Association between same-day discharge shoulder arthroplasty and risk of adverse events in patients with American Society of Anesthesiologists classification ≥3: a cohort study.

BACKGROUND: Same-day discharge for shoulder arthroplasty (SA) is well-supported in the literature; however, most studies have focused on healthier patients. Indications for same-day discharge SA have expanded to include patients with more comorbidities, but safety of same-day discharge in this population remains unknown. We sought to compare outcomes following same-day discharge vs. inpatient SA in a cohort of patients considered higher risk for adverse events, defined as an American Society of Anesthesiologists (ASA) classification of ≥3. METHODS: Data from Kaiser Permanente's SA registry were utilized to conduct a retrospective cohort study. All patients with an ASA classification of ≥3 who underwent primary elective anatomic or reverse SA in a hospital from 2018 to 2020 were included. The exposure of interest was in-hospital length of stay: same-day discharge vs. ≥1-night hospital inpatient stay. The likelihood of 90-day post-discharge events, including emergency department (ED) visit, readmission, cardiac complication, venous thromboembolism, and mortality, was evaluated using propensity score-weighted logistic regression with noninferiority testing using a margin of 1.10. RESULTS: The cohort included a total of 1814 SA patients, of whom 1005 (55.4%) had same-day discharge. In propensity score-weighted models, same-day discharge was not inferior to an inpatient stay SA regarding 90-day readmission (odds ratio [OR] = 0.64, one-sided 95% upper bound [UB] = 0.89) and overall complications (OR = 0.67, 95% UB = 1.00). We lacked evidence in support of noninferiority for 90-day ED visit (OR = 0.96, 95% UB = 1.18), cardiac event (OR = 0.68, 95% UB = 1.11), or venous thromboembolism (OR = 0.91, 95% UB = 2.15). Infections, revisions for instability, and mortality were too rare to evaluate using regression analysis. CONCLUSIONS: In a cohort of over 1800 patients with an ASA of ≥3, we found same-day discharge SA did not increase the likelihood of ED visits, readmissions, or complications compared with an inpatient stay, and same-day discharge was not inferior to an inpatient stay with regard to readmissions and overall complications. These findings suggest that it is possible to expand indications for same-day discharge SA in the hospital setting.

Designing a Multilevel Strategy to Enhance Secondary Prevention of Heart Disease.

Background Coronary artery calcification (CAC), the presence and severity of which strongly predict underlying coronary artery disease (CAD), can be seen on dedicated cardiac imaging studies or incidentally on noncardiac ones; however, the latter findings are commonly managed by primary care clinicians without clear accompanying recommendations and may represent an underrecognized opportunity to optimize secondary prevention of CAD. Methods Standardized practice guidelines and a multilevel implementation strategy for improving secondary prevention of cardiovascular disease through incidentally identified CAC were developed by an interdisciplinary committee. Evidence-based implementation strategies were selected1 and included integrating practice guidelines into radiology reports within the electronic medical records. Outpatient noncardiac computerized tomography scans performed before and after this initiative were retrospectively reviewed to evaluate changes in statin prescribing. Results Authors demonstrated an increase in the percentage of patients with mild CAC prescribed a statin and an increase in the percentage of patients with severe CAC prescribed a high-intensity statin after implementation of standardized practice guidelines and evidence-based implementation strategies. Conclusion Incidental CAC identification is common, particularly in those without known CAD. A multilevel implementation strategy and use of standardized practice guidelines appeared to improve provider prescribing behavior in the primary care setting and may provide an opportunity to enhance secondary CAC prevention.

Identifying Opportunities for Greenhouse Gas Reductions and Cost Savings in Hospitals: A Knowledge Translation Tree.

Research has shown that the healthcare sector is among the least green sectors and constitutes one of the largest contributors to greenhouse gas (GHG) emissions, posing risks to human health. This review discusses the development of a knowledge translation tool that aims to compare a range of interventions that can be applied in hospital settings to reduce the local GHG emissions and associated financial costs. It discusses several interventions that potentially have the most impact on GHG reduction and compares these to interventions that are commonly used in different hospital departments. The authors propose opportunities to advance the implementation of these interventions within hospital operations across many other geographic locations.

Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Aspart (MYL-1601D) Compared with Originator Insulin Aspart (Novolog®) in Patients with Type 1 Diabetes After 24 Weeks: A Randomized Open-Label Study.

BACKGROUND: MYL-1601D is a proposed biosimilar of originator insulin aspart, Novolog®/NovoRapid® (Ref-InsAsp-US/Ref-InsAsp-EU). OBJECTIVE: This study assessed the immunogenicity, efficacy, and safety of MYL-1601D with Ref-InsAsp-US in patients with type 1 diabetes mellitus (T1D). METHODS: This was a 24-week, open-label, randomized, phase III study. Patients were randomized 1:1 to mealtime MYL-1601D or Ref-InsAsp-US in combination with insulin glargine (Lantus SoloSTAR®) once daily. The treatment-emergent antibody response (TEAR) rate (defined as patients who were anti-insulin antibody [AIA] negative at baseline and became positive at any timepoint post-baseline or patients who were AIA positive at baseline and demonstrated a 4-fold increase in titer values at any timepoint post-baseline) was the primary endpoint. The study also compared the change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), prandial, basal, and total daily insulin, 7-point self-monitored blood glucose (SMBG) profiles, immunogenicity, and adverse events (AEs) including hypoglycemia. RESULTS: In total, 478 patients were included in the intent-to-treat analysis (MYL-1601D: 238; Ref-InsAsp-US: 240) set. The 90% confidence interval (CI) for the primary endpoint was within the pre-defined equivalence margin of ±11.7% and the treatment differences (SE) in TEAR responders between the treatment groups was - 2.86 (4.16) with 90% CI - 9.71 to 3.99. The mean (SD) changes from baseline for HbA1c, FPG, and insulin dosages were similar in both groups at week 24. The safety profiles including hypoglycemia, immune-related events, AEs, and other reported variables were similar between the treatment groups at week 24. CONCLUSIONS: MYL-1601D demonstrated similar immunogenicity, efficacy, and safety profiles to Ref-InsAsp-US in patients with T1D over 24 weeks. CLINICAL TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03760068.

Phase III double-blind study comparing the efficacy and safety of proposed biosimilar MYL-1402O and reference bevacizumab in stage IV non-small-cell lung cancer.

PURPOSE: This phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks). RESULTS: A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was -1.6 (CI -9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%). CONCLUSIONS: MYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints. TRIAL REGISTRY INFORMATION: EU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32. PLAIN LANGUAGE SUMMARY: Previous studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O (n = 337) demonstrated comparable efficacy to bevacizumab (n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was -1.6 (95% CI -9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months (p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

COVID-19 and Gastrointestinal and Hepatobiliary Diseases.

Since its initial onset in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread quickly across the globe, resulting in the potentially life-threatening respiratory coronavirus disease 2019 (COVID-19). Although less commonly reported, COVID-19 has also been associated with gastrointestinal and hepatic manifestations, which may occur more frequently in children. This has also led to concern about the susceptibility of children to the SARS-CoV-2 virus who have underlying chronic digestive disease and may be treated with immune suppression. As such, recommendations and expert consensus regarding the management of chronic gastrointestinal and hepatobiliary disease have been of great interest during the pandemic and international database reporting has informed our understanding. The impact of COVID-19 on the gastrointestinal tract and its influence on the management of pediatric digestive disease is reviewed in this article. [Pediatr Ann. 2021;50(8):e315-e319.].

Similar immunogenicity profiles between the proposed biosimilar MYL-1501D and reference insulin glargine in patients with diabetes mellitus: the phase 3 INSTRIDE 1 and INSTRIDE 2 studies.

BACKGROUND: MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies. METHODS: INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti-host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2). RESULTS: Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999). CONCLUSIONS: In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively. TRIAL REGISTRATION: ClinicalTrials.gov, INSTRIDE 1 ( NCT02227862 ; date of registration, August 28, 2014); INSTRIDE 2 ( NCT02227875 ; date of registration, August 28, 2014).

Factors Affecting Selenium Status in Infants on Parenteral Nutrition Therapy.

INTRODUCTION: Selenium is an essential micronutrient that must be supplemented in infants and young children on exclusive parenteral nutrition (PN). We examined selenium status and clinical factors associated with a deficiency in infants on PN. METHODS: This was a retrospective cohort study of pediatric patients receiving PN with routine monitoring of selenium status. Deficiency was diagnosed using age-based norms of plasma selenium status. Associations between selenium deficiency and the following clinical factors were examined: birthweight status: extremely low birthweight (ELBW) versus very low birthweight (VLBW) versus low birthweight (LBW) versus normal birthweight (NBW), serum albumin status, presence of cholestasis, and co-administration of enteral feeds. RESULTS: A total of 42 infants were included with gestational age [median (interquartile range)] 28 weeks (25,34). The prevalence of selenium deficiency was 80% and the prevalence of albumin deficiency was 87.5%. The odds of selenium deficiency were higher in ELBW infants (odds ratio = 17.84, 95% confidence interval [4.04-78.72], P < 0.001) and VLBW infants (odds ratio = 16.26, 95% confidence interval [1.96-135.04], P < 0.001) compared to NBW infants. The odds of selenium deficiency were 5-fold higher in patients with low serum albumin (odds ratio = 5.33, 95% confidence interval [1.39-20.42], P = 0.015). There were no associations seen between selenium status and presence of cholestasis or co-administration of enteral feeds. CONCLUSION: In this cohort of infants on PN therapy, the main clinical factors associated with selenium deficiency were presence of hypoalbuminemia and history of ELBW or VLBW. These findings support dual measurement of serum albumin and serum selenium to improve interpretation of selenium status.

Devastating Postpartum Complications in an Adolescent Linked to New-Onset Inflammatory Bowel Disease and Antiphospholipid Antibody Syndrome.

Pregnancy can affect the severity of inflammatory bowel disease (IBD), and pregnant women with IBD are at a higher risk for venous thromboembolism compared with the general population. We report a previously healthy 16-year-old female who developed bloody diarrhea and venous thromboembolism following childbirth, with further evaluation revealing IBD and antiphospholipid antibody syndrome. This case highlights the impact pregnancy can have on IBD and other immunological disorders, and the potentially life-threatening risk of thrombosis in pregnant women with IBD.

Postoperative opioid utilization associated with revision risk following primary shoulder arthroplasty.

INTRODUCTION: With a substantial increase in utilization of primary shoulder arthroplasty, it is important to understand risk factors that may signal early failure and need for revision. Recent studies have reported that sustained postoperative opioid use is associated with a higher revision risk after total hip or knee arthroplasty. In this study, we evaluated postoperative opioid utilization as a risk factor for revision after primary shoulder arthroplasty. METHODS: We conducted a cohort study using data from a United States integrated health care system's Shoulder Arthroplasty Registry. Patients who had a primary elective shoulder arthroplasty were identified (2009-2017); those with cancer or who underwent other arthroplasty procedures (either shoulder, hip, or knee) within the preceding year were excluded. Cumulative daily opioid utilization during the first year postoperative, calculated as oral morphine equivalents (OME), was categorized into 3 exposure groups: high user (≥15 mg OME daily), moderate user (<15 mg OME daily), and no opioid use (reference group). The exposure window was stratified into 2 time periods: postoperative days 1-90 and postoperative days 91-360. Multivariable Cox proportional-hazards regression was used to evaluate the association between postoperative opioid use and aseptic revision risk. RESULTS: The final study sample included 8325 shoulder arthroplasty procedures. Of these individuals, 3707 (45%) received some opioid within the 1 year before the index procedure. We failed to observe a difference in aseptic revision risk between opioid utilization in the first 90 days postoperatively, regardless of dose. After the first 90 days, a higher revision risk was observed for high opioid users compared with nonusers (hazard ratio = 1.62, 95% confidence interval = 1.10-2.41), and no association was observed for moderate users (hazard ratio = 1.25, 95% confidence interval = 0.82-1.91). CONCLUSIONS: We found a positive association between opioid consumption and aseptic revision risk after primary shoulder arthroplasty. This study cannot determine if opioids have a direct physiological cause that increases the risk of revision; rather it is likely that opioid consumption is a marker of chronic pain, poor function, and/or poor coping mechanisms. Further study is needed to determine if programs designed to decrease opioid use may impact revision risk after shoulder arthroplasty.

An Unusual Lung Mass of Heterotopic Pancreatic Tissue in a Neonate With an Elevated Immunoreactive Trypsinogen on Newborn Screen.

We present a case of a neonate with tracheoesophageal fistula and esophageal atresia along with a suspicious lung mass who had a false-positive newborn screen for cystic fibrosis due to an elevated serum immunoreactive trypsinogen with an additionally elevated serum lipase. The infant's lung mass was found to contain heterotopic pancreatic tissue consisting of acini, ducts, and islet cells, without an associated gastrointestinal duplication cyst. This constellation of congenital abnormalities has not been described in previous literature. Also, this is the first reported case of a neonate with elevated serum pancreatic enzymes in which the underlying etiology was discovered to be heterotopic pancreas.

Risk Factors for Opioid Use After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: The misuse of opioid medications has contributed to a significant national crisis affecting public health as well as patient morbidity and medical costs. After orthopaedic surgical procedures, patients may require prescription (Rx) opioid medication, which can fuel the opioid epidemic. Opioid Rx usage after anterior cruciate ligament reconstruction (ACLR) is not well characterized. PURPOSE: To determine baseline utilization of Rx opioids in patients undergoing ACLR and examine demographic, patient, and surgical factors associated with greater and prolonged postoperative opioid utilization. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Primary elective ACLRs were identified using Kaiser Permanente's ACLR registry (2005-2015). We studied the association of perioperative risk factors on the number of dispensed opioid Rx in the early (0-90 days) and late (91-360 days) postoperative recovery periods using logistic regression. RESULTS: Of 21,202 ACLRs, 25.5% used at least 1 opioid Rx in the 1-year preoperative period; 17.7% and 2.7% used ≥2 opioid Rx in the early and late recovery periods, respectively. Risk factors associated with greater opioid Rx in both the early and the late periods included the following: ≥2 preoperative opioid Rx, age ≥20 years, American Society of Anesthesiologists classification ≥3, other activity at the time of injury, chondroplasty, chronic pulmonary disease, and substance abuse. Risk factors associated with opioid Rx use during the early period only included the following: other race, acute injury, meniscal injury repair, multiligament injury, and dementia/psychosis. Risk factors associated with greater opioid Rx during the late period only included the following: 1 preoperative opioid Rx, female sex, body mass index ≥25 kg/m2, motor vehicle accident as the mechanism of injury, and hypertension. CONCLUSION: A quarter of ACLR patients had at least 1 opioid Rx before the procedure, but usage dropped to 2.7% toward the end of the postoperative year. We identified several perioperative risk factors for greater and prolonged opioid usage after ACLR.

Risk factors for postoperative opioid use after elective shoulder arthroplasty.

BACKGROUND: The opioid epidemic remains a serious issue in the United States with significant impact to the medical and socioeconomic welfare of communities. We sought to determine baseline opioid use in patients undergoing shoulder arthroplasty (SA) and identify patient characteristics, comorbidities, and surgical risk factors associated with postoperative opioid use. METHODS: A Shoulder Arthroplasty Registry identified the number of dispensed opioid medication prescriptions (Rxs) in the first postoperative year in patients who underwent elective primary SA from 2008 to 2014. We used Poisson regression to study the effect of preoperative risks factors on number of dispensed opioid Rxs in the first postoperative year, evaluated quarterly (Q1: days 0-90, Q2: days 91-180, Q3: days 181-270, Q4: days 271-360). RESULTS: Included were 4243 SAs from 3996 patients, and 75% used opioids in the 1-year preoperative period. The factors associated with increased opioid use in all postoperative quarters (Q4 incident rate ratio [IRR] shown) were age <60 years (IRR, 1.40; 95% confidence interval [CI], 1.29-1.51), preoperative opioid use (1-4 Rxs: IRR, 2.15; 95% CI, 1.85-2.51; ≥5 Rxs: IRR, 9.83; 95% CI , 8.53-11.32), anxiety (IRR, 1.11; 95% CI, 1.03-1.20), opioid dependence (IRR, 1.23; 95% CI, 1.05-1.43), substance abuse (IRR, 1.17; 95% CI, 1.07-1.28), and general chronic pain (IRR, 1.38; 95% CI, 1.28-1.50). CONCLUSION: Opioid usage in patients undergoing SA is widespread at 1 year, with three-fourths of patients having been dispensed at least one Rx. These findings emphasize the need for surgeon and patient awareness as well as education in the management of postoperative opioid usage associated with the indicated conditions. Surgeons may consider these risk factors for preoperative risk stratification and targeted deployment of preventative strategies.

Development and validation of an electrochemiluminescent ELISA for quantitation of oral insulin tregopil in diabetes mellitus serum.

AIM: Tregopil, a novel PEGylated human insulin is in clinical development for oral delivery in diabetes treatment. The aim of the study was to develop and validate a sensitive and specific ELISA method for quantitating Tregopil in diabetes subjects on basal Glargine, since most commercially available insulin kits either do not detect Tregopil or show significant reactivity to Glargine. METHODS: An electrochemiluminescent ELISA was developed and validated for Tregopil quantitation in diabetes serum. RESULTS: The method has a LLOQ of 0.25 ng/ml, shows minimum cross-reactivity to Glargine and was successfully tested using a subset of samples from Tregopil-dosed Type 1 diabetes mellitus patients. CONCLUSION: The ELISA method is sensitive and can be used to support accurate measurement of Tregopil with no cross-reactivity to Glargine and its metabolites in clinical studies.

Spatial habitats from multiparametric MR imaging are associated with signaling pathway activities and survival in glioblastoma.

Glioblastoma (GBM) show significant inter- and intra-tumoral heterogeneity, impacting response to treatment and overall survival time of 12-15 months. To study glioblastoma phenotypic heterogeneity, multi-parametric magnetic resonance images (MRI) of 85 glioblastoma patients from The Cancer Genome Atlas were analyzed to characterize tumor-derived spatial habitats for their relationship with outcome (overall survival) and to identify their molecular correlates (i.e., determine associated tumor signaling pathways correlated with imaging-derived habitat measurements). Tumor sub-regions based on four sequences (fluid attenuated inversion recovery, T1-weighted, post-contrast T1-weighted, and T2-weighted) were defined by automated segmentation. From relative intensity of pixels in the 3-dimensional tumor region, "imaging habitats" were identified and analyzed for their association to clinical and genetic data using survival modeling and Dirichlet regression, respectively. Sixteen distinct tumor sub-regions ("spatial imaging habitats") were derived, and those associated with overall survival (denoted "relevant" habitats) in glioblastoma patients were identified. Dirichlet regression implicated each relevant habitat with unique pathway alterations. Relevant habitats also had some pathways and cellular processes in common, including phosphorylation of STAT-1 and natural killer cell activity, consistent with cancer hallmarks. This work revealed clinical relevance of MRI-derived spatial habitats and their relationship with oncogenic molecular mechanisms in patients with GBM. Characterizing the associations between imaging-derived phenotypic measurements with the genomic and molecular characteristics of tumors can enable insights into tumor biology, further enabling the practice of personalized cancer treatment. The analytical framework and workflow demonstrated in this study are inherently scalable to multiple MR sequences.

FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients.

Fanconi anemia (FA), a rare heterogeneous genetic disorder, is known to be associated with 19 genes and a spectrum of clinical features. We studied FANCA molecular changes in 34 unrelated and 2 siblings of Indian patients with FA and have identified 26 different molecular changes of FANCA gene, of which 8 were novel mutations (a small deletion c.2500delC, 4 non-sense mutations c.2182C>T, c.2630C>G, c.3677C>G, c.3189G>A; and 3 missense mutations; c.1273G>C, c.3679 G>C, and c.3992 T>C). Among these only 16 patients could be assigned FA-A complementation group, because we could not confirm single exon deletions detected by MLPA or cDNA amplification by secondary confirmation method and due to presence of heterozygous non-pathogenic variations or heterozygous pathogenic mutations. An effective molecular screening strategy should be developed for confirmation of these mutations and determining the breakpoints for single exon deletions.

Identification of a novel large intragenic deletion in a family with Fanconi anemia: first molecular report from India and review of literature.

We report here an Indian case with Fanconi anemia (FA) presented with fever, pallor, short stature, hyperpigmentation and upper limb anomaly. Chromosome breakage analysis together with FANCD2 Western blot monoubiquitination assay confirmed the diagnosis as FA. Multiplex ligation-dependent probe amplification (MLPA) revealed a novel homozygous large intragenic deletion (exons 8-27 del) in the FANCA gene in the proband. His sib and parents were also analyzed and found to be heterozygous for the same mutation. We also reviewed the literature of FANCA large intragenic deletions found in FA patients from different countries and the mechanism involved in the formation of these deletions. To the best of our knowledge, this is the first molecular report from India on FA. The finding expands the mutation spectrum of the FANCA gene. Identification of the mutation confirms the diagnosis of FA at DNA level and helps in providing proper genetic counseling to the family.