The intestinal colonization rate of Aeromonas spp. was determined for 52 cesarean-born Peruvian neonates. Rectal swabs were obtained daily from newborns during their postdelivery hospitalization (x = 5.5 days), and the gross appearances of their feces (blind determinations) were recorded. Aeromonas spp. were recovered from rectal swabs of 12 of 52 (23.1%) infants during their first week of life; the isolates were obtained from 5 of 9 (55.6%) infants with at least one stool with a watery consistency and from 7 of 43 (16.3%) neonates with no watery stools (P = 0.022). None of the infected infants became clinically ill. No other commonly recognized enteropathogens were detected in watery stools. An environmental survey indicated that hospital water was the probable source of infection. These and other data indicated that Aeromonas colonization occurs transiently at a very early age in Peruvian neonates and that in some instances, initial infection may be followed several days later by one or more watery stools of normal volume.
A hypothetical scheme is presented to delineate the plausible cause for the slump of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) ‐ Cas9: “CRISPR‐associated protein 9”) labyrinthine gene editing of ARGR would gleam a catastrophic augmentation leading to an evolution of virulent bacterial pathogen(s) dithering sensitivity to antibiotics, impairing the effective treatment of antibiotic resistance bacterial pathogens induced sepsis, exacerbating disseminated intravascular coagulation (DIC) unto antibiotic resistance pandemic (ARP). Given the fact that AR is developmental malady enthralling intensive critical care inclusive of fluid resuscitation in a clinical emergency (patient cohort of sepsis treated with EGDT trial NCT01663701 resulting in‐hospital mortality.) A comparative model as intricate as CRISPR‐Cas‐9, while as sacrosanct as Chakravyūha: Chakra (spinning wheel), a strategy: (“vyuh”), with the lotus flowerets (Padmavyuh) made of seven circular paths characteristic of constant movement to that of a spiral down pattern of clustered regularly interspaced paths to the center core with strongest forces to mount resistance compare to that of the first layer with entrance ( Exhibit B1: https://www.youtube.com/watch?v=oy3Qzt74V6Q; Exhibit B2: https://youtu.be/hHc705uTOWc) was analyzed to derive an imperative of gene editing and its amelioration of antibiotic resistance. As suggested by the presenters, the formulation to break Chakravyūha is to increase the deployment of force in the following format per each path: force deployment per path would be 1/7 = 0.142857 where the denominator = total paths; whereas numerator is the specific number of path in the Chakravyūha. Therefore for path one force required to break and/or to overcome the resistance is = 1/7 = 0.142857142857; for path two = 0.142857 × 2 = 0.28571142857; for path three 0.142857 × 3= 0.428571142857; for path four 0.142857 × 4= 0.57142857142857; for path five = 0.142857 × 5 = 0.7142857142857; for path 0.142857 × 6 = 0.857142857142857; for path seven = 0.142857 × 7 = 0.857142857142857; and path seven @ core = 0.142857 × 7 = 0.999999142857 considered rounding off to 1. The unique six digits, 142857 is repeated among all paths similar to the basis of gene editing compare the Exhibit A: time 0.55 – 3.50 min; to that of the Exhibit B1: time:6.11 – 7.25 min & 2: Exhibit B2 time 5.51 – 7.25 for mitigating the AR by targeting and editing of antibiotic resistance genes (ARG) in ARGR would lead an increased inactivation of preexisting ARG conferring sensitivity to antibiotics benefiting the antibiotic therapy but not clinically evolving AR which is predominantly regulated by infection specific antibiotic regimen of a patient’s life span tacit of multifactorial inclusive of exposure to multitude AR bacteria (ARB) at different stages of life span, and patient specific clinical history. Treatment options where in which inherent off target errors of gene editing by CRISPR‐Cas9’s and inability to match the rate of commission versus correction [t...
NCT01663701: is a clinical trial with the principle hypothesis that early fluid resuscitation will significantly decrease in‐hospital mortality in patients with severe sepsis and hypotension. Based on the observations from NCT01663701, 209 adults with sepsis and hypotension presenting to an emergency department in Zambia, a 6‐hour sepsis protocol emphasizing administration of intravenous fluids, vasopressors, and blood transfusion significantly increased in‐hospital mortality compared with usual care (48.1% vs 33.0%, respectively)(Verbatim). Here, we present a rationale for the plausible reason for such an outcome of 48.1% mortality in sepsis protocol group as opposed to expected decrease in the mortality rate with a “time zero” of admittance to emergency room (ER) and 28 days. Based on the intake criteria of admission to ER, observations and limitations of this investigation, it is hypothesized that “Colonization Pressure” (CP) of “Persisters (Prs)” is the most ostensible factor for the sepsis and septic shock induced increase in mortality rate from “time zero” of admittance to ER. “Persisters”(Prs) are antibiotic‐sensitive bacterial populations have a small fraction (~10−6) of slow or non‐growing, antibiotic‐tolerant cells”. Stochastic switch of specific toxin‐antitoxin (TA) expression and alarmone (p) ppGpp has been implicated in evolution of AR. Additional contributing factors could be a. Lack of “Antibiogram” for P. aeruginosa, S. aureus, C. difficile (C. diff), b. failure to implementation of “Antibiotic Stewardship Program”; c. lack of information on the “CP” data on a daily basis. It is suggested that sustained “low tissue perfusion index (PI)”; “Oxygen Saturation of arterial hemoglobin (SpO2)” would hypothetically generate a chronic hypoxic state enabling the emergence of anaerobic gram negative bacilli (GNB)” acquiring antibiotic resistance via multidrug‐resistant (MDR); extensively drug‐resistant (XDR), Gain of function (GOF) mutations and Pandrug‐resistant (PDR) escalating the horizontal gene transfer. Chronic tissue hypoxia would likely to increase the “CP” of GNB due to the sub‐therapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and suboptimal infection control in the setting of outbreaks such as NCT01663701. Lack of information on utilization antifungals via antifungal stewardship is critical to reduce the morbidity & mortality by limiting emergence of MDR in the Intensive Care Units (ICU). Candida bloodstream infections (BSI) / Candidemia and candidiasis in (C.albicans, C.glabrata, C.auris with MDR and XDR attributes with higher “CP” indices transmitted via horizontal transmission (~30%) posing serious challenges in caring for chronically ill (HIV patients) in the long term care facilities, ICU, and also across the globe. Taken together, the observed 48% mortality in NCT01663701 is a consequence of solidification of factors beyond the realm of current clinical practices caring for chronically ill infectious diseases patients (ex. HIV) across the globe leading to ARP.Support or Funding InformationSupported by professional development funds from SWTJC and CME activities of Subburaj Kannan MDThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ProCESS, ARISE, ProMISe, PRISM, SSSP‐2, and FEAST are clinical trials exploring the implication of an early resuscitation with intravenous fluids, vasopressors, and blood transfusion (Early Goal Directed Therapy @ EGDT) to reduce mortality as compared with usual care for patients with H3 and S3 showed an overall increase in in‐hospital mortality. In an effort to delineate the underlying mechanism, we have analyzed the hemodynamic factors of NCT01663701. The patient cohort with hypotension had the blood pressure recorded as 95mmHg / 61mmHg (Mean IQR) after 6hr of intravenous fluid administration and SpO2 as 36 (p value<0.03). We have determined the pulse pressure (PP) of 34mmHg indicating the reduced perfusion index (PI) and hypovolemic shock. Our interpretation is that it is hypoxemia (an abnormally low arterial oxygen tension (PAO2) in the blood), escalating hypoxia to dysoxia and/or anoxia? As a result of sustained H3, the SpO2 (peripheral capillary oxygen saturation), as determined an average of 38% which is likely to cause a decrease in PI <50% far below normal PI (95%). Our inference is that such clinical scenario would likely to cause a shift in the hemoglobin ‐ oxygen saturation curve to the left (Ref Figure 41–8 Oxygen‐Hemoglobin Dissociation Curve, p530: Guyton‐Hall Med Phys Elsevier 13ed: 2016) while the Frank – Starling Curve to the left implicit of cardiac output failure with an ensuing endocarditis. It is our interpretation under these conditions; EGDT would unlikely to confer benefit in terms of PI. Our effort to determine the Cardiac Index (CI) was unsuccessful due to the fact that body surface area (BSA) was not available. We have determined the Mean Arterial Pressure (MAP) of 66 mmHg after 2 hr. starting the treatment while 72 mmHg after 6 hr. of intravenous fluid administration indicating an improvement in PI. However, patients with low hemoglobin level (<7g/dl) in sepsis protocol cohort would likely to suffer anemia leading to decrease oxygen delivery to tissues in turn decrease arterial oxygen content. SAPS‐3 (Simplified Acute Physiology Score (SAPS) 52 – 54 indicating the absolute risk of in‐hospital mortality by 15.1% reported in this study probably after the 6hr of intravenous fluid administration (Refer Figure 2 Intensive Care Med. 2005 31(10):1345). 86 patients in the sepsis protocol exhibiting Glasgow Coma Scale (GCS) score 13–15, while eleven patients were in GCS score range of 3–8 indicated that both cohort suffered a trauma possibly with traumatic brain injury (TBI) and meningitis. Based on aforesaid physiological factors, here with we propose that sustained “H3” in patients of sepsis protocol would likely to cause an increase in growth of the anaerobic bacteria leading to Septicemia and/or Bacteremia. With an ensuing septicemia, ARB like P. aeruginosa under hypoxia has been shown to have an increased expression of resistance‐nodulation‐division (RND) family of drug efflux pump genes, conferring AR selection pressure. Taken together, sustained H3 ‐ DIC exacerbate S3 lead ramping up ARG in ARB augmented mortality quotient.Support or Funding InformationSupported by professional development funds from SWTJC and CME activities of Subburaj Kannan MDThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Here we present a plausible pathophysiological cascade initiating the transition of laminar to turbulent flow as a cause for, but not limiting other unknown clinical variable for an increased mortality rate in NCT01663701‐SSSP‐2. Based on the correlation between Perfused Boundary Region (PBR) and number of rolling leukocytes in post‐capillary venules in sepsis cohort, the PBR has been suggested as an index of glycocalyx shedding enhancing the leukocyte–endothelium interaction. NCT00793442 observed that average number of rolling leukocytes was 26 in the sepsis group and 9.8 in the non‐infected control group per field. The sepsis cohort, had an increased number of adhered leukocytes in non‐survivors compared to non‐sepsis cohort. Correlation of aforesaid hemodynamic parameters implicating the LPE impacting the damaged endothelial surface, tissue perfusion and organ dysfunction due to septic shock not withstanding “DIC”. After the LPE start forming in the arterial end of the capillary bed, rolling up and formation of vortex. Amplification of LPE involves the formation of a single vortex of greater strength through the pairing of vortices. As the vortices progress deregulating starling forces from the arterial region in the capillary bed towards the venous end, vortices to become heavily distorted and less distinct. Due to presence of damaged endothelial surface with adhered LPE, flow breaks down, generating a large number of small‐scale eddies, and the flow undergoes rapid transition to the fully turbulent regime. Mixing layers and wakes behind bluff bodies exhibit a sequence of events, leading to transition and turbulent flow. It has known that initial linear instability occurs around Rex, crit = 91 000 forming an unstable two‐dimensional disturbances are called TSW waves. Increased LPE adhesion, endothelial damage, possible scar tissue formation and/or necrotic lesions in the capillary bed are likely to be large enough a secondary, non‐linear, instability mechanism causes the TSW to become three‐dimensional and finally evolve into hairpin Λ‐vortices. In the most common mechanism of transition, would be K‐type transition, where the hairpin vortices are aligned. The hairpin vortices with a high shear region is induced which intensifies, elongates and rolls up. Regions of intense and highly localized changes occur at random times and locations near the damaged endothelial wall. These turbulent spots are carried along with the flow and grow by spreading across the capillary bed, which causes increasing amounts of laminar fluid to take part in the turbulent motion. Under progressive hypotensive state induced endothelial damage and abrupt collapse of interstitial space would result CCP ensuing hypoxia. Such scenario may have been the cause for mortality in NCT01663701‐SSSP‐2. Support or Funding Information Supported by professional development funds and in part CME activities of Subburaj KannanMD PhD for www.aaets.org
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