As clinicians we want to further our understanding of work with adult clients who have experienced massive and cumulative psychic trauma to which there is no possible adaptive response strategy. This ...monograph of the 2008 John Bowlby Memorial Conference brings together papers by leading contributors to the field of attachment and trauma that explore the means by which individuals struggle to cope with exposure to war zones, both large scale conflicts and societal breakdown, and the domestic war zones where adults and children experience violence and sexual abuse. These papers seek to further our understanding of the intergenerational transmission of experiences of trauma, as in the examples of the Holocaust and slavery. In times where talk of terror is everywhere, psychotherapists offer a clinical perspective on terror which may translate to the world at large.
BackgroundFms-like tyrosine kinase 3 ligand (FLT3L) is a potent hematopoietic growth factor that mobilizes stem cells and increases the number of circulating dendritic cells (DCs) in blood and ...organs. In a murine lung adenocarcinoma model, FLT3L had modest activity as monotherapy but demonstrated synergy when combined with high-dose radiotherapy.1 Clinical trials have demonstrated that FLT3L is safe but has minimal activity in cancer patients. We performed a prospective trial for patients with advanced non-small cell lung cancer (NSCLC) to evaluate the immune correlates of combining FLT3L with stereotactic body radiotherapy (SBRT).MethodsTwenty-nine subjects were enrolled between October 2016 and January 2020 in a Phase II clinical, and all subjects failed at least one previous round of treatment (median 3 lines, range 1 to 5). Subcutaneous CDX-301 (75 µg/kg) was administered daily for five days with concomitant treatment of SBRT (figure 1). To identify immune cell signatures of response, we developed two high dimensional flow cytometry panels measuring 31 unique subsets found in peripheral blood mononuclear cells (PBMCs) and performed multiplex proteomic analysis measuring 92 different proteins at baseline, 2 weeks, 4 weeks, and 8 weeks post treatment.ResultsIn our trial, 55% of patients achieved progression free survival four months (PSF4) after treatment with 31% of the patients achieving abscopal responses. SBRT and CDX-301 induced significant increases in the myeloid compartment, including subsets of monocytes, myeloid-derived suppressor cells (MDSCs) and DCs (figure 2). Within the DC compartment, we found heterogeneity, with FceR1-expressing DC2 and DC3 being the most responsive to treatment. Despite the strong responses from DCs and MDSCs to SBRT and CDX-301, cellular responses returned to baseline 8 weeks post treatment. Notably, the treatment induced greater co-expression of HLADR and Ki67 on CD4 T cells than CD8 T cells. In abscopal responders, CD4 T cell phenotype continued to evolve over a longer time period with concomitant increases of Th1-like CD4 T cells, IL21, and DC1 over 4 weeks (figure 3).ConclusionsCDX-301 and SBRT emerge as a compelling approach to reactivate the immune system that has facilitated the progression of NSCLC. Patients with abscopal responses exhibit distinct cellular responses to FLT3L and SBRT that align with the emerging significance of DC1 and CD4 T cells. This sustained Type 1 response over 4 weeks in abscopal responders independent of high grade adverse events, indicating a unique therapeutic axis to harness systemic immunity against metastatic lesions in NSCLC.AcknowledgementsThe authors would like to thank patients and families who enrolled into the study. Furthermore, the authors thank the Wherry and Guha labs for valuable scientific discussions.ReferenceChakravarty PC. Flt3-ligand administration after radiation therapy prolongs survival in a murine model of metastatic lung cancer. Cancer Res.1999;59;6028–32.Ethics ApprovalThis study (2015–5267) was approved by the Albert Einstein College of Medicine IRB on 9/30/2015. All participants provided informed consentAbstract 1522 Figure 1Trial schemeAbstract 1522 Figure 2Patient level PCA using aggregated flow cytometry data representing 31 unique immune populations. Each point is colored by timepoint with the green arrow representing the mean of PC1 and PC2 at each timepoint. Variable contributions for the PC1 axis (right) and PC2 axis (bottom) are ranked by magnitude and direction of contribution and colored by parent populationAbstract 1522 Figure 3Spearman rank correlations of the fold change from T4 to T0 (baseline) in DC1, preDC, pDC, CD14-DC3, CD14+DC3, CD5+DC2, CDS- DC2, Th1-like CD4 T cells (CXCR5+), exhausted CD8 T cells (PD1+CD39+), activated CD4 T cells (HLADR+Ki67+), activated CD8 T cells (HLADR+Ki67+), and the top 10 cytokines from that are changing the most with time. Nodes are colored by associated group (cytokine, T cells, and DCs). Green edges represent positive correlations and red edges represent negative correlations. Correlations >0.7 for inclusion in correlation network
Unmet needs can impede optimal care engagement, impacting the health and well-being of people living with HIV (PLWH); yet, whether unmet needs differ by care engagement status is not well understood. ...Using surveys and qualitative interviews, we examined and compared unmet needs for PLWH (n = 172) at different levels of care engagement. Unmet needs varied only slightly by care status. Survey findings revealed that provision of housing, emergency financial assistance, employment assistance, and food security were the greatest unmet need; for those in care, housing was the greatest unmet need, whereas for those sporadically in care or out of care, employment assistance was the greatest unmet needs. Qualitative interviews likewise illustrated that a lack of financial resources including insurance, housing, employment, and transportation presented barriers to care engagement across all care groups. Our findings indicate that unmet needs among PLWH are complex and multi-faceted across care engagement status.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Point-of-care ultrasound examination of the chest has evolved into a radiation-free bed-side diagnostic tool for a variety of pulmonary disorders, including pneumothorax, pleural effusion, ...consolidation, edema and ARDS 1-3. The detection of atelectasis by ultrasound, however, remains a diagnostic challenge. Atelectasis presents as primary or secondary. During secondary atelectasis, the lung is externally compressed by air or fluid in the pleural space. The diagnosis of secondary atelectasis by ultrasound is demanding, but feasible 4,5. Primary atelectasis, caused by airway obstruction, results in complete lung, lobar or segmental collapse. Ultrasonography allows early detection of total lung collapse with the “lung pulse” sign, consisting of transmission of the heart beat to the pleural line through collapsed lung tissue 6. The recognition of primary lobar or segmental atelectasis using ultrasound hasn't been previously described.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Critical administration threshold (≥3 units of packed red blood cells/h or CAT+) has been proposed as a new definition for massive transfusion (MT) that includes volume and rate ...of blood transfusion. CAT+ has been shown to eliminate survivor bias and be a better predictor of mortality than the traditional MT (>10 units/24 h). End-tidal CO2 (ET CO2 ) negatively correlates with lactate and is an early predictor of shock in trauma patients. We conducted a pilot study to test the hypothesis that low ET CO2 on admission predicts CAT+. Methods ET CO2 via capnography and serum lactate were prospectively collected on admission for 131 patients requiring trauma team activation. Demographic data were obtained from patient charts. Excluded were patients with isolated head injuries, traumatic arrests, or pre-hospital intubations. CAT± status was determined for each hour up to 6 h from admission as described; likewise, MT± status was determined up to 24 h from admission. Results After exclusion criteria, 67 patients were analyzed. Mean age was 41.2 (SD 18.5). Thirty-three patients had a blunt mechanism of injury (49%), median ISS was 9 (interquartile range 4–19), and there were 6 deaths (9%). ET CO2 and lactate were negatively correlated by Spearman rank-based correlation (rho = −0.41, p = 0.0006). Twenty-one (31%) and 8 (12%) patients were CAT+ and traditional MT+, respectively. There were a significantly greater proportion of patients with ISS > 15, ET CO2 <35, or who died found to be CAT+. A binomial logistic regression model adjusting for age, SBP <90, HR, and ISS >15 revealed ET CO2 < 35 to be independently predictive of CAT+ (OR 9.24, 95% CI 1.51-56.57, p = 0.016). Conclusions This pilot study demonstrated that low ET CO2 had strong association with standard indicators for shock and was predictive of patients meeting CAT+ criteria in the first 6 h after admission. Further study to verify these results and to elucidate CAT criteria’s association with mortality will require a larger sample size.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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Background: In a murine non-small cell lung cancer (NSCLC) model, we demonstrated synergy between localized radiotherapy and the dendritic cell growth factor fms-like tyrosine ...kinase 3 (FLT3) ligand. We now present results from a phase II study testing this combination in patients with advanced and treatment-refractory NSCLC. Methods: Advanced NSCLC patients with multifocal active disease after at least one line of systemic therapy and ECOG performance status 0-2 received 5 daily subcutaneous injections of CDX-301 (75 µg/kg) concurrent with stereotactic body radiotherapy (SBRT, 30-54 Gy in 1-5 fractions based on target size and location) directed at a single site of disease. Additional “cycles” of SBRT and CDX-301 could be administered at least four months after the initial study treatment, at the discretion of the treating physicians. The primary endpoint was progression-free survival four months after treatment initiation (PFS4), with a hypothesis that the PFS4 rate would exceed 40%. Secondary endpoints included overall survival (OS) duration, responses on PET (PERCIST criteria) and CT (RECIST criteria), and dose-limiting toxicities (grade ≥3 adverse events within 30 days). Lesions targeted with SBRT were excluded from response assessments. The intended sample size was 29 subjects. Blood samples were obtained for flow cytometry and other analyses of immune activation. Results: Twenty-nine subjects received study therapy between October 2016 and January 2020. Subjects received a median of 3 lines (range: 1-5) of systemic therapy prior to study enrollment, including immune checkpoint inhibitors targeting the PD-1/PD-L1 axis in 26 subjects (90%). At the time of this analysis, the actuarial PFS4 rate is 60%, which exceeds our pre-specified efficacy objective. With a median follow-up duration for living patients of 12 months, the actuarial 12-month OS rate is 55%. Partial response of lesions not targeted with SBRT (“abscopal effect”) was observed in 9 subjects (31%) using PET criteria and in 4 subjects (14%) using CT criteria. Seven subjects (24%) received a second course of SBRT and CDX-301 after initial study therapy. No dose-limiting toxicities have been observed. Only six subjects (21%) have received additional chemotherapy or immunotherapy after study treatment. Conclusions: The combination of CDX-301 and SBRT is well-tolerated and has activity as systemic therapy for advanced NSCLC. Additional studies to maximize the efficacy of this in situ vaccination approach with the addition of an agonist anti-CD40 antibody (CDX-1140) are planned. Clinical trial information: NCT02839265 .
Parents often face a trade-off between allocating resources to many young with lower survival, or fewer young with higher survival. To examine trade-offs in litter size and juvenile survival in mule ...deer, and how survival was influenced by the nutritional condition of the female, we compared the survival of 30 twin and singleton mule deer (Odocoileus hemionus) fawns during their 1st summer in eastern Washington. Overall fawn mortality was high (51.6%), especially during the 1st half of the summer (61.3%). Coyote predation caused 58.3% of all identified fawn mortalities. Twin fawns had a risk of dying 2.6 times higher than single fawns, and the difference between twin and singleton survival was most drastic during the first 1.5 months of life. Body fat of females during their last trimester of pregnancy predicted the number of fetuses they were carrying and whether they had at least 1 fawn surviving until the fall, but not the number of fawns surviving. Under these conditions, a litter size of 2 would be considered optimal because mothers giving birth to twins produced an average of 0.92 fawns by fall, whereas mothers producing singles ended up with only 0.75 fawns. However, our model suggested that a population producing only twins would be expected to increase only 4% faster than one producing only singletons.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Previous research has demonstrated the sensitivity of the developing rat to the hypothyroxinemic and ototoxic effects of perinatal exposure to Aroclor 1254 (A1254). We tested the hypothesis that ...postnatal exposure via lactation is the major cause of the ototoxicity by cross fostering animals at birth. Primiparous rats (22-24/dose) received 0 or 6 mg/kg A1254 (po in corn oil) from gestation day (GD) 6 to postnatal day (PND) 21. On the day of birth, half of the treated litters and half of the control litters were cross-fostered, resulting in the following groups: Ctrl/Ctrl (controls); A1254/A1254 (perinatal exposure); A1254/Ctrl (prenatal exposure only); and Ctrl/A1254 (postnatal exposure only). We assessed offspring at a number of ages for: serum thyroid hormone concentrations, liver and brain concentrations of PCBs, body weight, mortality, age of eye opening, auditory startle amplitudes, and auditory thresholds for 1 kHz and 40 kHz tones. Circulating thyroxine (T(4)) concentrations were sharply reduced at GD 21 in the A1254-exposed group, and on PND 3, 7, 14, and 21 in the A1254/A1254 and the Ctrl/A1254 groups. Smaller decreases in T(4) were observed in the A1254/Ctrl group on PND 3, 7, and 14. PCB concentrations in the liver on PND 21 were sharply elevated in the A1254/A1254 and Ctrl/A1254 groups. Much smaller increases were seen in the A1254/Ctrl group. Age of eye-opening and startle amplitudes were unaffected by treatment. A1254 exposure caused permanent hearing deficits (20 dB increase) at the low frequency (1 kHz) in the A1254/A1254 and Ctrl/A1254 groups. The present findings demonstrated that the critical period for the ototoxicity of developmental A1254 exposure is within the first few postnatal weeks in the rat. This effect is consistent with the greater degree of postnatal hypothyroxinemia resulting from the greater magnitude of exposure that occurs postnatally via lactation.
Background:
In adults, anterior glenohumeral instability has been associated with a tall and narrow glenoid morphology, assessed using the glenoid index (GI; glenoid height-to-width ratio) on ...magnetic resonance imaging (MRI). This morphological association has not been assessed in children and adolescents.
Purpose/Hypothesis:
To examine the association of GI and other MRI measurements of interest supported in studies on adults with anterior glenohumeral dislocation in patients aged ≤19 years. We hypothesized that these patients would have a significantly greater GI (relatively taller and narrower glenoid morphology) compared with healthy controls.
Study Design:
Case-control study; Level of evidence, 3.
Methods:
An institutional radiology database was queried over a 10-year period to identify patients aged ≤19 years who had been diagnosed with radiographically confirmed anterior shoulder dislocation and who underwent glenohumeral magnetic resonance arthrography as well as those without dislocation with normal shoulder arthrogram studies (controls). Patients with bony Bankart lesions were excluded. The following glenohumeral dimensions were measured on shoulder arthrogram: GI, glenoid version, coracohumeral interval, and rotator interval width/depth. Comparative analysis between the 2 groups was performed using the Student t test for each variable, followed by receiver operating characteristic (ROC) analysis to determine discriminative ability when statistically significant.
Results:
Overall, 55 participants (33 male and 22 female patients; mean age, 15.4 ± 2.1 years) were enrolled; 22 patients were in included in the dislocator group and 33 patients comprised the control group. The mean GI in the dislocator group was significantly greater than the control group (1.55 ± 0.14 vs. 1.38 ± 0.08; P < .001). ROC analysis revealed adequate discrimination of GI in predicting glenohumeral dislocation (area under the curve = 0.88). A GI ≥1.45 was 83% sensitive and 79% specific for predicting dislocation in the study cohort.
Conclusion:
Patients with anterior glenohumeral dislocation had increased GI (taller and narrower glenoid morphology) than controls. This useful MRI measurement may help identify patients at risk for primary or recurrent anterior glenohumeral instability events and may therefore help with guiding treatment and prevention.
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