A common benign intronic deletion masking a pathogenic deep intronic PCCB variant - genome sequencing and RNA studies to the rescue.

Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by variants in PCCA or PCCB, both sub-units of the propionyl-CoA carboxylase (PCC) enzyme. PCC is required for the catabolism of certain amino acids and odd-chain fatty acids. In its absence, the accumulated toxic metabolites cause metabolic acidosis, neurologic symptoms, multi-organ dysfunction and possible death. The clinical presentation of PA is highly variable, with typical onset in the neonatal or early infantile period. We encountered two families, whose children were diagnosed with PA. Exome sequencing (ES) failed to identify a pathogenic variant, and we proceeded with genome sequencing (GS), demonstrating homozygosity to a deep intronic PCCB variant. RNA analysis established that this variant creates a pseudoexon with a premature stop codon. The parents are variant carriers, though three of them display pseudo-homozygosity due to a common large benign intronic deletion on the second allele. The parental presumed homozygosity merits special attention, as it masked the causative variant at first, which was resolved only by RNA studies. Arriving at a rapid diagnosis, whether biochemical or genetic, can be crucial in directing lifesaving care, concluding the diagnostic odyssey, and allowing the family prenatal testing in subsequent pregnancies. This study demonstrates the power of integrative genetic studies in reaching a diagnosis, utilizing GS and RNA analysis to overcome ES limitations and define pathogenicity. Importantly, it highlights that intronic deletions should be taken into consideration when analyzing genomic data, so that pseudo-homozygosity would not be misinterpreted as true homozygosity, and pathogenic variants will not be mislabeled as benign.

Ethical Dilemma: Elexacaftor-Tezacaftor-Ivacaftor or Lung Transplantation in Cystic Fibrosis and End-Stage Lung Disease?

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of this disease. We present an ethical dilemma involving an 11-year-old child with CF and end-stage lung disease. Shortly after starting treatment with elexacaftor-tezacaftor-ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other are limited. A survey of CF center team members was conducted for the purpose of this article. Ethical principles that may guide us in these situations are discussed. Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared with other team members, are more likely to provide a specific recommendation vs presenting the information to the family and letting them decide (OR, 4.0; 95% CI, 1.2-12.8; P = .021). A shared decision-making model, stressing our moral obligation as physicians to respect autonomy by appreciating family values, while offering to participate in the decision-making process and ensuring nonmaleficence, is presented. In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. The current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making, which is focused on respecting autonomy, is our preferred approach in these situations.

Increased prevalence of attention-deficit hyperactivity disorder symptomatology in patients with familial Mediterranean fever.

OBJECTIVES: Previous studies suggest that exposure to inflammation in infancy may increase the risk for attention-deficit and hyperactivity disorder (ADHD). We studied the ADHD manifestations among 124 familial Mediterranean fever (FMF) patients and examined the relationship between FMF patient characteristics and ADHD. METHODS: Clinical, demographic, and genetic data were abstracted from patients' medical records and supplemented by information obtained during clinic visits. ADHD manifestations were assessed using the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) questionnaire. RESULTS: ADHD was diagnosed in 42 (32.8%) FMF patients, a rate significantly higher than in unselected populations (∼8%). A majority (n = 27, 64.3%) had combined inattentive, hyperactive-impulsive manifestations. Eight (19%) had predominantly hyperactive-impulsive, and seven (16.6%) had predominantly inattentive symptoms. FMF patients with severe manifestations reported more ADHD symptoms. FMF patients with ADHD symptoms were less adherent to their treatment regimen, with only 61.9% of the patients with ADHD symptoms adhering to colchicine therapy compared to 92.7% of the patients without ADHD symptoms. CONCLUSION: The high prevalence of ADHD characteristics in children with FMF may support the neuroimmune hypothesis that chronic inflammation increases the risk for ADHD. Children with FMF should be screened for ADHD as its presence may adversely affect adherence to treatment.

Discontinuation of Colchicine Therapy in Children With Familial Mediterranean Fever.

OBJECTIVE: Colchicine has been considered a lifelong therapy for familial Mediterranean fever (FMF). Recent studies describe patients who discontinued colchicine, but there is a lack of data pertaining to predictors of success. The aims of our study were to describe a cohort of pediatric patients with FMF who discontinued colchicine therapy, and to identify factors predicting successful termination of colchicine. METHODS: This study describes a cohort of pediatric patients with FMF who discontinued colchicine therapy following a relatively prolonged attack-free period (> 6 months), and identifies factors predicting successful termination. Data collected included demographic, clinical, and laboratory characteristics of children diagnosed with FMF aged < 16 years who underwent a trial of colchicine discontinuation. Data from patients who successfully ceased colchicine therapy were compared to those of patients who relapsed. RESULTS: Of 571 patients with FMF, 59 (10.3%) discontinued colchicine therapy. The average attack-free period before enrollment was 0.97 ± 1.4 years. Follow-up after ceasing colchicine was 5.0 ± 3.05 years, during which time 11 (20%) patients had an attack. The most common symptoms were fever (100%) and abdominal pain (80%). For those failing discontinuation, colchicine was restarted within 1.3 years (range 0.3-5.0, median 0.7 yrs). A longer attack-free period prior to colchicine discontinuation predicted success. Myalgia and arthritis prior to colchicine cessation were more common among children who required renewal of colchicine. CONCLUSION: Cessation of colchicine therapy should be considered following prolonged remission in a select group of patients. Patients with arthritis or myalgia are more likely to have an attack after ceasing colchicine therapy.

Moderate Gastrointestinal Complications Due to "Superglue" Ingestion in a Pediatric Patient.

ABSTRACT: Childhood cases of cyanoacrylates generally do not cause moderate or severe gastrointestinal complications. We report the case of a 3-year-old boy referred to our pediatric emergency room and admitted to the pediatric department with signs of upper gastrointestinal obstruction that required invasive intervention. Although it is rare, cyanoacrylate ingestion may injure esophageal and gastric mucosa in the pediatric population.

Coronavirus and People with Intellectual Disabilities: A Special Perspective.

BACKGROUND: The attention of the world is focused on the coronavirus disease-2019 (COVID-19) pandemic. There is s general awareness that certain population groups are at greater risk. However, some other populations may be transparent and may not be receiving the attention they warrant. We focused on those with intellectual disability explaining why they are vulnerable during the current pandemic and require special attention.

The science of hope.

Hope is a contextual term that has different connotations depending on the setting. We analyse the concept of hope with respect to its applicability for oncology. We review studies that present hope as a direct or secondary mediator of outcome. We posit that an individual's level of hope is often determined by innate personality characteristics and environmental factors, but can also be physiologically influenced by immune modulators, neurotransmitters, affective states, and even the underlying disease process of cancer. We argue that hope can be a therapeutic target and review evidence showing the effects of hope-enhancing therapies. Given the potential for hope to alter oncological outcomes in patients with cancer and the opportunity for improvement in quality of life, we suggest further research directions in this area.

Fetal alcohol spectrum disorder among pre-adopted and foster children.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disorders. Children in foster care or domestically adopted are at greater risk for FASD. The aim of this study was to determine the prevalence or risk for FASD in a selected population of foster and adopted children. METHODS: Children between 2 and 12 years who were candidates for adoption in foster care were evaluated for clinical manifestations and historical features of fetal alcohol spectrum disorder based on established criteria for FASD. RESULTS: Of the 89 children evaluated, 18 had mothers with a confirmed history of alcohol consumption during pregnancy. Two children had fetal alcohol syndrome and one had partial fetal alcohol syndrome. In addition, five had alcohol-related neurodevelopmental disorder, one had alcohol-related birth defects, and a single child had manifestations of both. Of the 71 children in which fetal alcohol exposure could not be confirmed, many had manifestations that would have established a diagnosis of FASD were a history of maternal alcohol consumption obtained. CONCLUSIONS: In a population of high-risk children seen in an adoption clinic, many had manifestations associated with FASD especially where prenatal alcohol exposure was established. The reported prevalence in this study is higher than that reported in our previous study of younger children. This is most likely due to the higher number of children diagnosed with alcohol-related neurodevelopmental disorders that typically manifest at an older age.

Hospice Care: Hope and Meaning in Life Mediate Subjective Well-Being of Staff.

OBJECTIVES: Subjective well-being has been associated with decreased work burnout and elevated work engagement. We investigated the impact of hope and meaning in life on subjective well-being among workers in a hospice care setting. Comparison was made to health-care workers in a rehabilitation unit. METHODS: Thirty-five hospice care workers were surveyed and their responses compared with those of 36 rehabilitation workers. Survey instruments measuring hope, meaning in life, work engagement, and satisfaction with life were utilized. RESULTS: Individuals working in a hospice care center have significantly higher levels of work engagement than their counterparts in rehabilitation. For both groups, hope was significantly related to subjective well-being. For hospice care but not rehabilitation workers, meaning in life was also related to subjective well-being. Multivariate analysis showed that hope and meaning in life were independent factors predicting subjective well-being in hospice care workers. SIGNIFICANCE OF RESULTS: Hospice care workers are highly engaged in their work despite the challenging nature of their work. What characterizes these workers is a level of subjective well-being that is related to both meaning in life and hope. Maintaining a high level of subjective well-being may be an important factor in preventing burnout among those working in hospice care settings.

Pyogenic sacroiliitis in children: don't forget the very young.

Pyogenic sacroiliitis (PS) is rare with less than 100 pediatric cases reported in the medical literature. To better characterize PS in the pediatric population, we investigated a series of children presenting with PS. Retrospective data analysis was done at an academic tertiary center between the years of 2000 and 2017. All hospitalized children ≤ 16 years of age with PS were evaluated. Of the 894 children hospitalized with osteoarticular infections, 18 were diagnosed with PS (2%) and are included in the review. Two clinically distinct groups were identified. PS in infants (n = 13, 72.2%, mean age 1.1 years) had an indolent course and a faster recovery without any bacterial source identified. In contrast, the group of older children (n = 5, 27.8%, mean age 11.6 years) had a more complicated course and a higher rate of identified bacterial infections.Conclusion: We describe an under-recognized entity of PS in infants with a mild clinical course and fast recovery that differ from the "classical" septic sacroiliitis. Infants with PS did not suffer from invasive complications, and pathogen characteristics of older children were not identified. Infants with fever, irritability, decreased range of motion in the pelvic area, and pain during diapering should alert the clinician to this diagnosis. What is Known: • Pediatric pyogenic sacroiliitis is an extremely rare condition usually caused by Staphylococcus aureus with highest incidence in adolescents. • The diagnosis of PS is challenging due to its rarity and difficulty in assessing the sacroiliac joint. What is New: • We describe an under-recognized entity of PS in infants with a mild clinical course, without invasive complications and with fast recovery that differ from "classical" septic sacroiliitis. • Infants with fever, irritability, decreased range of motion in the pelvic area and pain during diapering should raise clinical suspicion of this diagnosis.

Recoverable, Record-High Lactic Acidosis in a Patient with Glycogen Storage Disease Type 1: A Mixed Type A and Type B Lactate Disorder.

A 17-year-old patient with GSD type 1a (von Gierke disease) was hospitalized with an extremely elevated serum lactate following an intercurrent infection and interruption of his frequent intake of carbohydrates. The patient developed shock, oliguric renal failure, and cardiorespiratory failure requiring mechanical ventilation and inotropes. At the peak of metabolic decompensation and clinical instability, serum lactate reached a level of 47.6 mmol/L which was accompanied by a severe anion gap metabolic acidosis with a pH of 6.8 and bicarbonate of 4 meq/L. The patient was stabilized with massive infusions of sodium bicarbonate (45 meq/h) and glucose and recovered without the need for dialysis. This patient illustrates pathophysiologic mechanisms involved in the development of extreme mixed type A and type B lactic acidemia, reflecting altered metabolic pathways in GSD type 1, combined with tissue hypoperfusion. The rationale for the specific interventions in this case is outlined.

Sudden onset unexplained encephalopathy in infants: think of cannabis intoxication.

UNLABELLED: The use of cannabis as both a therapeutic agent and recreational drug is common, and its availability is increasing as a result of legalization in many countries. Among older children, the manifestations of cannabis intoxication are numerous and include both neurological and systemic manifestations that are frequently non-specific. There have been only a few reports detailing cannabis intoxication in infants and toddlers. We describe three infants who presented to the emergency department with encephalopathic signs without prominent systemic manifestations. During the initial interview of caregivers, no history of exposure to neurotoxic agents was obtained. All three patients were subsequently diagnosed with cannabis intoxication based on urine toxic screens for delta-9-tetrahydrocannabinol (THC). The infants recovered with supportive care that included fluids and monitoring. The non-specific symptomatology of cannabis intoxication in infants together with the wide differential for unexplained acute onset encephalopathy may delay diagnosis and lead to inappropriate procedures and interventions such as antimicrobial treatments and imaging studies. CONCLUSION: Healthcare personnel of emergency rooms, urgent care centers, and general clinics should be aware of the potential risk of cannabis ingestion in young infants. A thorough medical history and toxic screen are warranted in all infants with unexplained decreased sensorium.

Hospitalization of children with down syndrome.

INTRODUCTION: Children with Down syndrome present with multiple medical problems in a higher prevalence compared with the general population, which may lead to hospitalizations. METHODS: Analysis of 560 hospitalizations of 162 children aged 0-16 years with Down syndrome at Hadassah Medical Center during the years 1988-2007 compared with data on children in the general population, hospitalized at the same period. Data was collected from patient files and statistical data from the Ministry of Health. RESULTS: Respiratory infections were the leading cause for hospitalization of children with Down syndrome. The number of hospitalizations of children with Down syndrome compared to the number of all children, who were hospitalized was surprisingly similar to their proportion in the general population. Eleven children died during their hospitalization (five heart failure, three sepsis, one respiratory tract infection, and one due to complication after surgery). Nine of the 11 had a congenital heart anomaly. CONCLUSION: Children with Down syndrome can present with complex medical issues and we support the concept of a multidisciplinary team that has experience and knowledge to serve as a "one stop shop" for these individuals and their families, with timely visits in which a comprehensive evaluation is performed, problems attended to and prevention plans applied. In this way, we may prevent morbidity, hospitalizations, and mortality.

Israeli Dying Patient Act: physician knowledge and attitudes.

OBJECTIVES: The recently enacted Israeli Dying Patient Act was designed to strike balance between enhancing patient autonomy in end-of-life decision making and cultural/religious norms that are in opposition to active euthanasia and physician-assisted suicide (PAS). The current study evaluated physician attitudes regarding active and passive euthanasia, and their knowledge of specific aspects of the law. METHODS: A survey was administered to a convenience sample of hospital-based physicians treating terminal patients. Physicians were queried about their attitudes regarding euthanasia and PAS. Physicians were also queried about specific aspects of the law and whether they had sufficient resources to uphold the law. RESULTS: Surveys were distributed to 270 physicians and 100 were returned and evaluated (37%). Nearly all physicians supported passive euthanasia (withholding treatment), whereas over 40% maintained that active forms of euthanasia should be allowed for terminal patients in severe physical pain. Multivariate analysis showed a negative relationship between support for more active forms of euthanasia and physicians' self-reported religiosity. Physicians cited lack of time as a reason for not complying with the new law. Physicians had a familiarity with the general aspects of the new legislation, but a large proportion was not aware of the specifics of the law. CONCLUSIONS: Compared with previous surveys, a larger number of physicians support passive euthanasia. A sizable percentage of physicians would be willing to participate in active euthanasia and even PAS. Attitudes toward euthanasia are influenced by religious factors.

Dead sea water intoxication.

Near drowning in the Dead Sea is associated with both respiratory manifestations and severe electrolyte abnormalities. It is often difficult to distinguish between the contributions of sea water aspiration or ingestion to clinical manifestations. We present a unique case of accidental ingestion of a large amount of Dead Sea water through a gastrostomy tube in which a patient with familial dysautonomia presented with severe electrolyte disturbances. Forced diuresis with large amounts of intravenous fluids resulted in clinical and biochemical improvement. Full recovery was achieved after 2 days of treatment.

Localized reduction of gingival inflammation using site-specific therapy with a topical gingival patch.

METHODS: Sites of inflammation were identified on subjects with moderate-to-severe chronic periodontitis, and were allocated to either patch placement or untreated controls, both for 24 hours. Conventional treatment with scaling and root planing was postponed during the study period. Inflammation was evaluated measuring neutrophilic activity using gingival crevicular fluid (GCF) beta-glucuronidase (b-glu) levels, and clinical response was evaluated using the gingival index (GI). RESULTS: A total of 26 patients were recruited and 36 sites examined, with 22 sites on which the patch was placed and 14 controls. GCF b-glu levels at 24 hours were reduced following patch placement, significantly more so than with controls (17/22 vs. 3/14 sites, respectively; p = 0.002). The patch placement resulted in a significant reduction in mean b-glu levels (-2.52 +/- 1.62), with a reduction from baseline of 29.7%. This compared to untreated controls, for whom the mean b-glu levels and percent change from baseline increased (2.14 +/- 0.89 and 33%, respectively). At 24 hours, GI response rate for treated sites was better than for control sites (18/21 vs. 7/14; p = 0.053). No adverse events were reported in either group. CONCLUSION: This pilot study indicates that a topical gingival patch promotes reduction of gingival inflammation. Further clinical testing of this novel treatment of gingival inflammation is warranted.

An existential approach to oncology: meeting the needs of our patients.

PURPOSE OF REVIEW: Patients with cancer face both physical and psychological challenges. In the past, oncologists often limited themselves to the medical aspects of cancer care and delegated psychosocial interventions to professionals from other disciplines. In this review, we explore the methods by which oncologists can expand their role in treating cancer patients. RECENT FINDINGS: Recent studies have shown that individuals with cancer are not always satisfied with the care that they are receiving and believe that their existential needs are not being met. A model is suggested for improving the interaction between oncologists and their patients that involves focusing on the existential needs of an individual with cancer. Specific interventions and their appropriateness are discussed. SUMMARY: Oncologists should consider expanding their role and involving themselves in the more holistic aspects of cancer care. As a result of the bonds that they develop with patients, these professionals often find themselves in a position of being able to help and counsel cancer patients who are coping with feelings of isolation, loneliness, and fear.

Effect of an herbal mouth rinse in preventing periodontal inflammation in an experimental gingivitis model: a pilot study.

BACKGROUND: Gingivitis is a chronic inflammatory condition, resulting from gingival bacteria and bacterial byproducts. Antiplaque oral rinses reduce inflammation by removing or inhibiting plaque formation. The purpose of this pilot study was to examine the anti-inflammatory effects of HM-302, a mouth rinse based on natural products, on gingival inflammation. METHODS: A prospective, double-blinded, randomized parallel-group controlled trial involving 62 patients was conducted to assess efficacy and safety. During a 2-week period with no dental hygiene, subjects were randomized to receive either the study rinse (HM-302); a cetylpyridinium chloride (CPC) rinse; an essential oils (EO) rinse; or a water-only preparation. The gingival index (GI), plaque index (PI), and number of bleeding sites were measured at baseline and at the end of the study period. RESULTS: Progression of gingival inflammation resulting from lack of dental hygiene was lowest in patients treated with the HM-302 rinse, and was significantly less marked than in patients treated with the water-only preparation. When compared to the CPC and EO treatments, HM-302 was the only mouth rinse that was significantlybetter than the control, with respect to both the change in absolute GI scores (p = .006) and to the percent increase in GI scores (p = .012). No serious adverse effects were noted in any of the study groups. CONCLUSION: HM-302 is a safe and effective treatment for preventing the development of gingival inflammation in an experimental gingivitis model. Further research is needed to evaluate its long-term effects.