Tightly clustered outbreak of group A streptococcal disease at a long-term care facility.

OBJECTIVE: To describe investigation of a tightly clustered outbreak of invasive group A streptococcal (GAS) disease associated with a high mortality rate in a long-term care facility (LTCF). DESIGN: Cross-sectional carriage survey and epidemiologic investigation of LTCF resident and employee cohorts. SETTING: A 104-bed community LTCF between March 1 and April 7, 2004. PATIENTS: A cohort of LTCF residents with assigned beds at the time of the outbreak. INTERVENTIONS: Reinforcement of standard infection control measures and receipt of chemoprophylaxis by GAS carriers. RESULTS: Four confirmed and 2 probable GAS cases occurred between March 16 and April 1, 2004. Four case patients died. The final case occurred during the investigation, before the patient was determined to be a GAS carrier. No case occurred during the 6 months after the intervention. Disease was caused by type emm3 GAS; 16.5% of residents and 2.4% of employees carried the outbreak strain. Disease was clustered in 1 quadrant of the LTCF and associated with nonintact skin. GAS disease or carriage was associated with having frequent personal visitors. CONCLUSIONS: Widespread carriage of a virulent GAS strain likely resulted from inadequate infection control measures. Enhanced infection control and targeted prophylaxis for GAS carriers appeared to end the outbreak. In addition to employees, regular visitors to LTCFs should be trained in hand hygiene and infection control because of the potential for extended relationships over time, leading to interaction with multiple residents, and disease transmission in such residential settings. Specific attention to prevention of skin breaks and proper wound care may prevent disease. The occurrence of a sixth case during the investigation suggests urgency in addressing severe, large, or tightly clustered outbreaks of GAS infection in LTCFs.     

Inflammatory pseudotumor of the lung — fibrous histiocytoma type

A 7 1/2-year-old girl with an inflammatory pseudotumor of the lung is presented. The nature of the lesion was not recognized pre-or intraoperatively. The lesion was rubbery, yellowish, and well-defined but not encapsulated. Histologically, a spindle-cell lesion with a storiform pattern and chronic inflammatory-cell infiltrate was seen. The immunological and ultrastructural studies supported an inflammatory origin. The lesion corresponds to the fibrous histiocytoma variant of inflammatory pseudotumor of the lung, as defined recently by Matsubara et al. [17]. This must be distinguished from rare benign neoplasms of the lung such as benign fibrous histiocytoma, leiomyoma, Schwannoma, and histiocytosis.     

A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

The genetic basis of congenital heart malformations associated with disruption of left–right (L–R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left–right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab‐Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left–right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.     

Preclinical evaluation and structural optimization of anti-BCMA CAR to target multiple myeloma

Chimeric antigen receptor (CAR) T-cell based immunotherapy has become a promising treatment mainly for hematological malignancies. Following the major success of CD19-targeted CAR, new potential targets for other malignancies are required. As such, B-cell maturation antigen (BCMA) is an attractive tumor-associated antigen to be targeted in multiple myeloma (MM). Herein, we aimed at assessing the function and optimal configuration of different BCMA-specific CAR, based on the same targeting moiety but with a different hinge and co-stimulatory domain. We compared their function to that of a previously characterized BCMA-CAR used in clinical trials. All constructs were expressed at high levels by primary human T cells and could trigger cytokine production and cytotoxicity upon co-culture with multiple myeloma targets. Nonetheless, critical differences were observed in off-target activation, exhaustion, and activation marker expression and in vivo anti-tumoral activity mediated by these different constructs. Interestingly, we noted that CD8-based hinge, combined with a 4-1BB intracellular domain, proved superior compared to IgG4-connecting regions, and/or a CD28-signaling moiety respectively. Overall, this study emphasizes the influence of CAR primary structure on its function and led to the identification of a highly efficient BCMA-specific CAR, namely H8BB, which displayed superior anti-tumoral activity both in vitro and long-term in vivo efficacy.     

Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine

BACKGROUNDThe significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of the BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.METHODSA multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 study groups: vaccinated (n = 86); PCR-confirmed SARS-CoV-2 infected during pregnancy (n = 65), and unvaccinated noninfected controls (n = 62). Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using the Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD, and N).RESULTSThe BNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer ratio at birth was significantly lower for third-trimester as compared with second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group.CONCLUSIONAntenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.FUNDINGIsrael Science Foundation and the Weizmann Institute Fondazione Henry Krenter.     

The impact of surgical extent and sex on the hepatic metastasis of colon cancer

Purpose

Extensive oncological surgeries were previously suggested to increase cancer recurrence rates. We herein studied the impact of different surgical procedures and sex on colorectal cancer liver metastasis, employing several tumor inoculation approaches in BALB/c mice.

Methods

Experimental hepatic metastases of the syngeneic CT26 colorectal cancer line were induced either by intra-portal inoculation or intra-splenic inoculation, employing different tumor loads. Following intra-splenic inoculation, the entire spleen or an injected hemi-spleen was removed. Additionally, the magnitude of the surgical trauma accompanying the injection procedure was manipulated.

Results

Increasing the surgical trauma by adding laparotomy or extending the length of the surgery and hypothermia did not significantly affect the number of liver metastases or liver weight for any of the injection methods and tumor loads. The development of metastasis was significantly greater in males than in females under all conditions studied—a difference not explained by the direct effects of sex hormones on in vitro CT26 proliferation or vitality.

Conclusion

Concurring with less controlled clinical observations, the surgical extensiveness did not significantly affect CT26 hepatic metastasis, potentially due to a ceiling effect of the surgical trauma on the metastatic process. The sexual dimorphism observed for the CT26 metastasis should be investigated in the context of surgical stress and considering anti-CT26 immunoreactivity.     

An early intervention programme had no detectable influence on the health status of people with musculoskeletal injuries following road traffic crashes: Comparative study

Objective

To compare the health status of people with minor injuries from road traffic crashes that are exposed to an early, active intervention programme (intervention group) with those receiving usual care (control group) over a 12 month period.

Design

Prospective comparative study using sequential cohorts.

Subjects

People presenting to hospital emergency departments with mild to moderate musculoskeletal injuries following road traffic crashes.

Main outcome measures

Physical Component Score (PCS) and Mental Component Score (MCS) of the Short Form 36 (SF-36) health status measure; Hospital Anxiety and Depression Scale (HADS) and the Functional Rating Index (FRI) recorded immediately post-crash, at 6 months and at 12 months after injury.

Results

There were 95 participants allocated to the control group and 98 allocated to the intervention group. Participants were enrolled at a mean of 9.3 days following the crash. There were no significant differences in baseline health measures between the groups. Apart from a small improvement in anxiety for the intervention group, there were no significant differences in health status between the groups. Twenty percent of participants in the intervention group received treatment from external healthcare providers that was inconsistent with the recommendations of the intervention programme.

Conclusions

The intervention programme failed to result in a clinically significant improvement in health outcomes compared with usual care. There is some evidence to suggest that the intervention had some psychological benefits, as evidenced by the small improvement in anxiety levels. Limited adherence, frequent use of co-interventions, or other factors (such as intervention content or intensity) may have reduced its effect.