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Challenges in understanding the origin of recurrentPlasmodium vivaxinfections constrains the surveillance of antimalarial efficacy and transmission of this neglected parasite. Recurrent infections within an individual may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or new inoculations (reinfection). Molecular inference of familial relatedness (identity-by-descent or IBD) based on whole genome sequence data, together with analysis of the intervals between parasitaemic episodes (“time-to-event” analysis), can help resolve the probable origin of recurrences. Whole genome sequencing of predominantly low-densityP. vivaxinfections is challenging, so an accurate and scalable genotyping method to determine the origins of recurrent parasitaemia would be of significant benefit. We have developed aP. vivaxgenome-wide informatics pipeline to select specific microhaplotype panels that can capture IBD within small, amplifiable segments of the genome. Using a global set of 615P. vivaxgenomes, we derived a panel of 100 microhaplotypes, each comprising 3-10 high frequency SNPs within HE= 0.70-0.81) and it captured 89% (273/307) of the polyclonal infections detected with genome-wide datasets. Using data simulations, we demonstrate lower error in estimating pairwise IBD using microhaplotypes, relative to traditional biallelic SNP barcodes. Our panel exhibited high accuracy in predicting the country of origin (median Matthew’s correlation coefficient >0.9 in 90% countries tested) and it also captured local infection outbreak and bottlenecking events. The informatics pipeline is available open-source and yields microhaplotypes that can be readily transferred to high-throughput amplicon sequencing assays for surveillance in malaria-endemic regions.

Although recovery from borderline personality disorder (BPD) is common, not all individuals improve over time. This study sought to examine the features that contribute to response or non-response for individuals at different stages of recovery from BPD over a longitudinal follow-up. Participants were individuals with a diagnosis of BPD that were followed up after 1 year of receiving psychological treatment. There were no significant differences between participants at intake across key indices; however, at 1-year follow-up, two groups were distinguishable as either 'functioning well' (n = 23) or 'functioning poorly' (n = 25) based on symptomatology and functional impairment. Participant qualitative responses were analysed thematically and via Leximancer content analysis. Thematic analysis indicated three key themes: (1) love of self and others, (2) making a contribution through work and study and (3) stability in daily life. Participants who were 'functioning well' described meaningful relationships with others, enjoyment in vocation, and described less frequent or manageable life crises. The 'functioning poorly' group described relationship conflicts, vocational challenges, feelings of aimlessness and purposelessness, instability in daily living and frequent crises. Leximancer content analysis visually depicted these divergent thematic nomological networks. Corroborating quantitative analyses indicated significant differences between these groups for social, occupational and symptom profiles. These findings highlight the centrality of achieving the capacity to 'love and work' in fostering a sense of personal recovery. Treatments may need specific focus on these factors, as they appeared to reinforce symptomatic trajectories of either improvement or poor non-response to therapy.

Let Λ be an infinite connected graph, and let v 0 be a vertex of Λ. We consider the following positional game. Two players, Maker and Breaker, play in alternating turns. Initially all edges of Λ are marked as unsafe. On each of her turns, Maker marks p unsafe edges as safe, while on each of his turns Breaker takes q unsafe edges and deletes them from the graph. Breaker wins if at any time in the game the component containing v 0 becomes finite. Otherwise if Maker is able to ensure that v 0 remains in an infinite component indefinitely, then we say she has a winning strategy. This game can be thought of as a variant of the celebrated Shannon switching game. Given ( p , q ) and ( Λ , v 0 ) , we would like to know: which of the two players has a winning strategy? Our main result in this paper establishes that when Λ = Z 2 and v 0 is any vertex, Maker has a winning strategy whenever p ≥ 2 q , while Breaker has a winning strategy whenever 2 p ≤ q . In addition, we completely determine which of the two players has a winning strategy for every pair ( p , q ) when Λ is an infinite d-regular tree. Finally, we give some results for general graphs and lattices and pose some open problems.

We disprove a conjecture of Nagy on the maximum number of copies $N$($G$, $H$) of a fixed graph $G$ in a large graph $H$ with prescribed edge density. Nagy conjectured that for all $G$, the quantit...

Exposure to cigarette smoke has a proven detrimental impact on different aspects of human health. Increasing evidences link smoking to degeneration of joint tissues. However, the toxic mechanisms elicited by the different components of cigarette smoke have not been fully elucidated yet. We have previously shown that exposure to hydroquinone (HQ), a pro-oxidant chemical present in cigarette smoke, can promote joint tissue degradation in murine models of rheumatoid arthritis through the activation of the aryl hydrocarbon receptor (AhR) pathway. Osteoarthritis (OA) is a chronic debilitating articular disease characterized by progressive degradation of the articular cartilage, whose onset and progression have also been associated with smoking. In this work we aimed to investigate the effect of HQ exposure on articular chondrocytes and how it affects cartilage homeostasis. Cell viability, gene expression, oxidative stress and inflammatory parameters were quantified in primary articular chondrocytes exposed to HQ in presence or absence of IL-1β pre-stimulation. HQ stimulation downregulated phenotypic markers genes such as SOX-9 and Col2a1, whereas upregulated the expression of the catabolic enzymes MMP-3 and ADAMTS5. HQ also promoted oxidative stress and reduced proteoglycan content. HQ exacerbated the pro-inflammatory effects mediated by the IL-1β co-stimulation. Finally, we showed that HQ-degenerative effects were mediated by the activation of AhR. Together, our findings address the harmful effects of HQ in the articular cartilage health, providing novel evidence surrounding the toxic mechanisms of environmental pollutants underlying the onset of articular diseases.

Motivated by problems in percolation theory, we study the following two-player positional game. Let Λm×n be a rectangular grid-graph with m vertices in each row and n vertices in each column. Two players, Maker and Breaker, play in alternating turns. On each of her turns, Maker claims p (as yet unclaimed) edges of the board Λm×n, while on each of his turns Breaker claims q (as yet unclaimed) edges of the board and destroys them. Maker wins the game if she manages to claim all the edges of a crossing path joining the left-hand side of the board to its right-hand side, otherwise Breaker wins. We call this game the (p, q)-crossing game on Λm×n.Given m, n ∈ ℕ, for which pairs (p, q) does Maker have a winning strategy for the (p, q)-crossing game on Λm×n? The (1, 1)-case corresponds exactly to the popular game of Bridg-it, which is well understood due to it being a special case of the older Shannon switching game. In this paper we study the general (p, q)-case. Our main result is to establish the following transition. If p ≥ 2q, then Maker wins the game on arbitrarily long versions of the narrowest board possible, that is, Maker has a winning strategy for the (2q, q)-crossing game on Λm×(q+1) for any m ∈ ℕ.If p ≤ 2q − 1, then for every width n of the board, Breaker has a winning strategy for the (p, q)-crossing game on Λm×n for all sufficiently large board-lengths m.Our winning strategies in both cases adapt more generally to other grids and crossing games. In addition we pose many new questions and problems.

Background In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. Methods We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 30 BPM; SpO2/FiO2 Results In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72–0.74) and calibration (calibration slopes: 1.01–1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. Conclusions We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.

Aim A 'watch and wait' (W&W) strategy after neoadjuvant long-course chemoradiotherapy (NACRT) remains controversial. Whilst encouraging short-term data exist, the strategy will be judged on long-term data. We present long-term, real-world UK data from a single National Health Service trust. Methods An analysis was performed of a prospectively maintained W&W database over 9 years between 2010 and 2018. Outcome measures include incidence and time to regrowth and overall and disease-free survival. Results We diagnosed 563 rectal cancers in 9 years. In all, 283 patients underwent rectal resection (50.3%). NACRT was used in 155 patients for margin-threatened tumours on staging MRI. Forty-nine patients (31.6%) experienced either a 'near complete' or a complete clinical response (cCR) at their 10 weeks post-NACRT assessment (MRI and endoscopy). The median age was 69 years (range 44-83), and the male to female ratio was 32:17. The median follow-up was 38 months (range 12-96). The median tumour distance from the anal verge was 7 cm (1-15 cm). Twenty-two patients had a cCR on initial assessment and 27 patients had a 'near' cCR. Of those 27 who experienced a 'near' cCR, 17 (63%) progressed to cCR on repeat assessment and 10 (37%) did not. Of these 10 patients, seven underwent standard surgical resection and three were unfit for surgery. R0 for the seven with delayed resection was 100%. Of 39 patients (22 cCR and 17 'near' cCR who progressed to cCR) (25.2% of those receiving NACRT), six patients experienced local regrowth (15.4%). The median time to local regrowth was 29 months (15-60 months). One of these six patients underwent salvage abdominoperineal resection, one was advised to have contact radiotherapy and four opted against surgery and also had contact radiotherapy. The overall survival was 100% at 2 years and 90% at 5 years. Disease-free survival was 90.47% at 2 years and 74.8% at 5 years. Conclusion A W&W treatment strategy was employed safely in this patient cohort with acceptable rates of local regrowth and survival.

Given a graph $G$, a probability measure $\mu$ on the subsets of the edge set of $G$ is said to be $1$-independent if events determined by edge sets that are at graph distance at least $1$ apart in $G$ are independent. Call such a probability measure a $1$-ipm on $G$, and denote by $\mathbf{G}_{\mu}$ the associated random spanning subgraph of $G$. Let $\mathcal{M}_{1,\geqslant p}(G)$ (resp. $\mathcal{M}_{1,\leqslant p}(G)$) denote the collection of $1$-ipms $\mu$ on $G$ for which each edge is included in $\mathbf{G}_{\mu}$ with probability at least $p$ (resp. at most $p$). Let $\mathbb{Z}^2$ denote the square integer lattice. Balister and Bollob\'as raised the question of determining the critical value $p_{\star}=p_{1,c}(\mathbb{Z}^2)$ such that for all $p>p_{\star}$ and all $\mu \in \mathcal{M}_{1,\geqslant p}(\mathbb{Z}^2)$, $\left(\mathbf{\mathbb{Z}^2}\right)_{\mu}$ almost surely contains an infinite component. This can be thought of as asking for a $1$-independent analogue of the celebrated Harris--Kesten theorem. In this paper we investigate both this problem and connectivity problems for $1$-ipms more generally. We give two lower bounds on $p_{\star}$ that significantly improve on the previous bounds. Furthermore, motivated by the Russo--Seymour--Welsh lemmas, we define a $1$-independent critical probability for long paths and determine its value for the line and ladder lattices. Finally, for finite graphs $G$ we study $f_{1,G}(p)$ (respectively $F_{1,G}(p)$), the infimum (resp. supremum) over all $\mu\in \mathcal{M}_{1,\geqslant p}(G)$ (resp. all $\mu \in \mathcal{M}_{1,\leqslant p}(G)$) of the probability that $\mathbf{G}_{\mu}$ is connected. We determine $f_{1,G}(p)$ and $F_{1,G}(p)$ exactly when $G$ is a path, a complete graph and a cycle of length at most $5$. Many new problems arise from our work, which are discussed in the final section of the paper., Comment: 43 pages, 3 figures

We show that for any positive integer r there exists an integer k and a k-colouring of the edges of K 2 k + 1 with no monochromatic odd cycle of length less than r. This makes progress on a problem of Erdős and Graham and answers a question of Chung. We use these colourings to give new lower bounds on the k-colour Ramsey number of the odd cycle and prove that, for all odd r and all k sufficiently large, there exists a constant ϵ = ϵ ( r ) > 0 such that R k ( C r ) > ( r − 1 ) ( 2 + ϵ ) k − 1 .

BACKGROUND: A colposcopy examination is the main management option for women with an abnormal cervical screening test result. Although some women experience adverse psychological effects after colposcopy, those at greatest risk are unknown. We investigated predictors of worries about cervical cancer, sex, future fertility and general health during 12 to 30 months after colposcopy.METHODS: We invited 1,515 women, aged 20 to 59 years with low-grade cervical cytology who attended colposcopy to complete questionnaires at recruitment (∼8 weeks after cytology result) and after 12, 18, 24, and 30 months of follow up. Outcomes were worries about having cervical cancer, having sex, future fertility, and general health at any time during follow-up. Factors significantly associated with each outcome were identified using multiple logistic regression.RESULTS: At one or more time points during follow-up, 40% of women reported worries about having cervical cancer, 26% about having sex, 24% about future fertility, and 60% about general health. For all outcomes except sex, worries reported at recruitment were associated with significantly increased risk of worries during follow-up. Significant anxiety at recruitment was associated with all worries during follow-up. Women diagnosed with CIN2+ had significantly higher risks of worries about cervical cancer and future fertility. Management received was associated significantly with worries about cervical cancer and having sex. Younger women significantly more often reported worries about future fertility, whereas women who had children had reduced risk of future fertility worries but increased risk of cervical cancer worries.CONCLUSION: Clinical, sociodemographic, lifestyle, and psychological factors predicted risk of reporting worries after colposcopy.

There are many radiological imaging techniques for perianal fistulas; the choice of modality may depend on several factors other than simply diagnostic accuracy. Equipment availability and financial constraints vary between healthcare systems. Inexperienced clinical assessment may miss secondary extensions; the resulting recurrence is expensive and upsetting for patients. Fistulography no longer has a role in fistulas arising from the anus itself, but it may be useful in identifying extra-sphincteric tracts arising from abdominal organs, such as appendix, terminal ileum, and sigmoid colon. CT has a limited role acutely but otherwise there are better methods. In the right hands, Endo-anal ultrasonography is still more accurate than clinical examination alone, but requires considerable skill in interpretation, is operator dependent, and may not be suitable for all patients. magnetic resonance imaging scans are the gold standard for fistula.

We present an unique case report of pneumatosis intestinalis after fistuloclysis.

Adverse conditions, including exposures to drugs and other environmental influences during early development, may affect behaviors later in life. This study examined the role of environmental influences from the gestation and childhood on adolescent drinking behavior. 917 mother/offspring dyads were followed prospectively from pregnancy to a 16-year follow-up assessment. Interim assessments occurred at delivery, 6, 10, and 14 years. Prenatal exposures to alcohol, tobacco, and marijuana were measured during gestation. Data were collected at each phase on childhood environment, including parenting practices, quality of the home environment, maternal depression and hostility, and lifetime exposure to child maltreatment and community violence. Alcohol outcomes were offspring age of drinking initiation and level of drinking at age 16 years. Cox Proportional Hazards ratios were used to model offspring age of drinking initiation. Logistic regression analyses were used to evaluate significant predictors of drinking level. Childhood environment, including less parental strictness, greater exposure to violence and childhood maltreatment, significantly predicted earlier age of alcohol initiation. Level of drinking among the adolescent offspring was significantly predicted by prenatal exposure to alcohol, less parental strictness, and exposures to maltreatment and violence during childhood. Whites and offspring with older mothers were more likely to initiate alcohol use early and drink at higher levels. Early and heavier alcohol use was associated with early exposures to adversity such as prenatal alcohol exposure, and child exposures to maltreatment and violence. These results highlight the importance of environmental adversity and less effective parenting practices on the development of adolescent drinking behavior.

Aim We aimed to develop an intuitive, interactive, three-dimensional (3D) MRI modelling technique to produce a 3D image of fistula–in-ano. Method The 3D model was created from standard two-dimensional (2D) MRI sequences to produce an image that is anatomically correct. Individual muscle and soft-tissue layers were extracted from T1-weighted sequences and fistula pathology from short TI inversion recovery (STIR) sequences, to produce two separate volumes. These were then fused using postprocessing software (Vitrea Workstation version 6.3) to generate a 3D model. Results The final 3D model was incorporated into a PDF file that has an integrated computer aided design (CAD) viewer, allowing the surgeon to rotate it in any direction during preoperative planning or whilst in theatre. Conclusion As an adjunct to 2D MRI images and the associated radiology report, this model communicates the fistula anatomy to the clinician more clearly and should be particularly useful in complex cases.

A graph $G$ is $H$-saturated if it contains no copy of $H$ as a subgraph but the addition of any new edge to $G$ creates a copy of $H$. In this paper we are interested in the function sat$_{t}(n,p)$, defined to be the minimum number of edges that a $K_{p}$-saturated graph on $n$ vertices can have if it has minimum degree at least $t$. We prove that sat$_{t}(n,p) = tn - O(1)$, where the limit is taken as $n$ tends to infinity. This confirms a conjecture of Bollob\'as when $p = 3$. We also present constructions for graphs that give new upper bounds for sat$_{t}(n,p)$ and discuss an analogous problem for saturated hypergraphs., Comment: 15 pages

This article proposes a new way of assessing an investment manager's skill in the day-to-day management of portfolios. The authors argue that traditional investment performance measurement techniques, whilst appropriate for many purposes, do not provide the insights necessary to judge the skill of investment managers. To judge manager skill, it is necessary to consider the activity within the portfolio in terms of the purchases, sales and trades, and to determine the value added by that activity The authors set out a framework by which this analysis can be carried out using the OR Society's investment portfolio as an example, and indicate how the results can be interpreted.

It is recognized that survivors of Hodgkin's disease are at a substantially increased risk of lung cancer. A collaborative group of population-based cancer registries and major treatment centers carried out a case-control study, in which 98 cases of lung cancer were identified in patients who had survived at least 1 year following a diagnosis of Hodgkin's disease. A total of 259 matched controls were selected from patients with Hodgkin's disease who did not develop subsequent lung cancer, and for both cases and controls detailed information was abstracted from medical records concerning stage and treatment of Hodgkin's disease. Patients treated with chemotherapy alone had about twice the risk of developing lung cancer than those treated by radiotherapy alone or both modalities. There was no increase in risk with cumulative number of cycles of chemotherapy. Among patients treated with radiotherapy alone, there was an increase in risk related to estimated radiation dose to the lung. There was also a strong association between cigarette smoking and the risk of lung cancer. The finding of a higher risk following chemotherapy than following radiotherapy was unexpected, but could not be explained by any identified methodological flaws. A plausible inference from the study is that all forms of Hodgkin's disease therapy are carcinogenic to the lung and that, in particular, chemotherapy is associated with an increase in risk which is at least comparable to and perhaps higher than the risk produced by radiotherapy. © 1992 Wiley-Liss, Inc.

Severe malaria is a global problem, claiming at least 1 million lives annually. Few adequately powered clinical studies have been directed at improving the management of severe malaria over the years, but this situation is slowly changing. The antimalarial treatment of severe disease is being transformed by the development and deployment of the water-soluble artemisinin derivative artesunate. Parenteral artesunate is now the treatment of choice in low-transmission areas and in the 2nd and 3rd trimesters of pregnancy, and research is underway into whether it should replace quinine as the treatment of choice in African children. Development of good manufacturing practice (GMP) formulations should make parenteral artesunate more widely available in the near future. The development of artesunate suppositories offers another exciting prospect, the ability to treat patients with severe disease in remote rural settings, delaying the evolution of disease and buying them time to reach a health care facility. No adjunctive therapy has been shown to improve the outcome of severe malaria, but most studies have been underpowered. Future trials of interventions shown to be promising in pilot studies should be large and adequately powered. This will require multi-center designs and necessitate close collaboration between groups, as well as agreement on the research agenda. We suggest a list of candidate interventions for debate.

Most malaria-endemic countries are implementing a change in antimalarial drug policy to artemisinin combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. A comprehensive model was constructed incorporating important epidemiological and biological factors and used to illustrate the spread of resistance in low and high transmission settings. The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and that in low transmission areas ACTs slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. A major obstacle to achieving the benefits of high coverage is the current cost of the drugs. This argues strongly for a global subsidy to make ACTs generally available and affordable in endemic areas.

A case-referent study of birth defects was nested in a prevalence survey of adverse reproductive outcomes carried out among 8867 floriculture workers in Bogotá, Colombia. A total of 535 children born to these workers and reported by their parents as malformed and 1070 children selected at random as referents were invited to a medical examination including consultation with a geneticist and a clinical teratologist and a review of the medical records. Seventy-six percent of both groups attended the examination. Of 403 children reported as malformed, a birth defect was confirmed for only 154 (38%). On the other hand, of the 817 children reported as normal, 735 (90%) were normal, but 68 had a birth defect and 14 had other conditions. A case-referent analysis was then carried out including 222 children with birth defects and 443 referents. An increased risk was found only for birthmarks, and specifically for hemangiomas, for children with parents exposed to pesticides in the floriculture industry.

The etiology of bloodstream infections in febrile patients remain poorly characterized in Nepal. A retrospective study of febrile patients presenting to Dhulikhel Hospital Kathmandu University Teaching Hospital from July 2002 to June 2004 was performed to evaluate the etiology of bloodstream infections and the drug sensitivity patterns of cultured organisms. The medical and laboratory records of all febrile patients with an axillary temperatureor = 38 degrees C who had a blood culture taken (n = 1,774) were retrieved and analyzed. Of these, 122 (6.9%) patients had positive blood cultures, of which 40.1% were age 11 to 20 years. The male to female ratio was 1.7:1. Antibiotics had been taken prior to hospital presentation by 39 (32%) patients. Salmonella enterica serovar Typhi and serovar Paratyphi A were isolated in 50 (41.0%) and 13 (10.7%) cases, respectively. All S. Typhi and S. Paratyphi isolates were susceptible to ceftriaxone, while susceptibility to ciprofloxacin and chloramphenicol was recorded in 94.8% and 94.5% of cases, respectively. Cephalexin and amoxicillin had the lowest rates of susceptibility (64.2% and 54.1%, respectively). Salmonella spp were usually sensitive to chloramphenicol. These findings provide clinicians in this region of Nepal with a better understanding of the spectrum of pathogens causing bloodstream infections and will help guide empiric antibiotic choice.

Smoking has recently been recognised as causally associated with the development of gastric cancer (GC). However, evidence on the effect by sex, duration and intensity of smoking, anatomic subsite and cessation of smoking is limited. Our objective was to assess the relation between tobacco use and GC incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC). We studied data from 521,468 individuals recruited from 10 European countries taking part in the EPIC study. Participants completed lifestyle questionnaires that included questions on lifetime consumption of tobacco and diet in 1991-1998. Participants were followed until September 2002, and during that period 305 cases of stomach cancer were identified. After exclusions, 274 were eligible for the analysis, using the Cox proportional hazard model. After adjustment for educational level, consumption of fresh fruit, vegetables and preserved meat, alcohol intake and body mass index (BMI), there was a significant association between cigarette smoking and gastric cancer risk: the hazard ratio (HR) for ever smokers was 1.45 (95% confidence interval [CI] = 1.08-1.94). The HR of current cigarette smoking was 1.73 (95% CI = 1.06-2.83) in males and 1.87 (95% CI = 1.12-3.12) in females. Hazard ratios increased with intensity and duration of cigarette smoked. A significant decrease of risk was observed after 10 years of quitting smoking. A preliminary analysis of 121 cases with identified anatomic site showed that current cigarette smokers had a higher HR of GC in the cardia (HR = 4.10) than in the distal part of the stomach (HR = 1.94). In this cohort, 17.6 % (95% CI = 10.5-29.5 %) of GC cases may be attributable to smoking. Findings from this large study support the causal relation between smoking and gastric cancer in this European population. Stomach cancer should be added to the burden of diseases caused by smoking.