progression to moderate or severe obstructive sleep apnoea.

Open space, not reduced herbivory, facilitates invasion of a marine macroalga, implying it is a disturbance-mediated "passenger" of change.

Sargassum horneri, a brown macroalga, recently invaded the California coast, including into critical foundational communities such as kelp (Macrocystis pyrifera) forests. Despite its rapid spread, empirical tests that evaluate mechanisms underlying S. horneri's invasion success are lacking. To fill this knowledge gap, we conducted three field experiments on temperate rocky reefs in southern California using growth as a proxy for invasion success. We first tested whether S. horneri success differed with herbivory strength and native diversity by conducting a 2-factor experiment varying site (with different baseline levels of urchin densities and native algal diversity) and urchin access. We found S. horneri growth only differed among urchin treatments and not sites. We then evaluated whether S. horneri could successfully invade established algal canopies as a driver or whether it required open space as a passenger via a 2-factor experiment varying S. horneri size (small, medium, large) and canopy type (S. horneri, kelp, -canopy). We found that all S. horneri sizes grew fastest when canopy was lacking and light was high and slower in both canopy habitats with lower light; overall, small S. horneri grew slowest. Finally, we evaluated whether herbivore consumption for native species could facilitate S. horneri's invasion by conducting a 2-factor experiment varying species (M. pyrifera, S. horneri) and herbivore access. We found uncaged algae were consumed and caged algae grew, but there was no difference between species. Taken together, our results suggest that S. horneri is a "passenger" invader that will take advantage of points in time and space where light is plentiful, such as when M. pyrifera is removed via disturbance. Further, our results suggest that herbivory and native algal diversity are likely not key determining factors of the invasion success of S. horneri.

Protective effect of oral contraceptive against Helicobacter pylori infection in US adult females: NHANES 1999-2000.

Recently, the antibacterial properties of oestrogen and progestogen were discovered. The aim of this study was to find the cross-sectional association between oral contraceptive use and Helicobacter pylori seroprevalence. Data were obtained from the US National Health and Nutrition Examination Survey (NHANES). The H. pylori immunoglobulin G (IgG) enzyme-linked immunosorbent assays were used to categorise participants as seropositive or seronegative. The study population included 799 female participants who had information on H. pylori seroprevalence and all other covariates and had not been taking any medications (except oral contraceptives). The bivariate Rao-Scott chi-square test indicated a significant association between H. pylori seroprevalence and contraceptive use (P < 0.01). The variables of race, education, poverty income ratio, smoking, and blood lead and cadmium levels were also significantly associated with H. pylori seroprevalence (P < 0.01). Multiple logistic regression analysis of the age-adjusted model revealed that contraceptive users are 65% less likely of being H. pylori seropositive as compared to non-contraceptive users (odds ratio (OR): 0.35, 95% confidence interval (CI): 0.18-0.68). This association is stronger with the final multivariate model (OR: 0.46, 95% CI: 0.23-0.89). Conclusions: This finding reveals the potential protective effect of oral contraceptives against H. pylori infection and serves as a foundation study for further investigations.

A tale of two algal blooms: Negative and predictable effects of two common bloom-forming macroalgae on seagrass and epiphytes.

Recent evidence suggests macroalgal blooms may play a role in the worldwide decline in seagrass, but the shape of the functional relationship between seagrass health and dominant bloom-forming macroalgae is poorly characterized. We tested whether the impact of varying abundances of two cosmopolitan bloom-forming macroalgal genera caused linear/quasi-linear or sudden threshold changes in measures of eelgrass, Zostera marina, meadow health. We conducted two caging experiments in a shallow Z. marina bed (∼1 m depth) in Bodega Harbor, California, USA where we maintained six densities within the range of natural abundances of macroalgae, Ulva (0-4.0 kg m-2) and Gracilariopsis (0-2.0 kg m-2), as well as uncaged controls over a 10-week period. Shoot density, blade growth, and epiphyte load were measured every two weeks and algal treatments reset. We did not find support for threshold transitions between algal abundance and measures of seagrass bed health using sigmoidal and broken-stick regression analyses for each data set; these models are commonly used to identify threshold patterns in ecological shifts. Instead, final measurements of shoot density and epiphyte load were best modelled as linear or slightly non-linear declines with increasing Ulva abundance. A negative linear relationship also existed between shoot density and Gracilariopsis abundance and a trend towards linear negative effects on epiphyte load. The similar shape of these functional relationships across different types of algae suggests the relationship may be generalizable. At algal abundances that are commonly observed, we found smooth and predictable negative impacts to Z. marina by decline in shoot density and potential impacts to food webs by loss of epiphytes rather than sudden threshold shifts or "ecological surprises". Our work contrasts with the growing body of literature suggesting highly non-linear shifts in response to human impact; thus, it is important to broaden understanding of shifts to more than just pattern but to the processes that drive different patterns of shifts.

First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours.

BACKGROUND: PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly. METHODS: Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. RESULTS: A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months. CONCLUSION: PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.

Mass balance, excretion and metabolism of [¹4C] ASA404 in cancer patients in a phase I trial.

PURPOSE: To determine the mass balance, excretion and metabolism of the small molecule flavonoid tumour vascular disrupting agent ASA404 in patients with advanced cancer. METHODS: Seven cancer patients were given a single dose of 3,000 mg [(14)C] ASA404 by intravenous infusion over 20 min prior to collection of samples of plasma, urine and faeces. Pharmacokinetic samples were analysed by HPLC, liquid scintillation counting, mass spectrometry, glusulase treatment and comparison to authentic standards. Descriptive pharmacokinetic parameters were generated by noncompartmental analysis. RESULTS: Mass balance was achieved (mean recovery of radioactivity in excreta = 86.9% of the dose) with balanced excretion between urine (mean recovery of radioactivity in urine = 53.9% of dose) and faeces (mean recovery of radioactivity in faeces = 33.3% of dose). ASA404 was eliminated as parent drug, three known metabolites (6-methylhydroxy-ASA404, ASA404 acyl glucuronide and 6-methylhydroxy-ASA404 acyl glucuronide) and two novel metabolites (an ASA404 dimer and an ASA404 dimer glucuronide conjugate). Unchanged ASA404 was the major radioactivity component detected in plasma within the first 24 h after dosing. At later time points, irreversibly protein bound ASA404 and all of the metabolites that had been detected in excreta contributed to total plasma radioactivity. CONCLUSION: This study defined the substantial excretion of ASA404, mainly as metabolites, in both urine (over half of the dose) and faeces (about one-third of the dose) after intravenous administration. Two novel metabolites were identified that were not reported by previous studies using nonradioactive techniques.

The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study.

BACKGROUND: This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel. METHODS: Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m(-2) docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated. RESULTS: In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of > or =6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of >or =3 mg kg(-1). Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had > or =5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from > or =5 to <5 CTCs and 9 out of 10 (90%) had a > or =30% decline in CTCs after therapy. CONCLUSIONS: Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.

Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC).

BACKGROUND: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A dose of 13 mg/m(2) was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (H(o) = 0.10, H(a) = 0.30; alpha and beta = 0.10). RESULTS: Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting > or = 6 months, along with a confirmed prostate-specific antigen decline of > or = 50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity. CONCLUSIONS: At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.

GaN/ZnO nanorod light emitting diodes with different emission spectra.

Light emitting diodes (LEDs) consisting of p-GaN epitaxial films and n-ZnO nanorods have been fabricated and characterized. The rectifying behavior and emission spectra were strongly dependent on the electronic properties of both GaN film and ZnO nanorods. Light emission under both forward and reverse bias was obtained in all cases, and emission spectra could be changed by annealing the ZnO nanorods. The emission spectra could be further tuned by using a GaN LED epiwafer as a substrate. Both forward and backward diode behavior has been observed and the emission spectra were significantly affected by both the properties of the GaN substrate and the annealing conditions for the ZnO nanorods.

A case-crossover study on transient risk factors of work-related eye injuries.

OBJECTIVES: To investigate modifiable risk and preventive factors of work-related eye injuries. METHODS: A case-crossover study conducted to explore the associations between transient risk factors and work-related eye injuries. Patients seen at seven medical centres in Taiwan with work-related eye injuries over a 4-year period were enrolled in the study. Clinical information was collected from medical charts and detailed information on exposure to eight potentially modifiable factors during the 60 minutes prior to the occurrence of each injury, as well as during the same time interval on the last work day prior to the injury, were obtained using questionnaire surveys. Matched-pair interval analysis was adopted to assess the odds ratios (ORs) for work-related eye injuries given exposure to the eight modifiable factors. RESULTS: A total of 283 subjects were interviewed. Most of these injured workers were young, male, and self-employed or small enterprise workers. The most common injury type was photokeratitis (33.2%), mainly caused by welding (30.4%). The OR for a work-related eye injury was increased with the performance of an unfamiliar task (57.0), operation of a faulty tool or piece of equipment (48.5), distractions (24.0), being rushed (13.0), or fatigued (10.0), and a poor work environment (4.3). Wearing eye protection devices was found to have a significant protective effect on workers who might otherwise have been exposed to eye injuries (OR = 0.4; 95% CI 0.2 to 0.7). CONCLUSION: Potential modifiable risk and preventive factors for work-related eye injuries were identified using a case-crossover study. This information should be helpful in the development of preventive strategies.

Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience.

BACKGROUND: The purpose of this study was to evaluate the association of circulating tumour cell (CTC) counts, before and after commencing treatment, with overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: A 7.5 ml of blood was collected before and after treatment in 119 patients with CRPC. CTCs were enumerated using the CellSearchSystem. RESULTS: Higher CTC counts associated with baseline characteristics portending aggressive disease. Multivariate analyses indicated that a CTC >or=5 was an independent prognostic factor at all time points evaluated. Patients with baseline CTC >or=5 had shorter OS than those with <5 [median OS 19.5 versus >30 months, hazard ratio (HR) 3.25, P=0.012]; patients with CTC >50 had a poorer OS than those with CTCs 5-50 (median OS 6.3 versus 21.1 months, HR 4.1, P<0.001). Patients whose CTC counts reduced from >or=5 at baseline to <5 following treatment had a better OS compared with those who did not. CTC counts showed a similar, but earlier and independent, ability to time to disease progression to predict OS. CONCLUSION: CTC counts predict OS and provide independent prognostic information to time to disease progression; CTC dynamics following therapy need to be evaluated as an intermediate end point of outcome in randomised phase III trials.

Norfluoxetine induces spawning and parturition in estuarine and freshwater bivalves.

Fluoxetine, a commonly prescribed antidepressant (Prozac), has been detected in sewage effluent. Its active metabolite norfluoxetine is more potent and has been detected in sewage influent and in fish tissues. We tested the effects of norfluoxetine on spawning and parturition in bivalves. Norfluoxetine induced significant spawning in zebra mussels and dark false mussels at concentrations as low as 5 microM. Norfluoxetine induced significant parturition in fingernail clams at 10 microM. Fluoxetine also induced spawning in dark false mussels at concentrations as low as 100 nM. Implications for environmental impacts of norfluoxetine and fluoxetine on native and exotic bivalves are discussed.

The bradykinin type 2 receptor BE1 polymorphism and ethnicity influence systolic blood pressure and vascular resistance.

We examined the effect of -58 C/T and BE1 +9/-9 polymorphisms in the bradykinin B2 receptor gene on forearm vascular resistance (FVR) before and during intrabrachial artery infusion of the B2 receptor-, endothelium-dependent agonist bradykinin and the endothelium-independent agonist sodium nitroprusside in 228 normotensive subjects. In 166 white Americans, systolic blood pressure (SBP) and pulse pressure were highest in the BE1 +9/+9 group (118+/-2 and 51+/-2 mm Hg, respectively; P<0.05 versus -9/-9 for either), intermediate in the +9/-9 group (114+/-1 and 49+/-1 mm Hg, P<0.05 versus -9/-9 for pulse pressure), and lowest in the -9/-9 group (110+/-2 and 44+/-2 mm Hg). In 62 black Americans, FVR was 25% higher in the BE1 +9/+9 group compared with the BE1 +9/-9 and -9/-9 groups at baseline (P=0.038) or during bradykinin (P=0.03). Increased SBP or vascular resistance may contribute to increased left ventricular mass reported previously in individuals with the BE1+9/+9 genotype.

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours.

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m(-2) in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m(-2) in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug-drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m(-2) and 420 mg pertuzumab following a loading dose of 840 mg.

Vascular invasion in pancreatic cancer: evaluation of endoscopic ultrasonography, computed tomography, ultrasonography, and angiography.

PRINCIPLES: Current methods for detecting vascular invasion in pancreatic cancer can be inaccurate, invasive, and expensive. The aim of this study is to assess the value of current imaging modalities in determining vascular invasion by pancreatic cancer. METHODS: The results of Endoscopic Ultrasonography (EUS), Computed Tomography (CT), Ultrasonography (US), and Angiography performed in 170 patients, suffering from pancreatic cancer, were retrospectively studied and correlated with intra-operative findings and surgical anatomopathological diagnosis after resection. We assessed sensitivity, specificity, positive and negative predictive values, and accuracy for detecting vascular invasion. RESULTS: EUS turned out to be the most reliable imaging technique for detecting vascular invasion in pancreatic cancer, with a sensitivity of 55%, specificity of 90%, positive predictive value of 61.1%, negative predictive value of 87.5%, and accuracy of 82.2%. CT results were 39.4%, 90%, 52%, 84.4%, and 79.1% for the respective categories, with however, better results with multislice CT. The US results were 3.7% for the sensitivity, 96.3% for the specificity, 25% for the positive predictive value, 75.2% for the negative predictive value, and 73.4% for the accuracy. For angiography, the sensitivity, the specificity, the positive predictive value, the negative predictive value, and the accuracy were 52.6%, 72.3%, 43.5%, 79.1%, and 66.7% respectively. CONCLUSION: In this study, EUS was the most valuable imaging modality in assessing vascular invasion (especially for venous invasion) for pancreatic cancer, with an accuracy of more than 80%. A further prospective study should be carried out to evaluate the combination of imaging modalities for the detection of vascular involvement, especially with multi-slice CT which almost reached the performances obtained by EUS.

Combining functional and linkage disequilibrium information in the selection of tag SNPs.

UNLABELLED: We have developed an online program, WCLUSTAG, for tag SNP selection that allows the user to specify variable tagging thresholds for different SNPs. Tag SNPs are selected such that a SNP with user-specified tagging threshold C will have a minimum R2 of C with at least one tag SNP. This flexible feature is useful for researchers who wish to prioritize genomic regions or SNPs in an association study. AVAILABILITY: The online WCLUSTAG program is available at http://bioinfo.hku.hk/wclustag/

Increased gene coverage and Alu frequency in large linkage disequilibrium blocks of the human genome.

The human genome has linkage disequilibrium (LD) blocks, within which single-nucleotide polymorphisms show strong association with each other. We examined data from the International HapMap Project to define LD blocks and to detect DNA sequence features inside of them. We used permutation tests to determine the empirical significance of the association of LD blocks with genes and Alu repeats. Very large LD blocks (>200 kb) have significantly higher gene coverage and Alu frequency than the outcome obtained from permutation-based simulation, whereas there was no significant positive correlation between gene density and block size. We also observed a reduced frequency of Alu repeats at the gaps between large LD blocks, indicating that their enrichment in large LD blocks does not introduce recombination hotspots that would cause these gaps.