Israel Medical Association Journal

Nail-patella syndrome (NPS, OMIM: #161200), also known as Fong disease, hereditary osteo-onychodysplasia (HOOD), and Turner-Kieser syndrome, is a rare pleiotropic, multisystemic condition with an estimated incidence of 1 per 50,000. It is characterized mainly by developmental defects of dorsal limb structures due to symmetrical mesodermal and ectodermal abnormalities. It manifests as a classic clinical tetrad of distal digital abnormalities and fingernail dysplasia, which are typically bilateral and symmetrical, hypoplasia or absence of the patella, presence of iliac horns, and elbow deformities. It can also affect other structures (e.g., tendons, ligaments, and muscles), and may impact ophthalmic (glaucoma, increased ocular pressure and subsequent blindness), renal (nephropathy), neurological, orthopedic, and gastrointestinal systems. NPS can lead to sensorineural hearing loss and vasomotor problems [1,2]. Clinical manifestations vary greatly in frequency and severity. The prognosis is relatively good when clinical features are mild and cause no disability. However, serious and even life-threatening complications can occur. NPS is usually clinically diagnosed based on physical examination and radiological imaging. Genetic testing and renal biopsy can also assist in diagnosis confirmation.

Postmortem sperm retrieval allows for the procreation of biological children using the sperm of a deceased male; however, the data on how to optimize this procedure and its potential long-term effect are limited. We searched medical databases (PUBMED and Cochrane) and performed a systematic review of articles published from the databases' inception until December 2023. Case reports, case studies, and reviews reporting on and investigating the methodology and outcome of postmortem sperm retrieval were included. The primary search yielded 98 publications. After assessing eligibility and evaluating with a quality assessment tool, 17 articles remained, including 11 single case reports and 6 case series. Overall, 103 clinical cases of posthumous sperm retrieval were identified, and eight deliveries were reported. Most publications lacked information regarding the conditions to which the bodies were exposed before postmortem sperm retrieval. Moreover, sperm viability assessment was not performed routinely, and there was no examination of the potential genetic and epigenetic damage that may have occurred. Currently, there is a lack of standardization for postmortem sperm retrieval procedures. The lack of specific information regarding the potential hypoxic damage to the viable sperm cells may limit the safety of using these cells for procreation. These gaps in our current knowledge are relevant and should be expressed in the informed consent given to the potential users.

Background: Molybdenum cofactor deficiency (MoCD) is a group of three autosomal recessive disorders caused by deficiency of the de novo metabolic synthesis of molybdenum cofactor. Most patients present within the first weeks of life with intractable seizures and progressive encephalopathy. Type A is the most common form caused by pathogenic variants in MOCS1 gene that result in deficiency of the first enzyme, cyclic pyranopterin monophosphate synthase.

Objectives: To characterize MoCD type A clinical features, disease course, neuroradiology, and genetic features in Northern Israel.

Methods: In this retrospective study, we collected the clinical, brain imaging, and genetic data of confirmed MoCD type A patients in Northern Israel.

Results: The study included 10 confirmed MoCD type A patients (6 males, 4 females), all deceased. The patients were of consanguineous families. Nine patients were of Arab Muslim ethnicity and one was of Druze origin. A total of four different homozygous genotypes were identified. All patients presented initially between 1–4 days of life. Three died within the first month of life, five within the first year of life, and only two died after the age of 7 years. All patients who survived beyond the first month developed profound global developmental delays, had poorly controlled epilepsy, and developed severe microcephaly.

Conclusions: Although MoCD type A is an ultra-rare disease worldwide, it is relatively common in northern Israel due to several founder mutations and high consanguinity. All the patients presented the severe neonatal form of the disease with significant neurological deterioration and early lethality within infancy and childhood.

Background: Chest radiograph is a standard procedure for diagnosis of pneumonia; however, interpretation shows considerable variability among observers.

Objectives: To assess the extent of agreement between pediatric residents and board-certified radiologists in interpretation of chest radiography for detection of pneumonia. To evaluate the impact of resident experience, patient age, and signs of infection on this phenomenon.

Methods: The cohort included 935 patients with suspected pneumonia admitted to the pediatric emergency department at a non-tertiary medical center in Israel 2019–2021. All patients had chest radiographs interpreted by a resident and a radiologist. Interobserver agreement was assessed using Κ and prevalence-adjusted bias-adjusted κ (PABAK) with 95% confidence intervals (95%CI). Results were stratified by resident experience (junior or senior), patient age (≤ 3 vs. > 3 years), white blood cells (≤ 15,000 vs. > 15,000 cells/ml), C-reactive protein (≤ 5 vs. > 5.0 mg/dl), and temperature (< 38.0°C vs. ≥ 38.0°C).

Results: Moderate agreement between pediatric residents and radiologists was demonstrated for diagnosis of pneumonia (κ= 0.45). After adjustment for disease prevalence, the extent of agreement increased to near-substantial (PABAK= 0.59, 95% confidence interval 0.54–0.64). The extent of agreement was higher for children over 3 years of age and in patients without clinical or biochemical features of pneumonia, especially when diagnosis of pneumonia was ruled out.

Conclusions: A second reading of chest radiographs by an experienced radiologist should be considered, particularly for patients younger than 3 years of age and in those with signs of infection and an initial diagnosis of pneumonia.

Background: Understanding medical guidelines can be challenging for patients and their families, leading to incorrect use or dosages due to inadequate or unclear explanations. Graphic organizers are tools that can help improve comprehension of medical guidelines.

Objectives: To assess the effectiveness of using designed graphic organizers to enhance comprehension of medical guidelines.

Methods: A prospective randomized controlled study was conducted at Soroka University Medical Center between 2015 and 2017. Parents of children aged 1–7 years, admitted for asthma exacerbation requiring the use of an inhaler with a spacer or for febrile convulsion requiring rectal diazepam, were enrolled. Participants were randomly assigned to receive instructions through a graphic organizer (intervention group) or plain text (control group). An assessment form was administered to evaluate the understanding of the correct steps for using the inhaler with a spacer or administering rectal diazepam. A follow-up telephone assessment was conducted after 30–60 days to evaluate recollection.

Results: Seventy-four parents with similar demographic characteristics were enrolled (intervention group [38], control group [36]). There was no significant difference in comprehension between the two groups when using medical guidelines for the two interventions. However, there was a correlation between maternal education level and long-term recollection, with an average score of 24%, 42%, and 48% among mothers with less than 8 years, 8–12 years, and over 12 years of education, respectively (P = 0.004).

Conclusions: The use of graphic organizers did not improve parent comprehension of pediatric medical guidelines. However, long-term recollection was positively correlated with maternal education level.

Background: Wilson disease (WD) is an autosomal recessive disease characterized by a defect in hepatocellular copper transport with a wide spectrum of clinical manifestations and reported prevalence.

Objectives: To study the epidemiology and clinical manifestations of WD between two ethnic groups, Jewish and Bedouins, with different marriage patterns, in southern Israel.

Methods: We conducted a retrospective study investigating the clinical course and laboratory characteristics of children diagnosed with WD who were treated at Soroka University Medical Center.

Results: Sixteen patients were diagnosed between 2000 and 2021 (8 males, 50%), 14 were of Bedouins origin. The total cohort prevalence was 1:19,258 while the prevalence of the disease was significantly higher among Bedouins compared to Jews (1:10,828 vs.1:78,270, P-value = 0.004). The median age at diagnosis was 10.2 years, without a significant difference between the groups. The most common presenting symptom was hepatic manifestations: 81.2% had elevated transaminases, 12.5% had jaundice, 25% had neurological symptoms, one had a Kayser-Fleischer ring, and one had psychosis. The mean ceruloplasmin level was 3.0 mg/dl. During follow-up, nine patients normalized transaminases with treatment, while three required liver transplantation. There was no significant difference in the clinical presentation and disease course between the two ethnic groups.

Conclusions: Our cohort showed a high prevalence of WD compared to previous studies, especially among the Bedouin population, which has a high consanguinity rate. The prognosis of WD in our population is similar to other studies and depends mainly on treatment compliance.

Background: Acute bronchiolitis, primarily caused by respiratory syncytial virus (RSV), is the leading cause of hospitalization in young children. Despite international guidelines supporting clinical diagnosis, laboratory evaluations are often conducted with limited validity.

Objectives: To evaluate the association between C-reactive protein (CRP) serum levels on admission and disease severity in children hospitalized due to RSV bronchiolitis.

Methods: This retrospective cohort study included children (0–24 months old) who were hospitalized due to RSV bronchiolitis (2018–2022), CRP levels taken at admission.

Results: We included 1874 children (mean age of 6.7 months, 59% males); median CRP level 1.92 mg/dl. Children with elevated CRP (> 1.92 mg/dl) were significantly older (5.1 vs. 3.8 months, P < 0.001) and had higher rates of pneumonia (9.4% vs. 4.3%, P < 0.001), urinary tract infection (UTI), (2.2% vs. 0.2%, P < 0.001), acute otitis media (AOM) (1.7% vs. 0.2%, P < 0.001), admissions to the pediatric intensive care unit (PICU) (7.4% vs. 3.7%, P < 0.001), antibiotic treatment (49.8% vs. 37.2%, P < 0.001), and longer hospitalizations (3.83 vs. 3.31 days, P < 0.001). Multivariable analysis predicted increased risk for UTI, PICU admission, pneumonia, and longer hospitalization (relative risk 11.6, 2.25, 1.98, 1.44, respectively, P < 0.001). CRP thresholds of 3.51, 1.9, and 2.81 mg/dl for PICU admission, UTI, and pneumonia, were calculated using Youden's index with AUC 0.72, 0.62, and 0.61, respectively.

Conclusions: Elevated CRP levels at admission are associated with increased disease severity and higher complication rates in children hospitalized with RSV bronchiolitis.

A full-term 1-month-old female was brought to our pediatric emergency department (ED) due to 3 days of increasing respiratory distress. She was born at term to healthy, consanguineous (2nd degree) Bedouin parents after a pregnancy that lacked adequate monitoring. At birth, a physical examination revealed an imperforate anus and a recto-vestibular fistula, left hydronephrosis, large patent ductus arteriosus (PDA), and an atrial septal defect (ASD). The diagnosis of VACTER association was made. Importantly, she had no respiratory difficulties, nor hemivertebra or tethered cord.

On admission to the ED, she presented with severe respiratory distress, tachypnea, dyspnea, and hypoxemia without evidence of upper airway obstruction or stridor. Due to impending respiratory failure, she was transferred to the pediatric intensive care unit and started on non-invasive respiratory support through a high-flow nasal cannula (HFNC), which partially relieved her work of breathing. The nasal swab for respiratory viruses was positive for enterovirus, and her urine culture grew Escherichia coli. She was transferred to the pediatric ward after clinical improvement on day 3. Echocardiography performed for evaluation of pulmonary hypertension estimated normal pressures but revealed a vascular ring anomaly. A computed tomography (CT) angiography performed confirmed the presence of an aberrant left pulmonary artery also referred to as a left pulmonary artery sling (LPAS) [Figure 1A].

Anorexia nervosa (AN) is a common psychiatric disorder primarily affecting adolescents and young adults. It is characterized by extreme restriction of food intake, distorted body image, and weight-gain anxiety. We report a case with rapid progression and severe metabolic changes in a young restrictive-type AN patient, highlighting unique aspects of this presentation and discussing pathophysiology.

An 11-year-old girl presented with a significant 29% weight loss over 4 months, leading to a body mass index (BMI) of 11.7 (< 1st BMI percentile for her sex and age). She presented with severe bradycardia and metabolic abnormalities including hypoglycemia, hypercholesterolemia, and hypothyroidism. Following diagnosis with restrictive type AN based on the DSM-5 [1] criteria and stabilization at our department, she was transferred to a specialized unit. The hypercholesterolemia our patient presented with is more typical of binge-eating/purging subtype AN, yet it was markedly elevated in this restrictive-type case.

Inborn errors of immunity (IEI), formerly known as primary immunodeficiencies (PID), comprise a diverse group of genetic disorders characterized by increased susceptibility to infections, autoimmunity, autoinflammatory conditions, allergies, and malignancies. These disorders exhibit a broad spectrum of clinical manifestations, including extra-hematopoietic manifestations, which may also present later in life. IEI diagnosis has significantly advanced, in line with the common use of next-generation sequencing-based genetic platforms, such as whole-exome and whole-genome sequencing. Treatment approaches have evolved beyond infection management to include curative therapies such as hematopoietic stem cell transplantation, gene therapy, and targeted pharmacologic treatments. In this review, we explore recent advancements in the understanding, diagnosis, and treatment of IEI, emphasizing the rapid progress in this expanding field.

Gaucher disease (GD) is an inherited autosomal recessive genetic disorder caused by mutations in the glucocerebroside (GBA1) gene [1]. These variants result in decreased activity of the lysosomal enzyme β-glucocerebrosidase (GCase), which is essential for breaking down glucocerebroside into glucose and ceramide. Consequently, activated macrophages, known as Gaucher cells, accumulate undegraded glucocerebroside. The phagocytic role and naturally high-level GCase activity of macrophages may partly explain why these cells are particularly affected in GD. The accumulation of glucocerebroside in macrophages causes an expansion in the population of these cells, leading to symptoms like hepatosplenomegaly, thrombocytopenia, anemia, bleeding tendency, growth retardation, and bone issues. Bone marrow infiltration may result in bone infarction, episodes of bone crises, and osteonecrosis, mainly of large joints and less commonly as pathological fractures. These latter skeletal complications are the most critical irreversible consequence of untreated GD, significantly impacting the quality of life of patients, and hence should be avoided by early administration of specific therapy. The accumulation of glucocerebroside in lysosomes has been linked to a pro-inflammatory state [2]. In addition, the misfolding and retention of mutant GCase within the endoplasmic reticulum (ER) has been associated with ER stress and activation of the unfolded protein response, contributing to GD phenotypic heterogeneity, inflammation, and immune dysregulation [3].

Background: Coronavirus disease 2019 (COVID-19) is a respiratory illness with broad spectrum of clinical manifestations ranging from asymptomatic cases to severe complications such as acute respiratory failure, multi-organ dysfunction, and death.

Objectives: To evaluate the platelet-lymphocyte ratio (PLR) as a marker of disease severity and mortality in COVID-19 patients. To explore the relationship between PLR and other inflammatory indicators, specifically C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR).

Methods: The cohort included 400 patients (206 males, 194 females; mean age: 64.5 ± 17.1 years [range 20–100 years]) who were hospitalized between April 2020 and December 2021. Data were collected on demographic and clinical characteristics, including ward and critical care details. CRP, NLR, and PLR values were recorded on the first and last days of hospitalization. Patients were categorized based on their hospitalization outcomes.

Results: PLR statistically increased during hospitalization, from 245 ± 160 at admission to 341 ± 747 at discharge (P < 0.001). A significant association was found between PLR and both the length of hospital stay and mortality. The mean PLR in the deceased group was 445 ± 590, compared to 304 ± 795 in the survivors, P = 0.007. This finding showed a correlation between higher PLR and increased severity and mortality.

Conclusion: PLR has been identified as a relevant marker for assessing the severity of COVID-19. Elevated PLR levels are associated with cytokine storm, length of hospital stay, and mortality. The results highlight the relationship between elevated PLR and poor outcome in COVID‐19 patients, suggesting its use in monitoring disease progression and prognosis.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease pathway is heavily influenced by different inflammatory cytokines. There is ample evidence of cannabidiol (CBD) immunomodulation effects.

Objectives: To investigate the effect of CBD on patients with SARS-CoV-2 and to measure the impact on inflammatory cytokines.

Methods: A double blind, placebo-controlled study to compare the clinical outcomes and selected serum cytokine levels in patients with SARS-CoV-2 that received sublingual CBD extraction. Seven patients were randomized to the treatment arm and three to the placebo group.

Results: Clinical outcomes were better in the patient group that received sublingual CBD vs. patients receiving placebo treatment. Serum cytokine mean concentration levels showed differences between the two groups but of mixed trends.

Conclusions: Patients presenting with SARS-CoV-2 and receiving CBD sublingually had better outcomes than those receiving a placebo, although these results did not reflect in selected serum cytokines. Further study is needed.

Background: Burnout is prevalent among healthcare providers and characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment. The coronavirus disease 2019 (COVID-19) pandemic exacerbated burnout due to increased workloads, emotional strain, and heightened risk. Complementary medicine (CAM) interventions like shiatsu massage and reflexology have been explored as potential to mitigate burnout, particularly pandemic-related stress.

Objectives: To assess the efficacy of CAM interventions for alleviating burnout in healthcare providers treating COVID-19 patients during 2022, when the Delta variant was prevalent.

Methods: This prospective observational study included 86 healthcare providers at Rabin Medical Center, Beilinson Campus. Workers were divided into two groups: an intervention group participating in CAM activities and a control group. Participant burnout and post-traumatic stress disorder (PTSD) symptoms were evaluated using the Maslach Burnout Inventory and General Anxiety Disorder 7 at baseline and at one day and one week post-intervention.

Results: The CAM group demonstrated significant reduction in burnout scores, primarily due to an enhanced sense of accomplishment (P = 0.023), with enduring effects observed after one week, although not reaching statistical significance (P = 0.078). There was no observed difference in PTSD scores between the groups (P = 0.28).

Conclusions: The study reveals potential benefits of CAM interventions in reducing burnout symptoms among healthcare providers during the COVID-19 pandemic. The findings underscore the importance of integrating such interventions to address the mental well-being of healthcare providers, especially in high-stress environments. Further randomized controlled trials with diverse samples and extended follow-up are recommended to validate and explore these initial findings.

Background: Several studies have shown an association between increased red blood cell distribution width (RDW) and adverse outcomes in various acute diseases. Small studies have suggested that RDW is a useful predictor of acute pancreatitis severity.

Objectives: To determine the association between RDW at admission and early mortality in acute pancreatitis. To assess whether RDW adds to the predictive ability of the Glasgow Imrie Score.

Methods: In this observational study, we included all adult patients admitted with a primary diagnosis of acute pancreatitis between January 2008 and June 2021. Patients were divided into two groups according to RDW: normal RDW (RDW ≤ 14.5%) and elevated RDW (RDW > 14.5%).

Results: Within 30 days of admission, 29/438 patients (6.6%) with increased RDW and 20/1250 patients (1.6%) with normal RDW had died: univariate analysis (odds ratio 4.6, 95% confidence interval 2.45–7.9, P < 0.001), fully adjusted model (odds ratio 3.29, 95% confidence interval 1.75–6.26, P < 0.001). We calculated receiver operating characteristic curve (ROC) for RDW alone, Glasgow Imrie Score alone, and a combination of Glasgow Imrie Score with RDW. We assessed their ability to predict 30-day mortality. Area under the ROC curve (AUC) of RDW alone was 0.671 and Glasgow Imrie Score AUC was 0.682; Glasgow Imrie Score plus RDW had an AUC of 0.769.

Conclusions: In patients with acute pancreatitis, elevated RDW at admission was independently associated with increased 30-day mortality. The addition of RDW to a pancreatitis prognostic tool such as the Glasgow Imrie Score improves its predictive ability.