Review: Towards the next-generation models of the rumen microbiome for enhancing predictive power and guiding sustainable production strategies.

The rumen ecosystem harbours a galaxy of microbes working in syntrophy to carry out a metabolic cascade of hydrolytic and fermentative reactions. This fermentation process allows ruminants to harvest nutrients from a wide range of feedstuff otherwise inaccessible to the host. The interconnection between the ruminant and its rumen microbiota shapes key animal phenotypes such as feed efficiency and methane emissions and suggests the potential of reducing methane emissions and enhancing feed conversion into animal products by manipulating the rumen microbiota. Whilst significant technological progress in omics techniques has increased our knowledge of the rumen microbiota and its genome (microbiome), translating omics knowledge into effective microbial manipulation strategies remains a great challenge. This challenge can be addressed by modelling approaches integrating causality principles and thus going beyond current correlation-based approaches applied to analyse rumen microbial genomic data. However, existing rumen models are not yet adapted to capitalise on microbial genomic information. This gap between the rumen microbiota available omics data and the way microbial metabolism is represented in the existing rumen models needs to be filled to enhance rumen understanding and produce better predictive models with capabilities for guiding nutritional strategies. To fill this gap, the integration of computational biology tools and mathematical modelling frameworks is needed to translate the information of the metabolic potential of the rumen microbes (inferred from their genomes) into a mathematical object. In this paper, we aim to discuss the potential use of two modelling approaches for the integration of microbial genomic information into dynamic models. The first modelling approach explores the theory of state observers to integrate microbial time series data into rumen fermentation models. The second approach is based on the genome-scale network reconstructions of rumen microbes. For a given microorganism, the network reconstruction produces a stoichiometry matrix of the metabolism. This matrix is the core of the so-called genome-scale metabolic models which can be exploited by a plethora of methods comprised within the constraint-based reconstruction and analysis approaches. We will discuss how these methods can be used to produce the next-generation models of the rumen microbiome.

Animal board invited review: Quantification of resilience in farm animals.

Resilience, when defined as the capacity of an animal to respond to short-term environmental challenges and to return to the prechallenge status, is a dynamic and complex trait. Resilient animals can reinforce the capacity of the herd to cope with often fluctuating and unpredictable environmental conditions. The ability of modern technologies to simultaneously record multiple performance measures of individual animals over time is a huge step forward to evaluate the resilience of farm animals. However, resilience is not directly measurable and requires mathematical models with biologically meaningful parameters to obtain quantitative resilience indicators. Furthermore, interpretive models may also be needed to determine the periods of perturbation as perceived by the animal. These applications do not require explicit knowledge of the origin of the perturbations and are developed based on real-time information obtained in the data during and outside the perturbation period. The main objective of this paper was to review and illustrate with examples, different modelling approaches applied to this new generation of data (i.e., with high-frequency recording) to detect and quantify animal responses to perturbations. Case studies were developed to illustrate alternative approaches to real-time and post-treatment of data. In addition, perspectives on the use of hybrid models for better understanding and predicting animal resilience are presented. Quantification of resilience at the individual level makes possible the inclusion of this trait into future breeding programmes. This would allow improvement of the capacity of animals to adapt to a changing environment, and therefore potentially reduce the impact of disease and other environmental stressors on animal welfare. Moreover, such quantification allows the farmer to tailor the management strategy to help individual animals to cope with the perturbation, hence reducing the use of pharmaceuticals, and decreasing the level of pain of the animal.

Review: Reducing enteric methane emissions improves energy metabolism in livestock: is the tenet right?

The production of enteric methane in the gastrointestinal tract of livestock is considered as an energy loss in the equations for estimating energy metabolism in feeding systems. Therefore, the spared energy resulting from specific inhibition of methane emissions should be re-equilibrated with other factors of the equation. And, it is commonly assumed that net energy from feeds increases, thus benefitting production functions, particularly in ruminants due to the important production of methane in the rumen. Notwithstanding, we confirm in this work that inhibition of emissions in ruminants does not transpose into consistent improvements in production. Theoretical calculations of energy flows using experimental data show that the expected improvement in net energy for production is small and difficult to detect under the prevailing, moderate inhibition of methane production (≈25%) obtained using feed additives inhibiting methanogenesis. Importantly, the calculation of energy partitioning using canonical models might not be adequate when methanogenesis is inhibited. There is a lack of information on various parameters that play a role in energy partitioning and that may be affected under provoked abatement of methane. The formula used to calculate heat production based on respiratory exchanges should be validated when methanogenesis is inhibited. Also, a better understanding is needed of the effects of inhibition on fermentation products, fermentation heat, and microbial biomass. Inhibition induces the accumulation of H2, the main substrate used to produce methane, that has no energetic value for the host, and it is not extensively used by the majority of rumen microbes. Currently, the fate of this excess of H2 and its consequences on the microbiota and the host are not well known. All this additional information will provide a better account of energy transactions in ruminants when enteric methanogenesis is inhibited. Based on the available information, it is concluded that the claim that enteric methane inhibition will translate into more feed-efficient animals is not warranted.

Trends of incidence, mortality and survival of multiple myeloma in Spain. A twenty-three-year population-based study

Background Despite major advances, multiple myeloma remains an incurable disease. Epidemiological data from high-quality population-based registries are needed to understand the heterogeneous landscape of the disease. Methods Incidence, mortality and survival in multiple myeloma were comprehensively analyzed in the Girona and Granada population-based cancer registries, over a 23-year study (1994–2016), divided into three periods (1994–2001, 2002–2009 and 2010–2016). Joinpoint regression analysis was used to estimate the annual percentage change in incidence and mortality. Age-standardized net survival was calculated with the Pohar–Perme method. Results 1957 myeloma patients were included in the study, with a median age of 72 years. Age-standardized incidence and mortality rates decreased over time in both sexes and both rates were higher in males. Five-year age-standardized net survival by period was 27.4% (1994–2001), 38.8% (2002–2009), and 47.4% (2010–2016). Survival improved for all age groups: 32.4%, 74.1% and 78.5% for patients aged 15–49; 27.5%, 44.6%, and 58.5% for those aged 50–69; finally, 24.8%, 25.5%, and 26.3% for the older group. Conclusion Incidence remained overall stable throughout the study, with only a small increase for men. Mortality was progressively decreasing in both sexes. Both incidence and mortality were higher in men. Age plays a critical role in survival, with impressive improvement in patients younger than 70 years, but only a minor benefit in those older than 70 (AU)

Pulmonary Embolism Complicated by Acute Limb Ischemia Managed by Surgical Pulmonary Embolectomy.

Acute pulmonary embolism (PE) is a manifestation of venous thromboembolic disease with potential serious and life-threatening complications. Management options for acute PE have drastically improved over the last 15 years with the introduction of multidisciplinary pulmonary embolism response teams throughout the world. We present the case of an 18-year-old woman diagnosed with acute PE complicated by near-complete occlusion of her left common femoral artery from a paradoxical embolus in the setting of patent foramen ovale (PFO), managed with surgical pulmonary embolectomy and surgical PFO repair.

Trends of incidence, mortality and survival of multiple myeloma in Spain. A twenty-three-year population-based study.

BACKGROUND: Despite major advances, multiple myeloma remains an incurable disease. Epidemiological data from high-quality population-based registries are needed to understand the heterogeneous landscape of the disease. METHODS: Incidence, mortality and survival in multiple myeloma were comprehensively analyzed in the Girona and Granada population-based cancer registries, over a 23-year study (1994-2016), divided into three periods (1994-2001, 2002-2009 and 2010-2016). Joinpoint regression analysis was used to estimate the annual percentage change in incidence and mortality. Age-standardized net survival was calculated with the Pohar-Perme method. RESULTS: 1957 myeloma patients were included in the study, with a median age of 72 years. Age-standardized incidence and mortality rates decreased over time in both sexes and both rates were higher in males. Five-year age-standardized net survival by period was 27.4% (1994-2001), 38.8% (2002-2009), and 47.4% (2010-2016). Survival improved for all age groups: 32.4%, 74.1% and 78.5% for patients aged 15-49; 27.5%, 44.6%, and 58.5% for those aged 50-69; finally, 24.8%, 25.5%, and 26.3% for the older group. CONCLUSION: Incidence remained overall stable throughout the study, with only a small increase for men. Mortality was progressively decreasing in both sexes. Both incidence and mortality were higher in men. Age plays a critical role in survival, with impressive improvement in patients younger than 70 years, but only a minor benefit in those older than 70.

Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis.

Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development.

Towards the quantitative characterisation of piglets' robustness to weaning: a modelling approach.

Weaning is a critical transition phase in swine production in which piglets must cope with different stressors that may affect their health. During this period, the prophylactic use of antibiotics is still frequent to limit piglet morbidity, which raises both economic and public health concerns such as the appearance of antimicrobial-resistant microbes. With the interest of developing tools for assisting health and management decisions around weaning, it is key to provide robustness indexes that inform on the animals' capacity to endure the challenges associated with weaning. This work aimed at developing a modelling approach for facilitating the quantification of piglet resilience to weaning. A total of 325 Large White pigs weaned at 28 days of age were monitored and further housed and fed conventionally during the post-weaning period without antibiotic administration. Body weight and diarrhoea scores were recorded before and after weaning, and blood was sampled at weaning and 1 week later for collecting haematological data. A dynamic model was constructed based on the Gompertz-Makeham law to describe live weight trajectories during the first 75 days after weaning, following the rationale that the animal response is partitioned in two time windows (a perturbation and a recovery window). Model calibration was performed for each animal. Our results show that the transition time between the two time windows, as well as the weight trajectories are characteristic for each individual. The model captured the weight dynamics of animals at different degrees of perturbation, with an average coefficient of determination of 0.99, and a concordance correlation coefficient of 0.99. The utility of the model is that it provides biologically meaningful parameters that inform on the amplitude and length of perturbation, and the rate of animal recovery. Our rationale is that the dynamics of weight inform on the capability of the animal to cope with the weaning disturbance. Indeed, there were significant correlations between model parameters and individual diarrhoea scores and haematological traits. Overall, the parameters of our model can be useful for constructing weaning robustness indexes by using exclusively the growth curves. We foresee that this modelling approach will provide a step forward in the quantitative characterisation of robustness.

Single and dual-wavelength noise-like pulses with different shapes in a double-clad Er/Yb fiber laser.

We report an experimental study of passive harmonic mode-locking in an all-fiber switchable dual-wavelength Er/Yb double-clad laser. The proposed scheme supports single- and dual-wavelength operation of mode-locked pulses with rectangular, h-like and trapezoidal shapes in a noise-like pulse regime. Single-wavelength emissions at λ1 = 1545.1 and λ2 = 1563.6 nm were obtained for pump power values of 9.42 and 6.31 W, achieving pulse durations of up to 18 and 11.8 ns, respectively. At an intermediary pump power of 7.5 W, dual-wavelength emission is obtained and pulses of around 3.59 ns are generated. Additionally, the transition dynamics until 4th-order harmonic mode-locking is also observed. Different laser operation regimes of fundamental and different orders of harmonic mode-locking, with rectangular, h-shaped or trapezoidal shaped pulses are obtained with the same laser configuration with simple and well-defined plates and pump power adjustments.

A parsimonious software sensor for estimating the individual dynamic pattern of methane emissions from cattle.

Large efforts have been deployed in developing methods to estimate methane emissions from cattle. For large scale applications, accurate and inexpensive methane predictors are required. Within a livestock precision farming context, the objective of this work was to integrate real-time data on animal feeding behaviour with an in silico model for predicting the individual dynamic pattern of methane emission in cattle. The integration of real-time data with a mathematical model to predict variables that are not directly measured constitutes a software sensor. We developed a dynamic parsimonious grey-box model that uses as predictor variables either dry matter intake (DMI) or the intake time (IT). The model is described by ordinary differential equations.Model building was supported by experimental data of methane emissions from respiration chambers. The data set comes from a study with finishing beef steers (cross-bred Charolais and purebred Luing finishing). Dry matter intake and IT were recorded using feed bins. For research purposes, in this work, our software sensor operated off-line. That is, the predictor variables (DMI, IT) were extracted from the recorded data (rather than from an on-line sensor). A total of 37 individual dynamic patterns of methane production were analyzed. Model performance was assessed by concordance analysis between the predicted methane output and the methane measured in respiration chambers. The model predictors DMI and IT performed similarly with a Lin's concordance correlation coefficient (CCC) of 0.78 on average. When predicting the daily methane production, the CCC was 0.99 for both DMI and IT predictors. Consequently, on the basis of concordance analysis, our model performs very well compared with reported literature results for methane proxies and predictive models. As IT measurements are easier to obtain than DMI measurements, this study suggests that a software sensor that integrates our in silico model with a real-time sensor providing accurate IT measurements is a viable solution for predicting methane output in a large scale context.

Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC).

Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.

Vitamin D and Postoperative Vasopressor Use in Cardiopulmonary Bypass.

The use of cardiopulmonary bypass (CPB) in cardiac surgery often leads to a systemic inflammatory response. Up to 25% of patients undergoing CPB for cardiac surgery are reported to develop vasoplegic syndrome in the acute postoperative period, in which the patients are refractory to vasopressors. The purpose of this study is to assess vitamin D deficiency as a risk factor for vasoplegia after using CPB. We performed a retrospective review of 1322 patients undergoing adult cardiac surgery requiring CPB. Forty-six patients with previously recorded 25-hydroxy vitamin D (25(OH)D) levels within 6 months of surgery met the conditions of this study. The mean level of 25(OH)D was 32.7 ng/mL (standard deviation [SD] = 15.1). The mean age of patients was 67 (SD = 10.1) years old, most were male (63%) and white (78%). Average CPB time was 140 ± 44 minutes. Postoperative vasopressor use was compared to individual preoperative 25(OH)D levels. As a secondary end point, postoperative vasopressor use and vasoplegia were analyzed between 3 groups: Vitamin D deficient defined as 25(OH)D ≤20 ng/mL (n = 7), vitamin D insufficient defined as 25(OH)D between 20 and 29 ng/mL (n = 15), and vitamin D sufficient defined as 25(OH)D ≥30 ng/mL (n = 24). There was no correlation between vitamin D levels and postoperative vasopressor use. The mean doses of postoperative vasopressor use were 0.088 µg/kg/min (standard error of the mean [SEM] = 0.032), 0.085 µg/kg/min (SEM = 0.037), and 0.072 µg/kg/min (SEM = 0.024) of norepinephrine equivalents for the vitamin D deficient, insufficient, and sufficient groups, respectively. Incidence of vasoplegia for each group was the following: 0.143 for vitamin D deficient, 0.067 for vitamin D insufficient, and 0.125 for vitamin D sufficient. In this pilot study, there does not appear to be a relationship between vitamin D and vasopressor use following cardiac surgery utilizing CPB; however, there appears to be a trend toward an increased vasopressor usage in patients with decreased vitamin D levels. A larger sample size and a prospective analysis are warranted to further assess the significance of the relationship between vasoplegia and vitamin D deficiency. With further investigation, vitamin D has the potential to become a low-cost, low-risk therapeutic for improving outcomes in CPB surgery.

Review: To be or not to be an identifiable model. Is this a relevant question in animal science modelling?

What is a good (useful) mathematical model in animal science? For models constructed for prediction purposes, the question of model adequacy (usefulness) has been traditionally tackled by statistical analysis applied to observed experimental data relative to model-predicted variables. However, little attention has been paid to analytic tools that exploit the mathematical properties of the model equations. For example, in the context of model calibration, before attempting a numerical estimation of the model parameters, we might want to know if we have any chance of success in estimating a unique best value of the model parameters from available measurements. This question of uniqueness is referred to as structural identifiability; a mathematical property that is defined on the sole basis of the model structure within a hypothetical ideal experiment determined by a setting of model inputs (stimuli) and observable variables (measurements). Structural identifiability analysis applied to dynamic models described by ordinary differential equations (ODEs) is a common practice in control engineering and system identification. This analysis demands mathematical technicalities that are beyond the academic background of animal science, which might explain the lack of pervasiveness of identifiability analysis in animal science modelling. To fill this gap, in this paper we address the analysis of structural identifiability from a practitioner perspective by capitalizing on the use of dedicated software tools. Our objectives are (i) to provide a comprehensive explanation of the structural identifiability notion for the community of animal science modelling, (ii) to assess the relevance of identifiability analysis in animal science modelling and (iii) to motivate the community to use identifiability analysis in the modelling practice (when the identifiability question is relevant). We focus our study on ODE models. By using illustrative examples that include published mathematical models describing lactation in cattle, we show how structural identifiability analysis can contribute to advancing mathematical modelling in animal science towards the production of useful models and, moreover, highly informative experiments via optimal experiment design. Rather than attempting to impose a systematic identifiability analysis to the modelling community during model developments, we wish to open a window towards the discovery of a powerful tool for model construction and experiment design.

Adaptable Optical Fiber Displacement-Curvature Sensor Based on a Modal Michelson Interferometer with a Tapered Single Mode Fiber.

A compact, highly sensitive optical fiber displacement and curvature radius sensor is presented. The device consists of an adiabatic bi-conical fused fiber taper spliced to a single-mode fiber (SMF) segment with a flat face end. The bi-conical taper structure acts as a modal coupling device between core and cladding modes for the SMF segment. When the bi-conical taper is bent by an axial displacement, the symmetrical bi-conical shape of the tapered structure is stressed, causing a change in the refractive index profile which becomes asymmetric. As a result, the taper adiabaticity is lost, and interference between modes appears. As the bending increases, a small change in the fringe visibility and a wavelength shift on the periodical reflection spectrum of the in-fiber interferometer is produced. The displacement sensitivity and the spectral periodicity of the device can be adjusted by the proper selection of the SMF length. Sensitivities from around 1.93 to 3.4 nm/mm were obtained for SMF length between 7.5 and 12.5 cm. Both sensor interrogations, wavelength shift and visibility contrast, can be used to measure displacement and curvature radius magnitudes.

Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population.

OBJECTIVES: To examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab. MATERIAL AND METHODS: Multicenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: Acneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p<0.05); carriers of the G allele (genotypes TG+GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR=0.287 [95%CI=0.119-0.695]). Carriers of the A (GA+AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR=0.345 [0.124-0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximab-related toxicity (OR=0.266 [0.114-0.622]). CONCLUSION: This pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients.

Polarization evolution of vector wave amplitudes in twisted fibers pumped by single and paired pulses.

Nonlinear polarization dynamics of single and paired pulses in twisted fibers is experimentally and numerically studied. Accompanying a dramatic difference in the output spectrum when a single- or double-amplified soliton pulse is launched in the fiber, the output polarization for the two cases also reveals very different characteristics.

Epidemiological characteristics of a Spanish cohort of patients diagnosed with squamous cell carcinoma of head and neck: distribution of risk factors by tumor location

Purpose. Head and neck cancer is a highly heterogeneous disease comprising a large number of tumors located in the cervicofacial area. This study aimed to determine the epidemiological characteristics of squamous-cell carcinomas of the head and neck in the Spanish population, and the distribution of risk factors based on tumor locations. Methods/patients. A cohort of 459 patients (75 oral cavity, 167 oro-/hypopharyngeal and 217 laryngeal cancers) recruited in 19 hospitals participating in the Spanish head and neck cancer cooperative group were included over 3 years (2012-2014). Epidemiological parameters and risk factors were obtained from a self-administered questionnaire, and tumor characteristics were obtained from clinical records. Multivariate multinomial logistic regression was used to assess factors associated with tumor location. Results. Most patients were males (88.4 %), smokers (95 %) and drinkers (76.5 %). Relative to laryngeal cancer, pharyngeal cancer and oral cancer were more common in women than men (OR 3.58, p = 0.003 and 4.33, p = 0.001, respectively); pharyngeal cancer was more associated with rural environment (OR 1.81, p = 0.007) and weekly alcohol intake (10-140 g: OR 2.53, p = 0.012; 141-280 g: OR 2.47, p = 0.023; >280 g: OR 3.20, p = 0.001) and less associated with pack-years of smoking (21-40 packs: OR 0.46, p = 0.045; 41-70 packs: OR 0.43, p = 0.023; ≥71 packs: OR 3.20, p = 0.015). Conclusions. The distribution of these tumors differs between the sexes, with a higher proportion of oral cavity and pharyngeal tumors in women than in men. Oro-/hypopharyngeal cancers were more strongly associated with rural areas and with alcohol consumption, although less strongly associated with smoking than laryngeal tumors (AU)

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