To rapidly prognosticate and generate hypotheses on pathogenesis, leukocyte multi-cellularity was... more To rapidly prognosticate and generate hypotheses on pathogenesis, leukocyte multi-cellularity was evaluated in SARS-CoV-2 infected patients treated in India or the United States (152 individuals, 384 temporal observations). Within hospital (<90-day) death or discharge were retrospectively predicted based on the admission complete blood cell counts (CBC). Two methods were applied: (i) a “reductionist” one, which analyzes each cell type separately, and (ii) a “non-reductionist” method, which estimates multi-cellularity. The second approach uses a proprietary software package that detects distinct data patterns generated by complex and hypothetical indicators and reveals each data pattern’s immunological content and associated outcome(s). In the Indian population, the analysis of isolated cell types did not separate survivors from non-survivors. In contrast, multi-cellular data patterns differentiated six groups of patients, including, in two groups, 95.5% of all survivors. Some dat...
Canadian journal of veterinary research = Revue canadienne de recherche veterinaire, 2002
The number and function of bovine mammary-gland phagocytes were assessed in 8 lactating cows, eac... more The number and function of bovine mammary-gland phagocytes were assessed in 8 lactating cows, each tested at least twice within an 8-mo period (total number of observations, 20). Macrophages and polymorphonuclear (PMN) cells were evaluated by conventional cytology, flow cytometry, fluorescent microscopy, and somatic-cell count (SCC). Phagocytosis was evaluated from the uptake of fluorescent beads and expressed as median fluorescence intensity (MFI). Two major subpopulations of phagocytes, of low or high MFI (LFI or HFI), were observed, and there were up to 4 sub-subpopulations within the HFI subpopulation of both macrophages and PMN cells. Fluorescent microscopy identified phagocytes containing up to 4 beads per cell. Cows showing < or = 72.3% phagocytes by cytology were regarded as non-mastitic (11 observations), and those showing > or = 80.7% phagocytes were considered to be mastitic (8 observations). Phagocyte MFI was negatively associated with mastitis; that is, the higher...
Background: To effectively control the geographical dissemination of infectious diseases, their p... more Background: To effectively control the geographical dissemination of infectious diseases, their properties need to be determined. To test that rapid microbial dispersal requires not only susceptible hosts but also a pre-existing, connecting network, we explored constructs meant to reveal the network properties associated with disease spread, which included the road structure. Methods: Using geo-temporal data collected from epizoonotics in which all hosts were susceptible (mammals infected by
Background To determine whether CBC differentials of COVID+ inpatients can predict, at admission,... more Background To determine whether CBC differentials of COVID+ inpatients can predict, at admission, both maximum oxygen requirements (MOR) and 30-day mortality. Methods Based on an approved IRB protocol, CBC differentials from the first 3 days of hospitalization of 12 SARS CoV-2 infected patients were retrospectively extracted from hospital records and analyzed with a privately owned Pattern Recognition Software (PRS, US Patent 10,429,389 B2) previously validated in sepsis, HIV, and hantavirus infections. PRS partitions the data into subsets immunologically dissimilar from one another, although internally similar. Results Regardless of the angle considered, the classic analysis −which measured the percentages of lymphocytes, monocytes, and neutrophils− did not distinguish outcomes (A). In contrast, non-overlapping patterns generated by the PRS differentiated 3 (left, vertical, and right) groups of patients (B). One subset was only composed of survivors (B). The remaining subsets inclu...
Background: To control epidemics, decision-makers need information in real time and clinicians re... more Background: To control epidemics, decision-makers need information in real time and clinicians require data on locations more affected by mortality To that end
We conducted a matched case-control study to evaluate risk factors for infection with highly path... more We conducted a matched case-control study to evaluate risk factors for infection with highly pathogenic avian influenza (HPAI) H5N1 virus in poultry farms during the epidemic of 2006-2007 in Nigeria. Epidemiologic data were collected through the use of a questionnaire from 32 case farms and 83 control farms. The frequency of investigated exposure factors was compared between case and control farms by using conditional logistic regression analysis. In the multivariable analysis, the variables for (i) receiving visitors on farm premises (odds ratio [OR]=8.32; 95% confidence interval [CI]=1.87, 36.97; P<0.01), (ii) purchased live poultry/products (OR=11.91; 95% CI=3.11-45.59; P<0.01), and (iii) farm workers live outside the premises (OR=8.98; 95% CI=1.97, 40.77; P<0.01) were identified as risk factors for HPAI in poultry farms. Improving farm hygiene and biosecurity should help reduce the risk for influenza (H5N1) infection in poultry farms in Nigeria.
The presence of phagocyte-related cutoff points that distinguish protective from non-protective a... more The presence of phagocyte-related cutoff points that distinguish protective from non-protective anti-28 bacterial responses was investigated in bovine mastitis. Five lactating cows were intra-mammarily 29 infused with Staphylococcus aureus and CD 11 b surface density (expressed as median fluorescence 30 intensity or MFI) was assessed (before and three times after challenge) in blood and milk phagocytes 31 by flow cytometry. CD 11 b MFI was compared to bacterial counts of milk cultures, the somatic cell 32 count (SCC), as well as the surface density of several lymphocyte differentiation antigens. In addition, 33 the ratio ofphagocytes (monocytes or macrophages [M0] plus polymorphonuclear cells [PMN]) to 34 lymphocytes, and the ratio ofPMN to M0, were determined. These measures differentiated non-35 mastitic from mastitic animals, identified very early (1 day post-infusion or pi), early (1 week pi) and 36 late (2 weeks pi) inflammations, and revealed CD 11 b MFI cutoff points above which no bacterial growth in milk cultures and SCC <500,000 cells/ml were observed ("immune thresholds"). For any given cell type, identical thresholds were shown in relation to both outcome indicators. Lower critical cutoff points (resulting in protective effects) were observed at 2 wpi than at 1 dpi. Immune thresholds distinguished individuals prone to mount efficient immune responses from those unable to do so, and also provided predictions on future outcomes based on pre-challenge measures. It is suggested that measurement of immune thresholds may improve prognosis of, and animal selection against, bovine mastitis. Control of bovine mastitis has historically been based on outcome measures, such as the Somatic Cell 46 Count (SCC) and bacterial counts (Sargeant et al., 2001). However, some measures used in the current 65 replication cycles occur within 2 hours, it may be expected that the resulting immune response will have to clear only 40 bacteria. In contrast, if naive T cells have been involved or if sub-optimal (or non-sustained) T-cell stimulation has occurred, it may take > 6 hours to generate an immune response which then would have to face a number of bacteria in the order of millions. The bacterial agent can also determine the outcome of the immune response. For instance, S. aureus invasions of the bovine mammary gland appear to result in poor (if not absent) IL-2 de novo 71 mRNA transcription (Riollet et al., 2000; Alluwaimi et al., 2003). Therefore, it may be assumed that S. aureus invasions induce sub-optimal immune responses. That is, a "slow" TCR triggering process may occur due to lack of IL-2 mediated signaling, which translates as an excessive number of 74 bacterial multiplications. In such case, the number of bacteria to be cleared may exceed the ability of the cow's immune system and, consequently, microbes may succeed in colonizing mammary tissues. intensively managed flocks and related changes in the yield and quality of ewe milk. Small
To prevent antimicrobial resistance and inform better, antibiograms should distinguish different ... more To prevent antimicrobial resistance and inform better, antibiograms should distinguish different biomedical situations. It is also desirable that new antibiograms provide in vivo, temporal, and patient-specific immunological information. Here, the informative ability of a pattern recognition-based method was explored with data collected from patients that experienced seven infectious syndromes (pneumonia, endocarditis, tuberculosis, syphilis, as well as skin and soft tissue, intra-abdominal, and/or urinary tract infections associated with meningitis). Interactions among seven dimensions (7D) were investigated: (i) space, (ii) time, (iii) temporal data directionality, (iv) immunological multicellularity, (v) antibiotics, (vi) immunomodulation, and (vii) personalized data. Omissions and ambiguity (confounding different biological situations) occurred when static metrics were used in isolation, such as leukocyte percentages. In contrast, hidden information was uncovered when complexity...
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
More than 130,000 peer-reviewed studies have been published within one year after COVID-19 emerge... more More than 130,000 peer-reviewed studies have been published within one year after COVID-19 emerged in many countries. This large and rapidly growing field may overwhelm the synthesizing abilities of both researchers and policy-makers. To provide a sinopsis, prevent errors, and detect cognitive gaps that may require interdisciplinary research methods, the literature on COVID-19 is summarized, twice. The overall purpose of this study is to generate a dialogue meant to explain the genesis of and/or find remedies for omissions and contradictions. The first review starts in Biology and ends in Policy. Policy is chosen as a destination because it is the setting where cognitive integration must occur. The second review follows the opposite path: it begins with stated policies on COVID-19 and then their assumptions and disciplinary relationships are identified. The purpose of this interdisciplinary method on methods is to yield a relational and explanatory view of the field –one strategy likely to be incomplete but usable when large bodies of literature need to be rapidly summarized. These reviews identify nine inter-related problems, research needs, or omissions, namely: (1) nation-wide, geo-referenced, epidemiological data collection systems (open to and monitored by the public); (2) metrics meant to detect non-symptomatic cases –e.g., test positivity–; (3) cost-benefit oriented methods, which should demonstrate they detect silent viral spreaders even with limited testing; (4) new personalized tests that inform on biological functions and disease correlates, such as cell-mediated immunity, co-morbidities, and immuno-suppression; (5) factors that influence vaccine effectiveness; (6) economic predictions that consider the long-term consequences likely to follow epidemics that growth exponentially; (7) the errors induced by self-limiting and/or implausible paradigms, such as binary and reductionist approaches; (8) new governance models that emphasize problem-solving skills, social participation, and the use of scientific knowledge; and (9) new educational programs that utilize visual aids and audience-specific communication strategies. The analysis indicates that, to optimally address these problems, disciplinary and social integration is needed. By asking what is/are the potential cause(s) and consequence(s) of each issue, this methodology generates visualizations that reveal possible relationships as well as omissions and contradictions. While inherently limited in scope and likely to become obsolete, these shortcomings are avoided when this ‘method on methods’ is frequently practiced. Open-ended, inter-/trans-disciplinary perspectives and broad social participation may help researchers and citizens to construct, de-construct, and re-construct COVID-19 related research.
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
International Journal of Infectious Diseases, 2020
To control epidemics, sites more affected by mortality should be identified. Methods: Defining ep... more To control epidemics, sites more affected by mortality should be identified. Methods: Defining epidemic nodes as areas that included both most fatalities per time unit and connections, such as highways, geo-temporal Chinese data on the COVID-19 epidemic were investigated with linear, logarithmic, power, growth, exponential, and logistic regression models. A z-test compared the slopes observed. Results: Twenty provinces suspected to act as epidemic nodes were empirically investigated. Five provinces displayed synchronicity, long-distance connections, directionality and assortativitynetwork properties that helped discriminate epidemic nodes. The rank I node included most fatalities and was activated first. Fewer deaths were reported, later, by rank II and III nodes, while the data from rank I-III nodes exhibited slopes, the data from the remaining provinces did not. The power curve was the best fitting model for all slopes. Because all pairs (rank I vs. rank II, rank I vs. rank III, and rank II vs. rank III) of epidemic nodes differed statistically, rank I-III epidemic nodes were geo-temporally and statistically distinguishable. Conclusions: The geo-temporal progression of epidemics seems to be highly structured. Epidemic network properties can distinguish regions that differ in mortality. This real-time geo-referenced analysis can inform both decision-makers and clinicians.
To optimize epidemiologic interventions, predictors of mortality should be identified. The US COV... more To optimize epidemiologic interventions, predictors of mortality should be identified. The US COVID-19 epidemic data, reported up to 31 March 2020, were analyzed using kernel regularized least squares regression. Six potential predictors of mortality were investigated: (i) the number of diagnostic tests performed in testing week I; (ii) the proportion of all tests conducted during week I of testing; (iii) the cumulative number of (test-positive) cases through 3-31-2020, (iv) the number of tests performed/million citizens; (v) the cumulative number of citizens tested; and (vi) the apparent prevalence rate, defined as the number of cases/million citizens. Two metrics estimated mortality: the number of deaths and the number of deaths/million citizens. While both expressions of mortality were predicted by the case count and the apparent prevalence rate, the number of deaths/million citizens was ≈3.5 times better predicted by the apparent prevalence rate than the number of cases. In eigh...
International Journal of Infectious Diseases, 2020
Hoping to improve health-related effectiveness, a two-phase vaccination against rabies was design... more Hoping to improve health-related effectiveness, a two-phase vaccination against rabies was designed and executed in northern Tanzania in 2018, which included geo-epidemiological and economic perspectives. Methods: Considering the local bio-geography and attempting to rapidly establish a protective ring around a city at risk, the first phase intervened on sites surrounding that city, where the population density was lower than in the city at risk. The second phase vaccinated a rural area. Results: No rabies-related case has been reported in the vaccinated areas for over a year postimmunisation; hence, the campaign is viewed as highly cost-effective. Other metrics included: rapid implementation (concluded in half the time spent on other campaigns) and the estimated cost per protected life, which was 3.28 times lower than in similar vaccinations. Conclusions: The adopted design emphasised local bio-geographical dynamics: it prevented the occurrence of an epidemic in a city with a higher demographic density than its surrounding area and it also achieved greater effectiveness than average interventions. These interdisciplinary, policy-oriented experiences have broad and immediate applications in settings of limited and/or time-sensitive (expertise, personnel, and time available to intervene) resources and conditions.
Investigating disease pathogenesis and personalized prognostics are major biomedical needs. Becau... more Investigating disease pathogenesis and personalized prognostics are major biomedical needs. Because patients sharing the same diagnosis can experience different outcomes, such as survival or death, physicians need new personalized tools, including those that rapidly differentiate several inflammatory phases. To address these topics, a pattern recognition-based method (PRM) that follows an inverse problem approach was designed to assess, in <10 min, eight concepts: synergy, pleiotropy, complexity, dynamics, ambiguity, circularity, personalized outcomes, and explanatory prognostics (pathogenesis). By creating thousands of secondary combinations derived from blood leukocyte data, the PRM measures synergic, pleiotropic, complex and dynamic data interactions, which provide personalized prognostics while some undesirable features-such as false results and the ambiguity associated with data circularity-are prevented. Here, this method is compared to Principal Component Analysis (PCA) and evaluated with data collected from hantavirus-infected humans and birds that appeared to be healthy. When human data were examined, the PRM predicted 96.9 % of all surviving patients while PCA did not distinguish outcomes. Demonstrating applications in personalized prognosis, eight PRM data structures sufficed to identify all but one of the survivors. Dynamic data patterns also distinguished survivors from non-survivors, as well as one subset of non-survivors, which exhibited chronic inflammation. When the PRM explored avian data, it differentiated immune profiles consistent with no, early, or late inflammation. Yet, PCA did not recognize patterns in avian data. Findings support the notion that immune responses, while variable, are rather deterministic: a low number of complex and dynamic data combinations may be enough to, rapidly, unmask conditions that are neither directly observable nor reliably forecasted.
Evolution has conserved "economic" systems that perform many functions, faster or better, with le... more Evolution has conserved "economic" systems that perform many functions, faster or better, with less. For example, three to five leukocyte types protect from thousands of pathogens. To achieve so much with so little, biological systems combine their limited elements, creating complex structures. Yet, the prevalent research paradigm is reductionist. Focusing on infectious diseases, reductionist and non-reductionist views are here described. The literature indicates that reductionism is associated with information loss and errors, while non-reductionist operations can extract more information from the same data. When designed to capture one-to-many/many-to-one interactions-including the use of arrows that connect pairs of consecutive observations-non-reductionist (spatial-temporal) constructs eliminate data variability from all dimensions, except along one line, while arrows describe the directionality of temporal changes that occur along the line. To validate the patterns detected by non-reductionist operations, reductionist procedures are needed. Integrated (non-reductionist and reductionist) methods can (i) distinguish data subsets that differ immunologically and statistically; (ii) differentiate false-negative from-positive errors; (iii) discriminate disease stages; (iv) capture in vivo, multilevel interactions that consider the patient, the microbe, and antibiotic-mediated responses; and (v) assess dynamics. Integrated methods provide repeatable and biologically interpretable information.
Background Diagnostic errors can occur, in infectious diseases, when anti-microbial immune respon... more Background Diagnostic errors can occur, in infectious diseases, when anti-microbial immune responses involve several temporal scales. When responses span from nanosecond to week and larger temporal scales, any pre-selected temporal scale is likely to miss some (faster or slower) responses. Hoping to prevent diagnostic errors, a pilot study was conducted to evaluate a four-dimensional (4D) method that captures the complexity and dynamics of infectious diseases. Methods Leukocyte-microbial-temporal data were explored in canine and human (bacterial and/or viral) infections, with: (i) a non-structured approach, which measures leukocytes or microbes in isolation; and (ii) a structured method that assesses numerous combinations of interacting variables. Four alternatives of the structured method were tested: (i) a noisereduction oriented version, which generates a single (one data point-wide) line of observations; (ii) a version that measures complex, three-dimensional (3D) data interactions; (iii) a non-numerical version that displays temporal data directionality (arrows that connect pairs of consecutive observations); and (iv) a full 4D (single line-, complexity-, directionalitybased) version.
Conclusion: While the analysis of non-partitioned data can result in information loss, complex (c... more Conclusion: While the analysis of non-partitioned data can result in information loss, complex (combinatorial) data structures can uncover hidden patterns, which guide data partitioning into subsets that differ in mortality rates and immune profiles. Such information can facilitate diagnostics, monitoring of disease dynamics, and evaluation of subset-specific, patient-specific therapies.
To rapidly prognosticate and generate hypotheses on pathogenesis, leukocyte multi-cellularity was... more To rapidly prognosticate and generate hypotheses on pathogenesis, leukocyte multi-cellularity was evaluated in SARS-CoV-2 infected patients treated in India or the United States (152 individuals, 384 temporal observations). Within hospital (<90-day) death or discharge were retrospectively predicted based on the admission complete blood cell counts (CBC). Two methods were applied: (i) a “reductionist” one, which analyzes each cell type separately, and (ii) a “non-reductionist” method, which estimates multi-cellularity. The second approach uses a proprietary software package that detects distinct data patterns generated by complex and hypothetical indicators and reveals each data pattern’s immunological content and associated outcome(s). In the Indian population, the analysis of isolated cell types did not separate survivors from non-survivors. In contrast, multi-cellular data patterns differentiated six groups of patients, including, in two groups, 95.5% of all survivors. Some dat...
Canadian journal of veterinary research = Revue canadienne de recherche veterinaire, 2002
The number and function of bovine mammary-gland phagocytes were assessed in 8 lactating cows, eac... more The number and function of bovine mammary-gland phagocytes were assessed in 8 lactating cows, each tested at least twice within an 8-mo period (total number of observations, 20). Macrophages and polymorphonuclear (PMN) cells were evaluated by conventional cytology, flow cytometry, fluorescent microscopy, and somatic-cell count (SCC). Phagocytosis was evaluated from the uptake of fluorescent beads and expressed as median fluorescence intensity (MFI). Two major subpopulations of phagocytes, of low or high MFI (LFI or HFI), were observed, and there were up to 4 sub-subpopulations within the HFI subpopulation of both macrophages and PMN cells. Fluorescent microscopy identified phagocytes containing up to 4 beads per cell. Cows showing < or = 72.3% phagocytes by cytology were regarded as non-mastitic (11 observations), and those showing > or = 80.7% phagocytes were considered to be mastitic (8 observations). Phagocyte MFI was negatively associated with mastitis; that is, the higher...
Background: To effectively control the geographical dissemination of infectious diseases, their p... more Background: To effectively control the geographical dissemination of infectious diseases, their properties need to be determined. To test that rapid microbial dispersal requires not only susceptible hosts but also a pre-existing, connecting network, we explored constructs meant to reveal the network properties associated with disease spread, which included the road structure. Methods: Using geo-temporal data collected from epizoonotics in which all hosts were susceptible (mammals infected by
Background To determine whether CBC differentials of COVID+ inpatients can predict, at admission,... more Background To determine whether CBC differentials of COVID+ inpatients can predict, at admission, both maximum oxygen requirements (MOR) and 30-day mortality. Methods Based on an approved IRB protocol, CBC differentials from the first 3 days of hospitalization of 12 SARS CoV-2 infected patients were retrospectively extracted from hospital records and analyzed with a privately owned Pattern Recognition Software (PRS, US Patent 10,429,389 B2) previously validated in sepsis, HIV, and hantavirus infections. PRS partitions the data into subsets immunologically dissimilar from one another, although internally similar. Results Regardless of the angle considered, the classic analysis −which measured the percentages of lymphocytes, monocytes, and neutrophils− did not distinguish outcomes (A). In contrast, non-overlapping patterns generated by the PRS differentiated 3 (left, vertical, and right) groups of patients (B). One subset was only composed of survivors (B). The remaining subsets inclu...
Background: To control epidemics, decision-makers need information in real time and clinicians re... more Background: To control epidemics, decision-makers need information in real time and clinicians require data on locations more affected by mortality To that end
We conducted a matched case-control study to evaluate risk factors for infection with highly path... more We conducted a matched case-control study to evaluate risk factors for infection with highly pathogenic avian influenza (HPAI) H5N1 virus in poultry farms during the epidemic of 2006-2007 in Nigeria. Epidemiologic data were collected through the use of a questionnaire from 32 case farms and 83 control farms. The frequency of investigated exposure factors was compared between case and control farms by using conditional logistic regression analysis. In the multivariable analysis, the variables for (i) receiving visitors on farm premises (odds ratio [OR]=8.32; 95% confidence interval [CI]=1.87, 36.97; P<0.01), (ii) purchased live poultry/products (OR=11.91; 95% CI=3.11-45.59; P<0.01), and (iii) farm workers live outside the premises (OR=8.98; 95% CI=1.97, 40.77; P<0.01) were identified as risk factors for HPAI in poultry farms. Improving farm hygiene and biosecurity should help reduce the risk for influenza (H5N1) infection in poultry farms in Nigeria.
The presence of phagocyte-related cutoff points that distinguish protective from non-protective a... more The presence of phagocyte-related cutoff points that distinguish protective from non-protective anti-28 bacterial responses was investigated in bovine mastitis. Five lactating cows were intra-mammarily 29 infused with Staphylococcus aureus and CD 11 b surface density (expressed as median fluorescence 30 intensity or MFI) was assessed (before and three times after challenge) in blood and milk phagocytes 31 by flow cytometry. CD 11 b MFI was compared to bacterial counts of milk cultures, the somatic cell 32 count (SCC), as well as the surface density of several lymphocyte differentiation antigens. In addition, 33 the ratio ofphagocytes (monocytes or macrophages [M0] plus polymorphonuclear cells [PMN]) to 34 lymphocytes, and the ratio ofPMN to M0, were determined. These measures differentiated non-35 mastitic from mastitic animals, identified very early (1 day post-infusion or pi), early (1 week pi) and 36 late (2 weeks pi) inflammations, and revealed CD 11 b MFI cutoff points above which no bacterial growth in milk cultures and SCC <500,000 cells/ml were observed ("immune thresholds"). For any given cell type, identical thresholds were shown in relation to both outcome indicators. Lower critical cutoff points (resulting in protective effects) were observed at 2 wpi than at 1 dpi. Immune thresholds distinguished individuals prone to mount efficient immune responses from those unable to do so, and also provided predictions on future outcomes based on pre-challenge measures. It is suggested that measurement of immune thresholds may improve prognosis of, and animal selection against, bovine mastitis. Control of bovine mastitis has historically been based on outcome measures, such as the Somatic Cell 46 Count (SCC) and bacterial counts (Sargeant et al., 2001). However, some measures used in the current 65 replication cycles occur within 2 hours, it may be expected that the resulting immune response will have to clear only 40 bacteria. In contrast, if naive T cells have been involved or if sub-optimal (or non-sustained) T-cell stimulation has occurred, it may take > 6 hours to generate an immune response which then would have to face a number of bacteria in the order of millions. The bacterial agent can also determine the outcome of the immune response. For instance, S. aureus invasions of the bovine mammary gland appear to result in poor (if not absent) IL-2 de novo 71 mRNA transcription (Riollet et al., 2000; Alluwaimi et al., 2003). Therefore, it may be assumed that S. aureus invasions induce sub-optimal immune responses. That is, a "slow" TCR triggering process may occur due to lack of IL-2 mediated signaling, which translates as an excessive number of 74 bacterial multiplications. In such case, the number of bacteria to be cleared may exceed the ability of the cow's immune system and, consequently, microbes may succeed in colonizing mammary tissues. intensively managed flocks and related changes in the yield and quality of ewe milk. Small
To prevent antimicrobial resistance and inform better, antibiograms should distinguish different ... more To prevent antimicrobial resistance and inform better, antibiograms should distinguish different biomedical situations. It is also desirable that new antibiograms provide in vivo, temporal, and patient-specific immunological information. Here, the informative ability of a pattern recognition-based method was explored with data collected from patients that experienced seven infectious syndromes (pneumonia, endocarditis, tuberculosis, syphilis, as well as skin and soft tissue, intra-abdominal, and/or urinary tract infections associated with meningitis). Interactions among seven dimensions (7D) were investigated: (i) space, (ii) time, (iii) temporal data directionality, (iv) immunological multicellularity, (v) antibiotics, (vi) immunomodulation, and (vii) personalized data. Omissions and ambiguity (confounding different biological situations) occurred when static metrics were used in isolation, such as leukocyte percentages. In contrast, hidden information was uncovered when complexity...
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
More than 130,000 peer-reviewed studies have been published within one year after COVID-19 emerge... more More than 130,000 peer-reviewed studies have been published within one year after COVID-19 emerged in many countries. This large and rapidly growing field may overwhelm the synthesizing abilities of both researchers and policy-makers. To provide a sinopsis, prevent errors, and detect cognitive gaps that may require interdisciplinary research methods, the literature on COVID-19 is summarized, twice. The overall purpose of this study is to generate a dialogue meant to explain the genesis of and/or find remedies for omissions and contradictions. The first review starts in Biology and ends in Policy. Policy is chosen as a destination because it is the setting where cognitive integration must occur. The second review follows the opposite path: it begins with stated policies on COVID-19 and then their assumptions and disciplinary relationships are identified. The purpose of this interdisciplinary method on methods is to yield a relational and explanatory view of the field –one strategy likely to be incomplete but usable when large bodies of literature need to be rapidly summarized. These reviews identify nine inter-related problems, research needs, or omissions, namely: (1) nation-wide, geo-referenced, epidemiological data collection systems (open to and monitored by the public); (2) metrics meant to detect non-symptomatic cases –e.g., test positivity–; (3) cost-benefit oriented methods, which should demonstrate they detect silent viral spreaders even with limited testing; (4) new personalized tests that inform on biological functions and disease correlates, such as cell-mediated immunity, co-morbidities, and immuno-suppression; (5) factors that influence vaccine effectiveness; (6) economic predictions that consider the long-term consequences likely to follow epidemics that growth exponentially; (7) the errors induced by self-limiting and/or implausible paradigms, such as binary and reductionist approaches; (8) new governance models that emphasize problem-solving skills, social participation, and the use of scientific knowledge; and (9) new educational programs that utilize visual aids and audience-specific communication strategies. The analysis indicates that, to optimally address these problems, disciplinary and social integration is needed. By asking what is/are the potential cause(s) and consequence(s) of each issue, this methodology generates visualizations that reveal possible relationships as well as omissions and contradictions. While inherently limited in scope and likely to become obsolete, these shortcomings are avoided when this ‘method on methods’ is frequently practiced. Open-ended, inter-/trans-disciplinary perspectives and broad social participation may help researchers and citizens to construct, de-construct, and re-construct COVID-19 related research.
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
International Journal of Infectious Diseases, 2020
To control epidemics, sites more affected by mortality should be identified. Methods: Defining ep... more To control epidemics, sites more affected by mortality should be identified. Methods: Defining epidemic nodes as areas that included both most fatalities per time unit and connections, such as highways, geo-temporal Chinese data on the COVID-19 epidemic were investigated with linear, logarithmic, power, growth, exponential, and logistic regression models. A z-test compared the slopes observed. Results: Twenty provinces suspected to act as epidemic nodes were empirically investigated. Five provinces displayed synchronicity, long-distance connections, directionality and assortativitynetwork properties that helped discriminate epidemic nodes. The rank I node included most fatalities and was activated first. Fewer deaths were reported, later, by rank II and III nodes, while the data from rank I-III nodes exhibited slopes, the data from the remaining provinces did not. The power curve was the best fitting model for all slopes. Because all pairs (rank I vs. rank II, rank I vs. rank III, and rank II vs. rank III) of epidemic nodes differed statistically, rank I-III epidemic nodes were geo-temporally and statistically distinguishable. Conclusions: The geo-temporal progression of epidemics seems to be highly structured. Epidemic network properties can distinguish regions that differ in mortality. This real-time geo-referenced analysis can inform both decision-makers and clinicians.
To optimize epidemiologic interventions, predictors of mortality should be identified. The US COV... more To optimize epidemiologic interventions, predictors of mortality should be identified. The US COVID-19 epidemic data, reported up to 31 March 2020, were analyzed using kernel regularized least squares regression. Six potential predictors of mortality were investigated: (i) the number of diagnostic tests performed in testing week I; (ii) the proportion of all tests conducted during week I of testing; (iii) the cumulative number of (test-positive) cases through 3-31-2020, (iv) the number of tests performed/million citizens; (v) the cumulative number of citizens tested; and (vi) the apparent prevalence rate, defined as the number of cases/million citizens. Two metrics estimated mortality: the number of deaths and the number of deaths/million citizens. While both expressions of mortality were predicted by the case count and the apparent prevalence rate, the number of deaths/million citizens was ≈3.5 times better predicted by the apparent prevalence rate than the number of cases. In eigh...
International Journal of Infectious Diseases, 2020
Hoping to improve health-related effectiveness, a two-phase vaccination against rabies was design... more Hoping to improve health-related effectiveness, a two-phase vaccination against rabies was designed and executed in northern Tanzania in 2018, which included geo-epidemiological and economic perspectives. Methods: Considering the local bio-geography and attempting to rapidly establish a protective ring around a city at risk, the first phase intervened on sites surrounding that city, where the population density was lower than in the city at risk. The second phase vaccinated a rural area. Results: No rabies-related case has been reported in the vaccinated areas for over a year postimmunisation; hence, the campaign is viewed as highly cost-effective. Other metrics included: rapid implementation (concluded in half the time spent on other campaigns) and the estimated cost per protected life, which was 3.28 times lower than in similar vaccinations. Conclusions: The adopted design emphasised local bio-geographical dynamics: it prevented the occurrence of an epidemic in a city with a higher demographic density than its surrounding area and it also achieved greater effectiveness than average interventions. These interdisciplinary, policy-oriented experiences have broad and immediate applications in settings of limited and/or time-sensitive (expertise, personnel, and time available to intervene) resources and conditions.
Investigating disease pathogenesis and personalized prognostics are major biomedical needs. Becau... more Investigating disease pathogenesis and personalized prognostics are major biomedical needs. Because patients sharing the same diagnosis can experience different outcomes, such as survival or death, physicians need new personalized tools, including those that rapidly differentiate several inflammatory phases. To address these topics, a pattern recognition-based method (PRM) that follows an inverse problem approach was designed to assess, in <10 min, eight concepts: synergy, pleiotropy, complexity, dynamics, ambiguity, circularity, personalized outcomes, and explanatory prognostics (pathogenesis). By creating thousands of secondary combinations derived from blood leukocyte data, the PRM measures synergic, pleiotropic, complex and dynamic data interactions, which provide personalized prognostics while some undesirable features-such as false results and the ambiguity associated with data circularity-are prevented. Here, this method is compared to Principal Component Analysis (PCA) and evaluated with data collected from hantavirus-infected humans and birds that appeared to be healthy. When human data were examined, the PRM predicted 96.9 % of all surviving patients while PCA did not distinguish outcomes. Demonstrating applications in personalized prognosis, eight PRM data structures sufficed to identify all but one of the survivors. Dynamic data patterns also distinguished survivors from non-survivors, as well as one subset of non-survivors, which exhibited chronic inflammation. When the PRM explored avian data, it differentiated immune profiles consistent with no, early, or late inflammation. Yet, PCA did not recognize patterns in avian data. Findings support the notion that immune responses, while variable, are rather deterministic: a low number of complex and dynamic data combinations may be enough to, rapidly, unmask conditions that are neither directly observable nor reliably forecasted.
Evolution has conserved "economic" systems that perform many functions, faster or better, with le... more Evolution has conserved "economic" systems that perform many functions, faster or better, with less. For example, three to five leukocyte types protect from thousands of pathogens. To achieve so much with so little, biological systems combine their limited elements, creating complex structures. Yet, the prevalent research paradigm is reductionist. Focusing on infectious diseases, reductionist and non-reductionist views are here described. The literature indicates that reductionism is associated with information loss and errors, while non-reductionist operations can extract more information from the same data. When designed to capture one-to-many/many-to-one interactions-including the use of arrows that connect pairs of consecutive observations-non-reductionist (spatial-temporal) constructs eliminate data variability from all dimensions, except along one line, while arrows describe the directionality of temporal changes that occur along the line. To validate the patterns detected by non-reductionist operations, reductionist procedures are needed. Integrated (non-reductionist and reductionist) methods can (i) distinguish data subsets that differ immunologically and statistically; (ii) differentiate false-negative from-positive errors; (iii) discriminate disease stages; (iv) capture in vivo, multilevel interactions that consider the patient, the microbe, and antibiotic-mediated responses; and (v) assess dynamics. Integrated methods provide repeatable and biologically interpretable information.
Background Diagnostic errors can occur, in infectious diseases, when anti-microbial immune respon... more Background Diagnostic errors can occur, in infectious diseases, when anti-microbial immune responses involve several temporal scales. When responses span from nanosecond to week and larger temporal scales, any pre-selected temporal scale is likely to miss some (faster or slower) responses. Hoping to prevent diagnostic errors, a pilot study was conducted to evaluate a four-dimensional (4D) method that captures the complexity and dynamics of infectious diseases. Methods Leukocyte-microbial-temporal data were explored in canine and human (bacterial and/or viral) infections, with: (i) a non-structured approach, which measures leukocytes or microbes in isolation; and (ii) a structured method that assesses numerous combinations of interacting variables. Four alternatives of the structured method were tested: (i) a noisereduction oriented version, which generates a single (one data point-wide) line of observations; (ii) a version that measures complex, three-dimensional (3D) data interactions; (iii) a non-numerical version that displays temporal data directionality (arrows that connect pairs of consecutive observations); and (iv) a full 4D (single line-, complexity-, directionalitybased) version.
Conclusion: While the analysis of non-partitioned data can result in information loss, complex (c... more Conclusion: While the analysis of non-partitioned data can result in information loss, complex (combinatorial) data structures can uncover hidden patterns, which guide data partitioning into subsets that differ in mortality rates and immune profiles. Such information can facilitate diagnostics, monitoring of disease dynamics, and evaluation of subset-specific, patient-specific therapies.
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Papers by Ariel Rivas