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Augmenting the vascular supply to generate new tissues, a crucial aspect in regenerative medicine, has been challenging. Recently, our group showed that calcium phosphate can induce the formation of a functional neo-angiosome without the need for microsurgical arterial anastomosis. This was a preclinical proof of concept for biomaterial-induced luminal sprouting of large-diameter vessels. In this study, we investigated if sprouting was a general response to surgical injury or placement of an inorganic construct around the vessel. Cylindrical biocement scaffolds of differing chemistries were placed around the femoral vein. A contrast agent was used to visualize vessel ingrowth into the scaffolds. Cell populations in the scaffold were mapped using immunohistochemistry. Calcium phosphate scaffolds induced 2.7-3 times greater volume of blood vessels than calcium sulphate or magnesium phosphate scaffolds. Macrophage and vSMC populations were identified that changed spatially and temporally within the scaffold during implantation. NLRP3 inflammasome activation peaked at weeks 2 and 4 and then declined; however, IL-1β expression was sustained over the course of the experiment. IL-8, a promoter of angiogenesis, was also detected, and together, these responses suggest a role of sterile inflammation. Unexpectedly, the effect was distinct from an injury response as a result of surgical placement and also was not simply a foreign body reaction as a result of placing a rigid bioceramic next to a vein, since, while the materials tested had similar microstructures, only the calcium phosphates tested elicited an angiogenic response. This finding then reveals a potential path towards a new strategy for creating better pro-regenerative biomaterials.

Background: An increased serum glucose level is a common finding among patients admitted to hospital with acute illness, including the intensive care unit (ICU), even without a history of previous diabetes mellitus (DM). Glycated hemoglobin (HbA1c) is not only a diagnostic tool for DM but may also has prognostic value for diabetic and non-diabetic populations., Objectives: To assess the relationship between HbA1c level on admission and clinical outcome among patients admitted to the ICU due to cardiopulmonary disorders with hyperglycemia., Methods: Patients consecutively admitted to the ICU due to cardiopulmonary disorders who presented with hyperglycemia at admission were evaluated during a 6-month period. HbA1c and serum glucose levels were tested on admission and during the first 24-48 hours of hospitalization. Patients were divided according to HbA1c and compared in term of demographics. We evaluated the effect of HbA1c levels at admission on the clinical outcomes., Results: Of patients with cardiopulmonary disorders who presented with hyperglycemia at admission to the ICU, 73 had HbA1c levels ≥ 6%, 92 had HbA1c levels < 6%: 63/165 (38.2%) known as diabetic patients. The 30-day all-cause mortality was higher in the group with high HbA1c levels; 38/73 vs. 32/98 (P = 0.02). Increased length of stay in the ICU and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were associated with HbA1c ≥ 6% (P < 0.022 and P < 0.026), respectively., Conclusions: HbA1c ≥ 6% has an important clinical prognostic value among diabetic and non-diabetic patients with cardiopulmonary disorders and hyperglycemia.

Massive segmental bone defects (SBD) are mostly treated by removing the fibula and transplanting it complete with blood supply. While revolutionary 50 years ago, this remains the standard treatment. This review considers different strategies to repair SBD and emerging potential replacements for this highly invasive procedure. Prior to the technical breakthrough of microsurgery, researchers in the 1960s and 1970s had begun to make considerable progress in developing non autologous routes to repairing SBD. While the breaktthrough of vascularised bone transplantation solved the immediate problem of a lack of reliable repair strategies, much of their prior work is still relevant today. We challenge the assumption that mimicry is necessary or likely to be successful and instead point to the utility of quite crude (from a materials technology perspective), approaches. Together there are quite compelling indications that the body can regenerate entire bone segments with few or no exogenous factors. This is important, as there is a limit to how expensive a bone repair can be and still be widely available to all patients since cost restraints within healthcare systems are not likely to diminish in the near future. STATEMENT OF SIGNIFICANCE: This review is significant because it is a multidisciplinary view of several surgeons and scientists as to what is driving improvement in segmental bone defect repair, why many approaches to date have not succeeded and why some quite basic approaches can be as effective as they are. While there are many reviews of the literature of grafting and bone repair the relative lack of substantial improvement and slow rate of progress in clinical translation is often overlooked and we seek to challenge the reader to consider the issue more broadly., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In a multicenter, nationwide, retrospective study of patients hospitalized with spotted fever group rickettsiosis in Israel during 2010-2019, we identified 42 cases, of which 36 were autochthonous. The most prevalent species was the Rickettsia conorii Israeli tick typhus strain (n = 33, 79%); infection with this species necessitated intensive care for 52% of patients and was associated with a 30% fatality rate. A history of tick bite was rare, found for only 5% of patients; eschar was found in 12%; and leukocytosis was more common than leukopenia. Most (72%) patients resided along the Mediterranean shoreline. For 3 patients, a new Rickettsia variant was identified and had been acquired in eastern, mountainous parts of Israel. One patient had prolonged fever before admission and clinical signs resembling tickborne lymphadenopathy. Our findings suggest that a broad range of Rickettsia species cause spotted fever group rickettsiosis in Israel.

It has been suggested that some of the adverse, long-term cardiovascular outcomes of smoking are mediated by impaired autonomic nervous system (ANS) activity. Yet, this association is currently inconclusive. Heart rate variability (HRV) and the deep breathing test (DBT) represent common quantitative markers of ANS activity due to their simplicity and reliability. This large cross-sectional study was designed to assess the effect of active smoking on ANS function as manifested by HRV or DBT abnormalities. Electrocardiograms were recorded at rest for 5 min and during forced metronomic breathing. HRV and DBT were calculated according to accepted standards. Participants were divided into two groups based on current smoking status. The study included 242 healthy volunteers (196 nonsmokers and 46 smokers). There were no significant differences in age, sex, and BMI between groups. Cumulative smoking exposure burden (CSEB) for the study group was 5.3 ± 1.3 pack-years. Comparative analysis of HRV and DBT parameters according to smoking status revealed no significant differences between groups. Significant ( p < 0.05), yet weak or moderate correlations (r < 0.7) were found between CSEB and abnormal change in HRV parameters consistent with sympathetic overactivity and decreased parasympathetic tone. In conclusion, smoking for a relatively short period in healthy adults does not seem to lead to significant impairment in ANS function. Yet, the consequences of smoking seem to be amplified when cumulative exposure burden increases.

The development of alternatives to vascular bone grafts, the current clinical standard for the surgical repair of large segmental bone defects still today represents an unmet medical need. The subcutaneous formation of transplantable bone has been successfully achieved in scaffolds axially perfused by an arteriovenous loop (AVL) and seeded with bone marrow stromal cells or loaded with inductive proteins. Although demonstrating clinical potential, AVL-based approaches involve complex microsurgical techniques and thus are not in widespread use. In this study, 3D-printed microporous bioceramics, loaded with autologous total bone marrow obtained by needle aspiration, are placed around and next to an unoperated femoral vein for 8 weeks to assess the effect of a central flow-through vein on bone formation from marrow in a subcutaneous site. A greater volume of new bone tissue is observed in scaffolds perfused by a central vein compared with the nonperfused negative control. These analyses are confirmed and supplemented by calcified and decalcified histology. This is highly significant as it indicates that transplantable vascularized bone can be grown using dispensable vein and marrow tissue only. This is the first report illustrating the capacity of an intrinsic vascularization by a single vein to support ectopic bone formation from untreated marrow., Competing Interests: The authors declare no conflict of interest.

Background: Accurate diagnosis of community acquired pneumonia (CAP) is crucial to its proper management and to combating antibiotic resistance. Levels of C-reactive protein (CRP) have been shown to distinguish pneumonia from other pathological conditions and can be used to control the severity of infection during admission., Objectives: To investigate an association between consecutive measurements of CRP and the severity of CAP in hospitalized patients., Methods: A total of 500 patients with CAP were admitted to the hospital. Traditional markers of inflammation including CRP, leukocyte count, body temperature, were measured on the first, second, and fifth days of hospitalization. Correlations between these measures and the length of the hospital stay were calculated., Results: Mean levels of CRP, body temperature, and leukocyte count were significantly lower on the second day after hospital admission and even lower on the fifth day. A positive correlation of medium strength was found between the level of CRP on the second day of hospitalization and the length of hospital stay (P < 0.001, rs = 0.447), and a negative correlation was noted between the decrease in CRP level from the first to second day and the length of hospital stay., Conclusions: CRP levels correlated with body temperature and leukocyte count, traditional markers of inflammation. A greater decrease in CRP level between the first and second day of hospitalization was associated with shorter hospital stay and rapid improvement. These findings support the use of CRP as a marker for the severity and complication of CAP.

Intrathoracic goiters represent substantial enlargement and descent of cervical thyroid tissue into the thoracic cavity, usually in the anterior mediastinum. Rarely, they extend posteriorly, causing obstructive symptoms, sometimes with acute onset. Posterior mediastinal goiters should be differentiated from other mediastinal masses by appropriate work-up, while computed tomography is the most valuable technique. We report two cases of such symptomatic goiters. First reported case was atypically presented with aspiration pneumonia and second was successfully operated. Our overview aims to increase awareness of this rare clinical entity due to possible respiratory compromise. Reasonable surgical management is mandatory.

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are a major problem worldwide and are usually the main indication for mechanical ventilation (MV), especially in the intensive care unit (ICU). The rate of weaning failure is also high and prolonged MV leads to complications of intubation. The goal is to wean these patients as soon as possible., Objective: To determine the optimal time necessary to start the weaning process., Methods: In an attempt to determine the length of MV and stay in the ICU, we compared the length of MV, weaning, reintubations and discharge during a 10 month period. This study included 122 patients on MV due to severe exacerbation of COPD who were not suitable for non-invasive ventilation. For each patient serial arterial blood gases were measured at admission and during hospitalization. PeCO2 (mixed expired CO2) was tested using a Datex S/5 instrument at follow-up., Results: The study population comprised all patients who required MV; of these 122, 108 were ventilated from 6 to 140 hours (mean 48 +/- 42), 9 needed more than 168 hours, and 5 died due to severe ventilation-associated pneumonia. No correlation was found between pH, PCO2 and length of MV; these findings did not contribute to evaluation of the patient's condition nor did they enable us to predict the length of treatment necessary., Conclusion: Most of the patients (93%) ventilated for acute respiratory failure due to COPD required MV for only 6-90 hours.

Background: Community-acquired pneumonia requiring hospitalization is a severe illness with high mortality, especially if the appropriate treatment is delayed. Sometimes diagnosis is difficult due to an equivocal clinical picture or chest film, or to accompanying diseases that mask or simulate pneumonia., Objectives: To assess the usefulness of certain inflammatory markers in differentiating pulmonary edema from pneumonia throughout the hospital stay in patients admitted for pneumonia or pulmonary edema of non-infectious origin and to monitor the response to treatment., Methods: The study group comprised 50 patients admitted for pneumonia, 50 admitted for pulmonary edema and 30 healthy individuals. Blood samples for determination of leukocyte count, erythrocyte sedimentation rate (ESR), fibrinogen, C-reactive protein (CRP), albumin, sCD14 and oxidized fibrinogen were drawn upon admission, at 48 and 72 hours after admission, and at discharge from the intensive care unit., Results: The levels of sCD14 were similar in both patient groups but higher than control levels during the first 48 hours (P< 0.03). They decreased gradually with hospital stay. The concentration of oxidized fibrinogen was similar in both patient groups and significantly lower than that of the healthy control group throughout the hospitalization period., Conclusions: Oxidized fibrinogen and sCD14 are not reliable markers for the diagnosis of pneumonia, for its differential diagnosis from pulmonary edema, and for patient follow-up throughout hospitalization. The finding of elevated levels of oxidized fibrinogen in the group of healthy controls warrants further study to identify the factors responsible for altering fibrinogen oxidation. The other markers are more indicative.

Background: Renal artery stenosis is one of the most frequent causes of secondary hypertension. Appropriate methods for screening, diagnosis and therapy are currently under debate., Objectives: To evaluate and recommend methods for screening and diagnosing renal artery stenosis, and to assess the clinical outcomes of renal artery stenting., Methods: A total of 450 patients undergoing non-emergent coronary angiography fulfilled the selection criteria for selective renal arteriography; those with severe (luminal narrowing > or = 70%) renal artery stenosis underwent percutaneous transluminal renal angioplasty with renal artery stenting., Results: Of 166 patients (36.9%) with renal artery stenosis, 41 (9.1%) had severe stenosis that required renal artery stenting, and 83% had ostial renal stenosis. The primary success rate was 100% and there were no complications. During the follow-up period, two patients required a second PTRA. After stent deployment, significant reductions were observed in systolic and diastolic pressures (P < 0.001 and P = 0.01, respectively) and in the number of antihypertensive drugs used by the patients (P < 0.001). These reductions were sustained during follow-up. Hypertension was cured (systolic blood pressure < 130 mmHg) in 9 patients (21.4%) and improved in 27 (64.3%). Plasma creatinine did not change significantly., Conclusions: Selective renal angiography is an effective diagnostic tool for identifying symptomatic cases of renal artery stenosis in patients undergoing coronary angiography. Our finding of a high success rate and low complication rate supports the use of primary renal artery stenting in symptomatic patients with renal artery stenosis.

Background: Chronic obstructive pulmonary disease (COPD) is a condition in which there is limited airflow during expiration (exhaling, or breathing out) that is not fully reversible and usually worsens over time. The disease is estimated to kill more than 100,000 Americans each year, and costs related to care of patients with COPD are significant. Physiologically, COPD represents a disruption in ventilation and in the exchange of gases in the lungs. Laboratory tests indicate elevated CO2 levels, gradual reduction of the levels of oxygen and pH in arterial blood, and a consequent rise in the dead space fraction (DSF) of the lungs., Objective: Patients with COPD exacerbation represent a large portion of those artificially ventilated. In an attempt to develop a prognostic tool for length of treatment, we compared the proportion of DSF to the length of mechanical ventilation (MV)., Methods: This study included 73 patients admitted to the intensive care unit (ICU) where they received MV due to exacerbation of COPD. Each patient's arterial blood gases (ABG) were measured upon admission. PeCO2 was tested using a Datex S/5 instrument. Subsequently, DSF was calculated using the Bohr equation. Statistical data was analyzed using SPSS software., Results: Patients included in the study were ventilated from 6 to 160 hours (average 40 +/- 47). In addition to ABG measurements, PeCO2 (expired CO2) levels were measured and DSF calculated for each patient. DSF values varied from 0.21 to 0.76 (average 0.119 +/- 0.489). No correlation was found between DSF and length of artificial ventilation., Conclusion: Evaluation of DSF does not provide a factor in estimating the length of treatment for patients with acute respiratory failure due to COPD exacerbation.

The Phoenicians were the dominant traders in the Mediterranean Sea two thousand to three thousand years ago and expanded from their homeland in the Levant to establish colonies and trading posts throughout the Mediterranean, but then they disappeared from history. We wished to identify their male genetic traces in modern populations. Therefore, we chose Phoenician-influenced sites on the basis of well-documented historical records and collected new Y-chromosomal data from 1330 men from six such sites, as well as comparative data from the literature. We then developed an analytical strategy to distinguish between lineages specifically associated with the Phoenicians and those spread by geographically similar but historically distinct events, such as the Neolithic, Greek, and Jewish expansions. This involved comparing historically documented Phoenician sites with neighboring non-Phoenician sites for the identification of weak but systematic signatures shared by the Phoenician sites that could not readily be explained by chance or by other expansions. From these comparisons, we found that haplogroup J2, in general, and six Y-STR haplotypes, in particular, exhibited a Phoenician signature that contributed > 6% to the modern Phoenician-influenced populations examined. Our methodology can be applied to any historically documented expansion in which contact and noncontact sites can be identified.

Background: The temporal behavior of the coronary microcirculation in acute myocardial infarction may affect outcome. Diastolic deceleration time and early systolic flow reversal derived from coronary artery blood flow velocity patterns reflect microcirculatory function., Objectives: To assess left anterior descending coronary artery flow velocity patterns using Doppler transthoracic echocardiography after primary percutaneous coronary intervention, in patients with anterior AMI., Methods: Patterns of flow velocity patterns of the LAD were obtained using transthoracic echocardiography-Doppler in 31 consecutive patients who presented with anterior AMI. Measurements were done at 6 hours, 36-48 hours, and 5 days after successful PPCI. Measurements of DDT and pressure half times (Pt%), as well as observation for ESFR were performed., Results: In the first 2 days following PPCI, the average DDT (600 +/- 340 msec) was shorter than on day 5 (807 +/- 332 msec) (P < 0.012), FVP in the first 2 days were dynamic and bidirectional: from short DDT (< 600 msec) to long DDT (> 600 msec) and vice versa. On day 5 most DDTs became longer. Pt1/2 at 6 hours was not different than at day 2 (174 +/- 96 vs. 193 +/- 99 msec, P = NS) and became longer on day 5 (235 +/- 98 msec, P = 0.012). Bidirectional patterns were also observed in the ESFR in 6 patients (19%) at baseline, in 4 (13%) at 36 hours, and in 2 (6.5%) on day 5 after PPCI., Conclusions: Flow velocity patterns of the LAD after PPCI in AMI are dynamic and reflect unpredictable changes in microcirculation.

Lebanon is an eastern Mediterranean country inhabited by approximately four million people with a wide variety of ethnicities and religions, including Muslim, Christian, and Druze. In the present study, 926 Lebanese men were typed with Y-chromosomal SNP and STR markers, and unusually, male genetic variation within Lebanon was found to be more strongly structured by religious affiliation than by geography. We therefore tested the hypothesis that migrations within historical times could have contributed to this situation. Y-haplogroup J*(xJ2) was more frequent in the putative Muslim source region (the Arabian Peninsula) than in Lebanon, and it was also more frequent in Lebanese Muslims than in Lebanese non-Muslims. Conversely, haplogroup R1b was more frequent in the putative Christian source region (western Europe) than in Lebanon and was also more frequent in Lebanese Christians than in Lebanese non-Christians. The most common R1b STR-haplotype in Lebanese Christians was otherwise highly specific for western Europe and was unlikely to have reached its current frequency in Lebanese Christians without admixture. We therefore suggest that the Islamic expansion from the Arabian Peninsula beginning in the seventh century CE introduced lineages typical of this area into those who subsequently became Lebanese Muslims, whereas the Crusader activity in the 11(th)-13(th) centuries CE introduced western European lineages into Lebanese Christians.

Background: Hyperglycemia is common among patients admitted to intensive care units, and carries the risk for complications and prolonged ICU stay. With intensive insulin control of blood glucose, morbidity and mortality can be reduced., Objectives: To determine whether intensive or conventional insulin control of blood glucose in hyperglycemic ICU patients correlated with the prognosis., Methods: Following admission to the ICU, hyperglycemic patients were randomly assigned to a group treated intensively with insulin targeting glucose at 110-140 mg/dl, or to a conventional insulin therapy group, where glucose, upon exceeding 200 mg/dl, was controlled at 140-200 mg/dl. Rates of morbidity and mortality, hypoglycemic episodes, and insulin dosage were compared., Results: In the 41 patients treated intensively with insulin the glucose level was 142 +/- 14 mg/dl, as compared to 174+/-20 mg/dl in the 48 patients on conventional insulin treatment. Both groups were similar in age, acute physiology and chronic health evaluation score. Morbidity was also similar, except for increased vascular damage in the conventional treatment group and slightly shorter ICU stay in the intensive therapy group. Both groups had similar in-ICU, in-hospital, and 28 day mortalities, and similar rates of hypoglycemic episodes. The daily dosage of insulin was significantly higher with the conventional treatment (P= 0.004)., Conclusions: Intensive insulin treatment did not affect the mortality or morbidity rates in ICU patients. The increased insulin dosage of conventional insulin treatment was attributable to the group's higher prevalence of diabetes. Future studies should address this bias and determine the optimal glucose target.