Faster k-Medoids Clustering: Improving the PAM, CLARA, and CLARANS Algorithms

Clustering non-Euclidean data is difficult, and one of the most used algorithms besides hierarchical clustering is the popular algorithm Partitioning Around Medoids (PAM), also simply referred to as k-medoids. In Euclidean geometry the mean-as used in k-means-is a good estimator for the cluster center, but this does not hold for arbitrary dissimilarities. PAM uses the medoid instead, the object with the smallest dissimilarity to all others in the cluster. This notion of centrality can be used with any (dis-)similarity, and thus is of high relevance to many domains such as biology that require the use of Jaccard, Gower, or more complex distances. A key issue with PAM is its high run time cost. We propose modifications to the PAM algorithm to achieve an O(k)-fold speedup in the second SWAP phase of the algorithm, but will still find the same results as the original PAM algorithm. If we slightly relax the choice of swaps performed (at comparable quality), we can further accelerate the algorithm by performing up to k swaps in each iteration. With the substantially faster SWAP, we can now also explore alternative strategies for choosing the initial medoids. We also show how the CLARA and CLARANS algorithms benefit from these modifications. It can easily be combined with earlier approaches to use PAM and CLARA on big data (some of which use PAM as a subroutine, hence can immediately benefit from these improvements), where the performance with high k becomes increasingly important. In experiments on real data with k=100, we observed a 200-fold speedup compared to the original PAM SWAP algorithm, making PAM applicable to larger data sets as long as we can afford to compute a distance matrix, and in particular to higher k (at k=2, the new SWAP was only 1.5 times faster, as the speedup is expected to increase with k)

Hookworm Infection and Environmental Factors in Mbeya Region, Tanzania: A Cross-sectional, Population-based study.

Hookworm disease is one of the most common infections and cause of a high disease burden in the tropics and subtropics. Remotely sensed ecological data and model-based geostatistics have been used recently to identify areas in need for hookworm control. Cross-sectional interview data and stool samples from 6,375 participants from nine different sites in Mbeya region, south-western Tanzania, were collected as part of a cohort study. Hookworm infection was assessed by microscopy of duplicate Kato-Katz thick smears from one stool sample from each participant. A geographic information system was used to obtain remotely sensed environmental data such as land surface temperature (LST), vegetation cover, rainfall, and elevation, and combine them with hookworm infection data and with socio-demographic and behavioral data. Uni- and multivariable logistic regression was performed on sites separately and on the pooled dataset. Univariable analyses yielded significant associations for all ecological variables. Five ecological variables stayed significant in the final multivariable model: population density (odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.63-0.73), mean annual vegetation density (OR = 0.11; 95% CI = 0.06-0.18), mean annual LST during the day (OR = 0.81; 95% CI = 0.75-0.88), mean annual LST during the night (OR = 1.54; 95% CI = 1.44-1.64), and latrine coverage in household surroundings (OR = 1.02; 95% CI = 1.01-1.04). Interaction terms revealed substantial differences in associations of hookworm infection with population density, mean annual enhanced vegetation index, and latrine coverage between the two sites with the highest prevalence of infection. This study supports previous findings that remotely sensed data such as vegetation indices, LST, and elevation are strongly associated with hookworm prevalence. However, the results indicate that the influence of environmental conditions can differ substantially within a relatively small geographic area. The use of large-scale associations as a predictive tool on smaller scales is therefore problematic and should be handled with care

Ultrasound settings significantly alter arterial lumen and wall thickness measurements

Background. Flow-mediated dilation (FMD) and carotid intima-medial thickness (CIMT), measured by ultrasound, are widely used to test the efficacy of cardioprotective interventions. Although assessment methods vary, automated edge-detecting image analysis software is routinely used to measure changes in FMD and CIMT. We aimed to quantify the effect that commonly adjusted ultrasound settings have on arterial lumen and wall thickness measurements made with CIMT measurement software. Methods. We constructed phantom arteries from a tissue-mimicking agar compound and scanned them in a water bath with a 10 MHz multi-frequency linear-array probe attached to a high-resolution ultrasound machine. B-mode images of the phantoms were recorded with dynamic range (DR) and gain set at five decibel (dB) increments from 40 dB to 60 dB and -10 dB to +10 dB respectively. Lumen diameter and wall-thickness were measured off-line using CIMT measurement software. Results. Lumen measurements: there was a strong linear relationship between DR and gain and measured lumen diameter. For a given gain level, a 5 dB increase in DR reduced the measured lumen diameter by 0.02 ± 0.004 mm (p \u3c 0.001). For a given DR level, a 5 dB increase in gain reduced measured lumen diameter by 0.04 ± 0.004 mm (p \u3c 0.001). A 5 mm increase in distance between the ultrasound probe and the artery reduced measured lumen diameter by 0.04 ± 0.03 mm (p \u3c 0.001). CIMT measurements: For a fixed gain level, a 5 dB increase in DR increased measured wall thickness by 0.003 ± 0.002 mm (p \u3c 0.001). The effects of increasing gain were not consistent and appeared to vary depending on the distance between the artery and the ultrasound probe and the thickness of the artery wall. Conclusion. DR, gain and probe distance significantly alter lumen diameter and CIMT measurements made using image analysis software. When CIMT and FMD are used to test the efficacy of cardioprotective interventions, the DR, gain and probe position used to record baseline scans should be documented and replicated in post-treatment scans in individual trial subjects. If more than one sonographer or imaging centre is used to collect data, the study protocol should document specific DR and gain settings to be used in all subjects

Flavor conversion of cosmic neutrinos from hidden jets

High energy cosmic neutrino fluxes can be produced inside relativistic jets under the envelopes of collapsing stars. In the energy range E ~ (0.3 - 1e5) GeV, flavor conversion of these neutrinos is modified by various matter effects inside the star and the Earth. We present a comprehensive (both analytic and numerical) description of the flavor conversion of these neutrinos which includes: (i) oscillations inside jets, (ii) flavor-to-mass state transitions in an envelope, (iii) loss of coherence on the way to observer, and (iv) oscillations of the mass states inside the Earth. We show that conversion has several new features which are not realized in other objects, in particular interference effects ("L- and H- wiggles") induced by the adiabaticity violation. The neutrino-neutrino scattering inside jet and inelastic neutrino interactions in the envelope may produce some additional features at E > 1e4 GeV. We study dependence of the probabilities and flavor ratios in the matter-affected region on angles theta13 and theta23, on the CP-phase delta, as well as on the initial flavor content and density profile of the star. We show that measurements of the energy dependence of the flavor ratios will, in principle, allow to determine independently the neutrino and astrophysical parameters.Comment: 56 pages, 19 figures. Minor changes. Accepted by JHEP

Passerine Birds Breeding under Chronic Noise Experience Reduced Fitness

Background Fitness in birds has been shown to be negatively associated with anthropogenic noise, but the underlying mechanisms remain obscure. It is however crucial to understand the mechanisms of how urban noise impinges on fitness to obtain a better understanding of the role of chronic noise in urban ecology. Here, we examine three hypotheses on how noise might reduce reproductive output in passerine birds: (H1) by impairing mate choice, (H2) by reducing territory quality and (H3) by impeding chick development. Methodology/Principal Findings We used long-term data from an island population of house sparrows, Passer domesticus, in which we can precisely estimate fitness. We found that nests in an area affected by the noise from large generators produced fewer young, of lower body mass, and fewer recruits, even when we corrected statistically for parental genetic quality using a cross-fostering set-up, supporting H3. Also, individual females provided their young with food less often when they bred in the noisy area compared to breeding attempts by the same females elsewhere. Furthermore, we show that females reacted flexibly to increased noise levels by adjusting their provisioning rate in the short term, which suggests that noise may be a causal factor that reduces reproductive output. We rejected H1 and H2 because nestbox occupancy, parental body mass, age and reproductive investment did not differ significantly between noisy and quiet areas. Conclusions/Significance Our results suggest a previously undescribed mechanism to explain how environmental noise can reduce fitness in passerine birds: by acoustically masking parent–offspring communication. More importantly, using a cross-fostering set-up, our results demonstrate that birds breeding in a noisy environment experience significant fitness costs. Chronic noise is omnipresent around human habitation and may produces similar fitness consequences in a wide range of urban bird species

Phase II study of irinotecan with bolus and high dose infusional 5-FU and folinic acid (modified de Gramont) for first or second line treatment of advanced or metastatic colorectal cancer

We investigated the activity of irinotecan given with a more convenient modified bimonthly de Gramont regimen of bolus and infusional 5-fluorouracil [IrMdG] in advanced or metastatic colorectal cancer in the first and second line setting. Irinotecan 180 mg m−2 was infused over 90 min. L-folinic acid 175 mg or d,l folinic acid 350 mg was given over 2 h followed by a bolus of 5-fluorouracil (400 mg m−2) and a 46 h continuous infusion of 5-fluorouracil (2.4–2.8 g m−2). Forty-six previously untreated patients (Group A) and 36 who had received 5-fluorouracil for metastatic disease (Group B) were recruited. Seventy-eight patients were evaluable for response. A partial response was seen in 13 out of 43 (30% [95%CI 28.1–31.9%]) in Group A and 8/35 (23% [95% CI 17.9–28.1%]) in Group B. 40% (95%CI 38.1–41.9%) of Group A and 26% (95% CI 20.9–31.1%) of Group B patients achieved disease stabilisation. The median progression free survival from the start of this treatment was 7 months (95% CI 4.4–9.6 months) in Group A and 5 months (95% CI 2.8–7.2 months) in Group B. Median overall survival was 14 months (95% CI 9.0–18.9) in Group A and 11 months (95% CI 5.9–16.1) in Group B. Grade 3–4 toxicity in both treatment groups were similar; leucopenia 17% and diarrhoea 7–8%. Grade 3–4 mucositis was not seen and severe alopecia affected only three patients. IrMdG is an active and well-tolerated regimen for both the first and second line treatment of advanced colorectal cancer

Potentially inappropriate medication in older participants of the Berlin Aging Study II (BASE-II) - Sex differences and associations with morbidity and medication use

INTRODUCTION: Multimorbidity in advanced age and the need for drug treatment may lead to polypharmacy, while pharmacokinetic and pharmacodynamic changes may increase the risk of adverse drug events (ADEs). OBJECTIVE: The aim of this study was to determine the proportion of subjects using potentially inappropriate medication (PIM) in a cohort of older and predominantly healthy adults in relation to polypharmacy and morbidity. METHODS: Cross-sectional data were available from 1,382 study participants (median age 69 years, IQR 67-71, 51.3% females) of the Berlin Aging Study II (BASE-II). PIM was classified according to the EU(7)-PIM and German PRISCUS (representing a subset of the former) list. Polypharmacy was defined as the concomitant use of at least five drugs. A morbidity index (MI) largely based on the Charlson Index was applied to evaluate the morbidity burden. RESULTS: Overall, 24.1% of the participants were affected by polypharmacy. On average, men used 2 (IQR 1-4) and women 3 drugs (IQR 1-5). According to PRISCUS and EU(7)-PIM, 5.9% and 22.6% of participants received at least one PIM, while use was significantly more prevalent in females (25.5%) compared to males (19.6%) considering EU(7)-PIM (p = 0.01). In addition, morbidity in males receiving PIM according to EU(7)-PIM was higher (median MI 1, IQR 1-3) compared to males without PIM use (median MI 1, IQR 0-2, p<0.001). CONCLUSION: PIM use occurred more frequently in women than in men, while it was associated with higher morbidity in males. As expected, EU(7)-PIM identifies more subjects as PIM users than the PRISCUS list but further studies are needed to investigate the differential impact of both lists on ADEs and outcome. KEY POINTS: We found PIM use to be associated with a higher number of regular medications and with increased morbidity. Additionally, we detected a higher prevalence of PIM use in females compared to males, suggesting that women and people needing intensive drug treatment are patient groups, who are particularly affected by PIM use

Intranasal administration of acetylcholinesterase inhibitors

This short review outlines the rationale, challenges, and opportunities for intranasal acetylcholinesterases, in particular galantamine. An in vitro screening model facilitated the development of a therapeutically viable formulation. In vivo testing confirmed achievement of therapeutically relevant drug levels that matched or exceeded those for oral dosing, with a dramatic reduction in undesired emetic responses. Intranasal drug delivery is an effective option for the treatment of Alzheimer's disease and other central nervous system disorders

Carotid intima-medial thickness measured on multiple ultrasound frames: evaluation of a DICOM-based software system

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Cerebellar-dependent delay eyeblink conditioning in adolescents with Specific Language Impairment

Cerebellar impairments have been hypothesized as part of the pathogenesis of Specific Language Impairment (SLI), although direct evidence of cerebellar involvement is sparse. Eyeblink Conditioning (EBC) is a learning task with well documented cerebellar pathways. This is the first study of EBC in affected adolescents and controls. 16 adolescent controls, 15 adolescents with SLI, and 12 adult controls participated in a delay EBC task. Affected children had low general language performance, grammatical deficits but no speech impairments. The affected group did not differ from the control adolescent or control adult group, showing intact cerebellar functioning on the EBC task. This study did not support cerebellar impairment at the level of basic learning pathways as part of the pathogenesis of SLI. Outcomes do not rule out cerebellar influences on speech impairment, or possible other forms of cerebellar functioning as contributing to SLI