Association Between Pterygium and Ocular, Periocular, and Systemic Inflammatory Conditions: a Large-Scale National Study.

PURPOSE: The purpose of this study was to examine the incidence of ocular, periocular, and systemic inflammatory conditions among patients with pterygium and assess if these conditions are risk factors of pterygium development. METHODS: A case-control study was conducted using electronic medical records from Clalit Health Services in Israel between 2001 and 2022. Patients diagnosed with pterygium were included; for each case, 3 controls were matched based on birth year, sex, and ethnicity. Mixed models were used to assess differences in the groups' demographic characteristics of ocular and systemic diseases. Generalized estimating equation logistic regression was used to estimate the odds ratios (ORs) and adjust for confounders. RESULTS: A total of 94,652 patients diagnosed with pterygium and 378,608 matched controls were included in the study. The average age of patients with pterygium was 53 ± 16 years; 54% were male. A significant association was found between pterygium and vernal keratoconjunctivitis (OR 2.12, 95% confidence interval [CI], 1.90-2.36), chronic allergic conjunctivitis (OR 1.69, 95% CI 1.58-1.82), blepharitis (OR 1.66, 95% CI 1.61-1.70), and chalazion (OR 1.27, 95% CI 1.23-1.33). A significant association was also found between pterygium and systemic conditions as unspecified systemic allergy (OR 1.08, 95% CI 1.04-1.13), asthma (OR 1.08, 95% CI 1.04-1.11), and atopic dermatitis (OR 1.14, 95% CI 1.08-1.19). CONCLUSIONS: Various inflammatory and allergic diseases-ocular, periocular, and systemic-increase the risk of pterygium. Further research is needed to investigate the role of inflammation in pterygium development.

The Risk of Rectal Temperature Measurement in Neutropenia.

BACKGROUND: Avoiding rectal thermometry is recommended in patients with neutropenic fever. Permeability of the anal mucosa may result in a higher risk of bacteremia in these patients. Still, this recommendation is based on only a few studies. METHODS: This retrospective study included all individuals admitted to our emergency department during 2014-2017 with afebrile (body temperature <38.3°C) neutropenia (neutrophil count <500 cells/microL) who were over the age of 18. Patients were stratified by the presence or absence of a rectal temperature measurement. The primary outcome was bacteremia during the first five days of index hospitalization; the secondary outcome was in-hospital mortality. RESULTS: The study included 40 patients with rectal temperature measurements and 407 patients whose temperatures were only measured orally. Among patients with oral temperature measurements, 10.6% had bacteremia, compared to 5.1% among patients who had rectal temperature measurements. Rectal temperature measurement was not associated with bacteremia, neither in non-matched (odds ratio [OR] 0.36, 95% confidence interval [CI] 0.07-1.77) nor in matched cohort analyses (OR 0.37, 95% CI 0.04-3.29). In-hospital mortality was also similar between the groups. CONCLUSIONS: Patients with neutropenia who had their temperature taken using a rectal thermometer did not experience a higher frequency of events of documented bacteremia or increased in-hospital mortality.

Are Periocular and Systemic Allergy Conditions Risk Factors for Pterygium?

PURPOSE: To evaluate risk factors for pterygium and prevalence of periocular and systemic diseases among patients with pterygium. METHODS: A retrospective case-control study was conducted among members of Clalit Health Services (CHS) in Israel, from 2001 to 2022. A total of 13,944 patients diagnosed with pterygium were included. For each case, three controls were matched among all CHS patients according to year of birth, sex, and ethnicity. Mixed models were used to assess differences in demographic characteristics, ocular and systemic diseases between the groups. Generalized estimating equation (GEE) logistic regression was used to estimate the odds ratios (OR) and adjust for confounders. RESULTS: The average age of pterygium patients was 49 ± 17 years; 51% were male. The results showed significant associations between pterygium and risk factors of vernal kerato-conjunctivitis (OR 2.52, 95% confidence interval [CI]: [1.96-3.24]), chronic allergic conjunctivitis (OR 1.98, 95% CI: [1.65-2.39]), blepharitis (OR 1.91, 95% CI: [1.78-2.04]), chalazion (OR 1.47, 95% CI: [1.30-1.67]) and unspecified systemic allergy (OR 1.21, 95% CI [1.09-1.34]), after adjusting for rural residency status. Glaucoma (OR 0.74, 95% CI [0.64-0.85]) and smoking (OR 0.70, 95% CI [0.66-0.75]) were protective factors against pterygium. CONCLUSION: Systemic and periocular inflammatory and allergic diseases are risk factors for pterygium.

Changes within the P681 residue of spike dictate cell fusion and syncytia formation of Delta and Omicron variants of SARS-CoV-2 with no effects on neutralization or infectivity.

The rapid spread and dominance of the Omicron SARS-CoV-2 lineages have posed severe health challenges worldwide. While extensive research on the role of the Receptor Binding Domain (RBD) in promoting viral infectivity and vaccine sensitivity has been well documented, the functional significance of the 681PRRAR/SV687 polybasic motif of the viral spike is less clear. In this work, we monitored the infectivity levels and neutralization potential of the wild-type human coronavirus 2019 (hCoV-19), Delta, and Omicron SARS-CoV-2 pseudoviruses against sera samples drawn four months post administration of a third dose of the BNT162b2 mRNA vaccine. Our findings show that in comparison to hCoV-19 and Delta SARS-CoV-2, Omicron lineages BA.1 and BA.2 exhibit enhanced infectivity and a sharp decline in their sensitivity to vaccine-induced neutralizing antibodies. Interestingly, P681 mutations within the viral spike do not play a role in the neutralization potential or infectivity of SARS Cov-2 pseudoviruses carrying mutations in this position. The P681 residue however, dictates the ability of the spike protein to promote fusion and syncytia formation between infected cells. While spike from hCoV-19 (P681) and Omicron (H681) promote only modest cell fusion and formation of syncytia between cells that express the spike-protein, Delta spike (R681) displays enhanced fusogenic activity and promotes syncytia formation. Additional analysis shows that a single P681R mutation within the hCoV-19 spike, or H681R within the Omicron spike, restores fusion potential to similar levels observed for the Delta R681 spike. Conversely, R681P point mutation within the spike of Delta pseudovirus abolishes efficient fusion and syncytia formation. Our investigation also demonstrates that spike proteins from hCoV-19 and Delta SARS-CoV-2 are efficiently incorporated into viral particles relative to the spike of Omicron lineages. We conclude that the third dose of the Pfizer-BNT162b2 provides appreciable protection against the newly emerged Omicron sub-lineages. However, the neutralization sensitivity of these new variants is diminished relative to that of the hCoV-19 or Delta SARS-CoV-2. We further show that the P681 residue within spike dictates cell fusion and syncytia formation with no effects on the infectivity of the specific viral variant and on its sensitivity to vaccine-mediated neutralization.

Functional Analysis of Spike from SARS-CoV-2 Variants Reveals the Role of Distinct Mutations in Neutralization Potential and Viral Infectivity.

Enhanced viral transmission and escape from vaccine-elicited neutralizing antibodies drive worldwide spread of SARS-CoV-2 variants and promote disease progression. However, the impact of specific spike mutations that are carried by different viral variants on viral infectivity and neutralization sensitivity has not been completely defined. Here, we use pseudoviruses to assess the contribution of spike mutations within the Receptor Binding Domain (RBD) and the Furin Cleavage Site (FCS), and appear in circulating viral variants, on viral infectivity and neutralization potential against sera that was drawn from fully vaccinated individuals. Our functional analysis demonstrates that single, P681H, P681R or A701V-FCS mutations do not play a role in viral infectivity and neutralization potential. However, when in conjunction with the RBD-N501Y mutation, viral infectivity is enhanced. Similarly, combining the E484K-RBD mutation to the spike that carries FCS mutations reduces neutralization sensitivity with no effects on viral infectivity. Employing a similar approach onto the spike from Delta or Lota SARS-CoV-2 variants further reveals that specific RBD mutations affect neutralization sensitivity or viral infectivity differently. Our results validate the efficacy of the Pfizer third dose vaccine against Delta and Lota SARS-CoV-2 variants, and outline the significance of distinct RBD mutations in promoting viral infectivity and neutralization sensitivity to post-vaccination sera.

Perinatal outcome and long-term infectious hospitalizations of offspring born to women with known drug allergy.

PROBLEM: Maternal drug allergy has been associated with altered immune status and an inflammatory environment, which may affect the risk of future infectious diseases in the offspring. OBJECTIVES: We aimed to evaluate perinatal outcomes and long-term infectious hospitalization in the offspring of women with documented drug allergy. METHOD OF STUDY: The study was conducted at the Soroka University Medical Center (SUMC), a tertiary medical center. For perinatal outcomes, generalized estimation equation (GEE) models were used controlling for maternal age, maternal diabetes mellitus, smoking, and hypertensive disorders. The study groups were followed until 18 years of age for infectious-related hospitalizations. A Kaplan-Meier survival curve was used to compare the cumulative incidence of long-term infectious hospitalizations. A Cox proportional hazards model was conducted to control for confounders. RESULTS: During the study period, 243 682 deliveries met the inclusion criteria, of which 9756 (4.0%) occurred in women with documented drug allergy. Using GEE, maternal drug allergy was found to be a significant independent risk factor for hypertensive disorders, diabetes mellitus, intra-uterine growth restriction (IUGR), and preterm delivery. Offspring also had significantly higher rates of long-term infectious hospitalizations. Kaplan-Meier survival curves demonstrated significantly higher cumulative incidence rates of infectious hospitalization (log-rank p < .001). In a Cox proportional hazards model, being born to a mother with documented drug allergy was independently associated with infectious hospitalization of the offspring in the long term. CONCLUSIONS: Maternal documented drug allergy is independently associated with an adverse perinatal outcome such as IUGR and preterm delivery and increased risk of long-term infectious hospitalization of the offspring.

SARS-CoV-2 spike variants exhibit differential infectivity and neutralization resistance to convalescent or post-vaccination sera.

Toward eradicating the COVID-19 pandemic, vaccines that induce high humoral and cellular immune responses are essential. However, SARS-CoV-2 variants have begun to emerge and raise concerns, as they may potentially compromise vaccine efficiency. Here, we monitored neutralization potency of convalescent or Pfizer-BTN162b2 post-vaccination sera against pseudoviruses displaying spike proteins derived from wild-type SARS-CoV-2, or its UK-B.1.1.7 and SA-B.1.351 variants. Compared to convalescent sera, vaccination induces high titers of neutralizing antibodies, which exhibit efficient neutralization potential against pseudovirus carrying wild-type SARS-CoV-2. However, while wild-type and UK-N501Y pseudoviruses were similarly neutralized, those displaying SA-N501Y/K417N/E484K spike mutations moderately resist neutralization. Contribution of single or combined spike mutations to neutralization and infectivity were monitored, highlighting mechanisms by which viral infectivity and neutralization resistance are enhanced by N501Y or E484K/K417N mutations. Our study validates the importance of the Pfizer vaccine but raises concerns regarding its efficacy against specific SARS-CoV-2 circulating variants.

SARS CoV-2 Delta variant exhibits enhanced infectivity and a minor decrease in neutralization sensitivity to convalescent or post-vaccination sera.

Since their identification, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Kappa and Delta have rapidly spread to become globally dominant. However, their infectivity and sensitivity to administered vaccines have not been documented. We monitored the neutralization potential of convalescent or BNT162b2 post-vaccination sera against Kappa and Delta SARS-CoV-2 pseudoviruses. We show that both variants were successfully neutralized by convalescent and post-vaccination sera, exhibiting a mild decrease in their neutralization sensitivity. Of the two variants, Delta presented enhanced infectivity levels compared with Kappa or wild-type SARS-CoV-2. Nevertheless, both variants were not as infectious or resistant to post-vaccination sera as the Beta variant of concern. Interestingly, the Delta plus variant (AY.1/B.1.617.2.1) exhibited high resistance to post-vaccination sera, similar to that of the Beta SARS-CoV-2. However, its infectivity levels were close to those of wild-type SARS-CoV-2. These results account for the worldwide prevalence of Delta variant of concern and confirm the efficacy of the BNT162b2 vaccine against circulating other Delta variants.

Continuous Remote Patient Monitoring Shows Early Cardiovascular Changes in COVID-19 Patients.

COVID-19 exerts deleterious cardiopulmonary effects, leading to a worse prognosis in the most affected. This retrospective multi-center observational cohort study aimed to analyze the trajectories of key vitals amongst hospitalized COVID-19 patients using a chest-patch wearable providing continuous remote patient monitoring of numerous vital signs. The study was conducted in five COVID-19 isolation units. A total of 492 COVID-19 patients were included in the final analysis. Physiological parameters were measured every 15 min. More than 3 million measurements were collected including heart rate, systolic and diastolic blood pressure, cardiac output, cardiac index, systemic vascular resistance, respiratory rate, blood oxygen saturation, and body temperature. Cardiovascular deterioration appeared early after admission and in parallel with changes in the respiratory parameters, showing a significant difference in trajectories within sub-populations at high risk. Early detection of cardiovascular deterioration of COVID-19 patients is achievable when using frequent remote patient monitoring.

Minor Clinical Impact of COVID-19 Pandemic on Patients With Primary Immunodeficiency in Israel.

In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. While human immunity against COVID-19 is not fully understood, it is, so far, well documented, that both adaptive and innate cells have a critical role in protection against SARS-CoV-2. Here, we aimed to summarize the clinical and laboratory data on primary immunodeficiency (PID) patients in Israel, who were tested positive for SARS-CoV-2, in order to estimate the impact of COVID-19 on such patients. Data was collected from mid-February to end-September. During this time Israel experienced two "waves" of COVID-19 diseases; the first, from mid-February to mid-May and the second from mid-June and still ongoing at the end of data collection. A total of 20 PID patients, aged 4 months to 60 years, were tested positive for SARS-CoV-2, all but one, were detected during the second wave. Fourteen of the patients were on routine monthly IVIG replacement therapy at the time of virus detection. None of the patients displayed severe illness and none required hospitalization; moreover, 7/20 patients were completely asymptomatic. Possible explanations for the minimal clinical impact of COVID-19 pandemic observed in our PID patients include high level of awareness, extra-precautions, and even self-isolation. It is also possible that only specific immune pathways (e.g. type I interferon signaling), may increase the risk for a more severe course of disease and these are not affected in many of the PID patients. In some cases, lack of an immune response actually may be a protective measure against the development of COVID-19 sequelae.

Neurofibromatosis type 1 and masses of the appendix: a case report.

BACKGROUND: Neurofibromatosis type 1 is an autosomal dominant disease with high penetrance, affecting 1:3,000 pregnancies. Meningiomas and other benign central nervous system tumors, such as ependymomas, are common features. CASE: A patient with neurofibromatosis underwent cesarean section due to intrauterine growth restriction and nonreassuring fetal heart rate patterns. Examination of the abdominal cavity and intestines revealed a large (diameter, 12 cm), rubbery, fibrin-coated appendicular mass. The appendix was removed, and pathologic analysis confirmed the diagnosis of neuroma of the appendix. CONCLUSION: The case stresses the importance of careful inspection and evaluation of the abdominal cavity during surgery on patients with neurofibromatosis for the detection of possible associated masses.

Primary Immune Deficiencies in the Adult: A Previously Underrecognized Common Condition.

The large majority of classified primary immune deficiency (PID) diseases present in childhood. Yet, most patients with PID are adults, with a large proportion experiencing onset of symptoms beyond their childhood years. Most of these are diagnosed predominantly with antibody defects, but cellular and other disorders are increasingly being identified in older patients as well. Moreover, advances in clinical immunology are allowing pediatric patients, even those with severe disease, to reach adulthood. Because of differences in the physiology and pathophysiology of children and adults, the presentation, diagnosis, and management of a complex chronic disease could differ significantly between these patient populations and therefore require modifications in approach.

Differential, positional-dependent transcriptional response of antigenic variation (var) genes to biological stress in Plasmodium falciparum.

1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome - expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes.

pfmdr2 confers heavy metal resistance to Plasmodium falciparum.

Heavy metals are required by all organisms for normal function, but high levels of heavy metals are toxic. Therefore, homeostasis of these metals is crucial. In the human malaria-causing agent Plasmodium falciparum, the mechanisms of heavy metal transport have yet to be characterized. We have developed a P. falciparum line resistant to heavy metals from a wild-type line sensitive to heavy metals. A molecular and biochemical analysis of the involvement of the P. falciparum multidrug resistance 2 (pfmdr2) gene, an ABC-type transporter, in heavy metal homeostasis was studied. Using a novel uptake assay applied on these two strains, it was demonstrated that, when exposed to heavy metals, the sensitive line accumulates metal, whereas no accumulation was observed in the resistant line. The accumulation occurs within the parasite itself and not in the cytoplasm of the red blood cell. This difference in the accumulation pattern is not a result of amplification of the pfmdr2 gene or of a change in the expression pattern of the gene in the two lines. Sequencing of the gene from both lines revealed a major difference; a stop codon is found in the sensitive line upstream of the normal termination, resulting in a truncated protein that lacks 188 amino acids that contain a portion of the essential cytoplasmatic transporter domain, thereby rendering it inactive. In contrast, the resistant line harbors a full-length, active protein. These findings strongly suggest that the PFMDR2 protein acts as an efflux pump of heavy metals.