Normoferremia in Patients with Acute Bacterial Infections-A Hitherto Unexplored Field of the Dichotomy between CRP and Ferritin Expression in Patients with Hyper Inflammation and Failure to Increase Ferritin.

Ferritin is an acute phase response protein, which may not rise as expected in acute bacterial infections. This could be due to the time required for its production or to a lack of response of ferritin to the bacterial inflammatory process. Medical records of hospitalized patients with acute hyper inflammation were retrieved and studied, looking closely at two acute phase proteins: C-reactive protein (CRP) and ferritin. The estimated time between symptom onset and the procurement of blood tests was also measured. 225 patients had a median ferritin level of 109.9 ng/mL [IQR 85.1, 131.7] and a median CRP level of 248.4 mg/L [IQR 221, 277.5]. An infectious inflammatory process was identified in 195 patients. Ferritin levels were relatively low in comparison with the CRP in each group, divided according to time from symptom onset until the procurement of blood tests. The discrepancy between high CRP and low ferritin suggests that these two acute phase response proteins utilize different pathways, resulting in a failure to increase ferritin concentrations in a documented state of hyperinflammation. A new entity of normoferremic inflammation accounts for a significant percentage of patients with acute bacterial infections, which enables bacteria to better survive the inflammation and serves as a new "inflammatory stamp".

Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers. Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2. Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status. Exposures: Vaccination with a booster dose of BNT162b2 vaccine. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction. Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20). Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

Making rural health care better: How to attract interns to rural hospital.

OBJECTIVE: We examined the factors that influence medical school graduates' choices for the place of internship, so that they can guide policy-makers to attract interns to rural hospitals. DESIGN: A national survey. SETTING: Rural and metropoles of Israel. PARTICIPANTS: Three-hundred-and-thirty-nine interns who did their internships during the years 2016-2018. MAIN OUTCOME MEASURE: The participants completed a web survey. We used the results of this survey to deduce which factors were influential in helping the interns choose a hospital for their year of internship. RESULTS: We received 339 questionnaires from medical school graduates of years 2015-2017. We found that the most influential factors in attracting interns to rural hospital internships are the availability of desired residency and exposure to a rural curriculum in medical school. This far outweighed any economic or life quality incentives. In addition, we found that the exposure to rural hospitals during the medical school years increases the likelihood of choosing an internship in a rural hospital. CONCLUSIONS: The most important factor for choosing a hospital for internship is the availability of lucrative residencies. Thus, we believe the best way to attract good interns would be to make the desired residency positions available for them. Furthermore, it might be more successful to target either students who have studied in a university affiliated with rural hospital rotations or graduates of universities outside of the country.

Induction of depressive-like effects by subchronic exposure to cocaine or heroin in laboratory rats.

The effect of psychoactive drugs on depression has usually been studied in cases of prolonged drug addiction and/or withdrawal, without much emphasis on the effects of subchronic or recreational drug use. To address this issue, we exposed laboratory rats to subchronic regimens of heroin or cocaine and tested long-term effects on (i) depressive-like behaviors, (ii) brain-derived neurotrophic factor (BDNF) levels in reward-related brain regions, and (iii) depressive-like behavior following an additional chronic mild stress procedure. The long-term effect of subchronic cocaine exposure was a general reduction in locomotor activity whereas heroin exposure induced a more specific increase in immobility during the forced swim test. Both cocaine and heroin exposure induced alterations in BDNF levels that are similar to those observed in several animal models of depression. Finally, both cocaine and heroin exposure significantly enhanced the anhedonic effect of chronic mild stress. These results suggest that subchronic drug exposure induces depressive-like behavior which is accompanied by modifications in BDNF expression and increases the vulnerability to develop depressive-like behavior following chronic stress. Implications for recreational and small-scale drug users are discussed. In the present study, we examined the long-term effects of limited subchronic drug exposure on depressive-like symptoms. Our results demonstrate that short-term, subchronic administration of either cocaine or heroin promotes some depressive-like behaviors, while inducing alterations in BDNF protein levels similar to alterations observed in several animal models of depression. In addition, subchronic cocaine or heroin enhanced the anhedonic effect of chronic stress.

Rate of Correction and All-Cause Mortality in Patients With Severe Hypernatremia.

Importance: Hypernatremia is common among hospitalized patients and is associated with high mortality rates. Current guidelines suggest avoiding fast correction rates but are not supported by robust data. Objective: To investigate whether there is an association between hypernatremia correction rate and patient survival. Design, Setting, and Participants: This retrospective cohort study examined data from all patients admitted to the Tel Aviv Medical Center between 2007 and 2021 who were diagnosed with severe hypernatremia (serum sodium ≥155 mmol/L) at admission or during hospitalization. Statistical analysis was performed from April 2022 to August 2023. Exposure: Patients were grouped as having fast correction rates (>0.5 mmol/L/h) and slow correction rates (≤0.5 mmol/L/h) in accordance with current guidelines. Main Outcomes and Measures: All-cause 30-day mortality. Results: A total of 4265 patients were included in this cohort, of which 2621 (61.5%) were men and 343 (8.0%) had fast correction rates; the median (IQR) age at diagnosis was 78 (64-87) years. Slow correction was associated with higher 30-day mortality compared with fast correction (50.7% [1990 of 3922] vs 31.8% [109 of 343]; P < .001). These results remained significant after adjusting for demographics (age, gender), Charlson comorbidity index, initial sodium, potassium, and creatinine levels, hospitalization in an ICU, and severe hyperglycemia (adjusted odds ratio [aOR], 2.02 [95% CI, 1.55-2.62]), regardless of whether hypernatremia was hospital acquired (aOR, 2.19 [95% CI, 1.57-3.05]) or documented on admission (aOR, 1.64 [95% CI, 1.06-2.55]). There was a strong negative correlation between absolute sodium correction during the first 24 hours following the initial documentation of severe hypernatremia and 30-day mortality (Pearson correlation coefficient, -0.80 [95% CI, -0.93 to -0.50]; P < .001). Median (IQR) hospitalization length was shorter for fast correction vs slow correction rates (5.0 [2.1-14.9] days vs 7.2 [3.5-16.1] days; P < .001). Prevalence of neurological complications was comparable for both groups, and none were attributed to fast correction rates of hypernatremia. Conclusions and Relevance: This cohort study of patients with severe hypernatremia found that rapid correction of hypernatremia was associated with shorter hospitalizations and significantly lower patient mortality without any signs of neurologic complications. These results suggest that physicians should consider the totality of evidence when considering the optimal rates of correction for patients with severe hypernatremia.

Refining triage practices by predicting the need for emergent care following major trauma: the experience of a level 1 adult trauma center.

PURPOSE: We examined the predictability of selected parameters for establishing the need for urgent care following multi-trauma as a means to warrant the highest level of trauma activation and potentially improve over- and under-triage rates. METHODS: In this retrospective cohort study of multi-trauma patients aged ≥ 16 years performed at a level 1 trauma center, trauma activation criteria and additional characteristics were examined with respect to treatment urgency, defined as: a direct disposition to the operating room or intensive care unit, initiating acute intervention in the trauma room, and in-hospital death within 7 days of admission. RESULTS: We enrolled 1373 patients (median age 36.0 years). The following parameter were inserted into the final multivariable model: age > 75 years, male sex, Charlson comorbidity index, trauma circumstances and mechanism, signs of respiratory distress, systolic BP ≤ 110 and GCS ≤ 13. Adjusted independent predictors of acute care requirement were as follows: GCS ≤ 13 (aOR 5.27 [95% CI 3.45-8.05], p < 0.001), systolic BP ≤ 110 mmHg (aOR 2.15 [95% CI 1.45-3.21], p < 0 .001), respiratory distress (aOR 2.05 [95% CI 1.53-2.77], p < 0.001), and age ≥ 75 years (aOR 1.90 [95% CI 1.18-3.08], p = 0.008). CONCLUSION: A GCS ≤ 13, systolic BP < 110 mmHg, signs of respiratory distress, and age > 75 years best predicted the need for acute care following multisystem trauma. Prospective studies are warranted to confirm the predictability of these criteria and to assess the extent to which their implementation will refine over- and under-triage rates.

Early signaling of inflammation in patients following traumatic injury with accurately estimated time of injury by profiling C-reactive protein levels.

BACKGROUND: Despite its widespread use, the precise dynamics of CRP response in clinical practice remain poorly defined. We employed a novel quadratic model to explore the time-course analysis of CRP values in trauma patients with known precise time of injury. METHODS: Relevant data on all adult patients admitted to our hospital following traumatic incidents between January 1st 2010 to December 31, 2020 were retrospectively collected. Those with a documented time of injury and who underwent CRP evaluation within the first 24 h since injury were studied. RESULTS: Based on the findings from our annual health check-up center, we established a reference upper normal CRP value of 12.99 mg/L. Within the first 7 h after injury, the CRP levels of 8-9% of the 1545 study patients exceeded the reference threshold. The proportion of patients with CRP levels > 12.99 mg/L increased to 18.5% at 8-9 h later and rose sharply to 91.6% at 22-24 h later. Our quadratic model yielded the equation: CRP = 5.122-0.528xTime + 0.139xTime 2. It accounted for > 40% of the variance in CRP levels (R2 = 42.4%). CONCLUSIONS: Clear and prominent CRP elevations following atraumatic event are detected only 9-12 h following the insult. This novel finding has crucial implications for accurate CRP assessment of inflammatory responses to physical injuries.

Early signaling of bacteremia in patients who present to the department of emergency medicine with relatively low C-reactive protein (CRP) concentrations.

OBJECTIVES: Examiningthe usefulness of C-reactive protein velocity (CRPv) as an early biomarker for the presence of bacteraemia in patients presenting to the Department of Emergency Medicine with acute infection/inflammation and suspected bacteraemia. METHODS: A retrospective study examining a cohort of patients who presented to the E.R and in whom blood cultures were taken. CRPv was calculated as the difference in mg/hour/litter between two consecutive CRP tests performed within 12 h. RESULTS: 256 patients were included in the cohort. Using CRPv in patients who at first presented with a relatively low (17.9 ≤ mg/L 1stquartile) CRP concentration, we found an AUC of 0.808 ± 0.038 (p < 0.001) for the presence of positive versus negative blood cultures (what is AUC?). This was better than the AUC that was obtained when the WBC for the same purpose. CONCLUSIONS: CRPv may be a useful biomarker in the identification of patients with suspected bacteremiaand a low CRP-a challenging situation for clinicians who may underestimate the severity of illness in this patient group.

Age-Dependent Biomarkers for Prediction of In-Hospital Mortality in COVID-19 Patients.

Background: Several biomarkers and models have been proposed to predict in-hospital mortality among COVID-19 patients. However, these studies have not examined the association in sub-populations. The present study aimed to identify the association between the two most common inflammatory biomarkers in the emergency department and in-hospital mortality in subgroups of patients. Methods: A historical cohort study of adult patients who were admitted to acute-care hospital between March and December 2020 and had a diagnosis of COVID-19 infection. Data on age, sex, Charlson comorbidity index, white blood cell (WBC) count, C-reactive protein (CRP), and in-hospital mortality were collected. Discrimination ability of each biomarker was observed and the CHAID method was used to identify the association in subgroups of patients. Results: Overall, 762 patients (median age 70.9 years, 59.7% males) were included in the study. Of them, 25.1% died during hospitalization. In-hospital mortality was associated with higher CRP (median 138 mg/L vs. 85 mg/L, p < 0.001), higher WBC count (median 8.5 vs. 6.6 K/µL, p < 0.001), and higher neutrophil-to-lymphocyte ratio (NLR) (median 9.2 vs. 5.4, p < 0.001). The area under the ROC curve was similar among all biomarkers (WBC 0.643, NLR 0.677, CRP 0.646, p > 0.1 for all comparisons). The CHAID method revealed that WBC count was associated with in-hospital mortality in patients aged 43.1−66.0 years (<11 K/µL: 10.1% vs. 11+ K/µL: 27.9%), NLR in patients aged 66.1−80 years (≤8: 15.7%, >8: 43.3%), and CRP in patients aged 80.1+ years (≤47 mg/L: 18.8%, 47.1−149 mg/L: 43.1%, and 149.1+: 71.7% mortality). Conclusions: WBC, NLR, and CRP present similar discrimination abilities. However, each biomarker should be considered as a predictor for in-hospital mortality in different age groups.

REGEN-COV antibody combination in patients with lymphoproliferative malignancies and SARS-CoV-2 infection.

Patients with lymphoproliferative diseases are at high risk for SARS-CoV-2-related complications and mortality. The role of casirivimab and imdevimab (REGEN-COV), a neutralizing antibody cocktail, to treat immunocompromised hemato-oncological patients with SARS-CoV-2 disease 2019 (Covid-19) remains unknown. Here, we present our clinical experience on the outcome of 15 hematological patients treated with REGEN-COV for SARS-CoV-2 infection. Most patients failed to respond or achieved low antibody titer after 2-3 doses of BNT162b2 mRNA vaccine. All patients experienced clinical improvement with no mortality within a median follow-up of 70 days. In conclusion, early administration of REGEN-COV to high-risk hematological patients may prevent clinical deterioration and mortality from SARS-CoV-2 infection. The effectiveness of neutralizing antibodies may vary depending on the virus variants and in particular with the omicron variant (B.1.1.529).