Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11-q13 imprinting region.

BACKGROUND: The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11-q13 duplication syndrome (resulting from the two common forms of duplications-either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region. METHODS: Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11-q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms. RESULTS: This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11-q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11-q13 duplication syndrome. CONCLUSION: Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype-phenotype correlation for patients impacted by variable structural variations within the 15q11-q13 region.

Mutational spectrum and phenotypic variability of Duchenne muscular dystrophy and related disorders in a Bangladeshi population.

Duchenne muscular dystrophy (DMD) is a severe rare neuromuscular disorder caused by mutations in the X-linked dystrophin gene. Several mutations have been identified, yet the full mutational spectrum, and their phenotypic consequences, will require genotyping across different populations. To this end, we undertook the first detailed genotype and phenotype characterization of DMD in the Bangladeshi population. We investigated the rare mutational and phenotypic spectrum of the DMD gene in 36 DMD-suspected Bangladeshi participants using an economically affordable diagnostic strategy involving initial screening for exonic deletions in the DMD gene via multiplex PCR, followed by testing PCR-negative patients for mutations using whole exome sequencing. The deletion mapping identified two critical DMD gene hotspot regions (near proximal and distal ends, spanning exons 8-17 and exons 45-53, respectively) that comprised 95% (21/22) of the deletions for this population cohort. From our exome analysis, we detected two novel pathogenic hemizygous mutations in exons 21 and 42 of the DMD gene, and novel pathogenic recessive and loss of function variants in four additional genes: SGCD, DYSF, COL6A3, and DOK7. Our phenotypic analysis showed that DMD suspected participants presented diverse phenotypes according to the location of the mutation and which gene was impacted. Our study provides ethnicity specific new insights into both clinical and genetic aspects of DMD.

Health System Strengthening Through Professional Midwives in Bangladesh: Best Practices, Challenges, and Successes.

In 2008, a cadre of professional midwives was introduced in Bangladesh. Since then, 120 midwifery educational programs have been established. There are 2,556 midwives serving at 667 government health facilities, and there are more midwives working in nongovernmental organizations and the private sector. This case study documents the process of establishing a midwifery profession with distinct midwifery expertise in Bangladesh and aims to guide other low- and middle-income countries in best practices and challenges. We describe the national administrative groundwork for the profession's launch, roll-out of an education program aligned with the International Confederation of Midwives, national deployment, enabling environments in deployment, and the professional association. Bangladesh's professional midwives' roles in humanitarian response and the COVID-19 pandemic are also discussed. The first and final authors were closely involved in supporting the government's establishment of the profession, and their direct experience is drawn upon to contextualize the topics. In addition, the authors conducted a desk review of documents that supported the profession's integration into the health system and documented its results. Both routine program data and existing research studies were reviewed. Outcomes show that midwives are deployed to 95% of government subdistrict hospitals. About 50% of these hospitals are fully staffed with 4 midwives, and within the hospitals, midwives are in charge of 90% of the maternity wards and attend 75%-85% of the births. Since the midwives' deployment, significant quality improvement for most World Health Organization indicators has been found, along with increases in service utilization. The experience of establishing a new midwifery profession in Bangladesh shows that it is possible for a lower middle-income country to introduce a globally standard midwifery profession, distinct from nursing, to improve quality sexual, reproductive, maternal, newborn, and adolescent health services in both humanitarian and development settings.

Midwife-led pandemic telemedicine services for maternal health and gender-based violence screening in Bangladesh: an implementation research case study.

BACKGROUND: The COVID-19 pandemic disrupted maternal and newborn health services in Bangladesh, exacerbating the large gaps in service utilization that existed prior to the pandemic. As part of its response, Bangladesh initiated remote antenatal and postnatal care telemedicine services led by midwives in 36 sub-district hospitals across five of Bangladesh's 64 districts. Gender-based violence screening and referral were integrated into the service to address a reported rise in violence following the country's pandemic lockdown. METHODS: Mixed-methods implementation research was used to develop an intrinsic case study describing the design and implementation of the telemedicine program. Qualitative analysis comprised document review, key informant interviews, and focus group discussions. Quantitative analysis employed an interrupted time series analysis with segmented multi-variate regression to compare maternity care service use trends before and after implementation. Poisson regression analysis was used to examine the trend in number of gender-based violence remote screenings, sessions held, and cases identified. RESULTS: A statistically significant change in trend for onsite antenatal and postpartum care as well as women seeking care at the hospital as a result of postpartum hemorrhage arising in the community was observed following the introduction of telemedicine. Facility births and cases of eclampsia appropriately identified and managed also had significant increases. In addition, over 6917 women were screened for GBV, 223 received counseling and 34 referrals were made, showing a statistically significant increase in frequency over time following the implementation of the telemedicine program. Challenges included that not all midwives adopted GBV screening, some women were reluctant to discuss GBV, there was an unanticipated need to introduce a patient visit scheduling system in all intervention hospitals, and many women were not reachable by phone due to lack of access or network coverage. CONCLUSIONS: Maternal health and gender-based violence telemedicine led by midwives was an effective, low-cost intervention in Bangladesh for addressing pandemic and pre-pandemic gaps in service use. Other low and middle-income countries planning to implement remote maternal health interventions via midwives should consider whether a patient visit scheduling system needs to be introduced, as well as limitations around mobile phone access and connectivity. Future research should include care quality oversight and improvement, and a more well-informed strategy for facilitating effective GBV screening.

To support the continuation of sexual and reproductive health services following pandemic lockdowns, Bangladesh introduced a midwife-led telemedicine program. Through the program, midwives who were already employed within the health system delivered remote antenatal and postnatal care, including gender-based violence screening and referral. The program operated in 36 sub-district hospitals across five of Bangladesh's 64 districts. Intrinsic implementation research was used to develop a case study describing the design and implementation of the telemedicine program. Qualitative and quantitative methods comprised document review, key informant interviews, focus group discussions, and service use trends. Analysis of the data identified a statistically significant trend increase for most maternity care services. Although they did increase significantly over time, referrals for GBV were less than expected, which may have been related to some midwives not screening for GBV, and/or that many women were reluctant to discuss GBV. In addition, there was an unanticipated need to introduce a patient visit scheduling system in all intervention hospitals, and many women were not reachable by phone due to lack of access or network coverage. In spite of this, 6197 women were screened for GBV. Of those, 223 received counseling and 34 received referrals. Overall, telemedicine led by midwives was an effective, low-cost intervention for maternal health, and a step toward stronger GBV response in Bangladesh. Other low and middle-income countries planning to implement remote maternal health interventions via midwives should consider what is needed to facilitate comfort for both providers and women as related to GBV screening, as well as practical issues regarding introducing scheduling systems and limitations of mobile phone access and connectivity.

Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders.

Introduction: Copy number variations (CNVs) play a critical role in the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh. Methods: We have conducted chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare CNVs. To identify candidate genes within the rare CNVs, gene constraint metrics [i.e., "Critical-Exon Genes (CEGs)"] were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using the R package. Results: Of all the samples assayed, 12.26% (26/212) and 57.08% (121/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. While 2.83% (6/212) patients' pathogenic CNVs were found to be located in the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs compared to males (OR = 4.2; p = 0.0007). We have observed an increased number of Loss of heterozygosity (LOH) within cases with 23.85% (26/109) consanguineous parents. Our analyses on imprinting genes show, 36 LOH variants disrupting 69 unique imprinted genes and classified these variants as VOUS. ADOS-2 subset shows severe social communication deficit (p = 0.014) and overall ASD symptoms severity (p = 0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs in our NDD cohort and we identified PSMC3 gene as a strong candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability. Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis, therapy and management of NDD patients.

Radiological Analysis of Gentamicin Eluting Synthetic Bone Graft Substitute Used in the Management of Patients With Traumatic Bone Voids.

Background Management of traumatic bone voids has always been challenging. Gentamicin eluting synthetic bone graft substitute (Cerament-G) showed encouraging results in achieving good bone healing with a satisfactory degree of resorption when utilised as a void filler. This study aims to assess the radiological signs of Cerament-G remodelling when used for patients with traumatic bone voids. Methods Retrospective data analysis of all patients admitted to our unit between 2015 and 2021 with traumatic bone voids who had Cerament-G applied intraoperatively as a void filler. Postoperative radiographic images of the fracture site at six weeks, three months, six months, and at the final follow-up were reviewed. The radiological signs of Cerament-G integration, percent of void healing at the final follow-up were assessed. Results A total of 51 patients (52 fractures) were included in the study. Among them 10 were female and 41 were male with a mean age of 42.7 (11 - 90) years. The mean void size was 6.58 cm3. Mean follow-up duration was 9.73 months. Primary fracture union was achieved in 44 (86.3%) patients. Delayed union was reported in six (11.7%) patients, while one (1.9%) patient had non-union. Twenty-seven (52%) patients had >90% of void healing with normal trabecular bone. Twenty (38.5%) patients had 50-90% void healing with normal bone. Whereas only five (9.5%) patients had less than 50% of void healing. Conclusion Cerament-G used as a void filler for patients with traumatic bone void has resulted 98% fracture union rate with good signs of radiological remodelling into a trabecular bone. More than 50% void filling with new trabecular bone was reported in more than 90% of patients. Non-union was reported in only one patient.

One-stage combined "fix and flap" approach for complex open Gustilo-Anderson IIIB lower limbs fractures: a prospective review of 102 cases.

BACKGROUND: Management of open fractures is challenging and requires a multidisciplinary team approach. This study aims to evaluate outcomes of open Gustilo-Anderson IIIB fractures managed at a single Ortho-Plastic centre following One-stage "Fix and Flap" approach. METHODS: Prospective data review for patients presenting with Gustilo-Anderson IIIB Fractures to our centre and managed with one-stage "Fix and Flap" approach. Postoperative outcomes are presented only for the patients who had a minimum of 12 months postoperative follow-up. RESULTS: 120 patients were included (83 males and 37 females). Mean age was 43 years (10-96). Tibia diaphysis was the most common site of injury (60%). 55.9% of injuries were road traffic accidents (RTA). 102 out of 120 patients had a minimum of 12 months follow-up (mean follow-up duration 25 months). Meantime from injury until definitive surgery was 7.71 days. Primary union achieved in 86.73%. Delayed union was encountered in 10.20%. 3.06% of patients had non-union. Limb salvage rate was 97.05% and Deep infection rate was only 0.98%. CONCLUSION: Our results showed that low infection rate, high limb salvage rate, and high union rate can be achieved in these complex injuries with meticulous technique, combined Ortho-Plastic (Fix and Flap) approach, and MDT input.

Detection of mold on the food surface using YOLOv5.

The study aimed to identify different molds that grow on various food surfaces. As a result, we conducted a case study for the detection of mold on food surfaces based on the "you only look once (YOLO) v5" principle. In this context, a dataset of 2050 food images with mold growing on their surfaces was created. Images were obtained from our own laboratory (850 images) as well as from the internet (1200 images). The dataset was trained using the pre-trained YOLOv5 algorithm. A laboratory test was also performed to confirm that the grown organisms were mold. In comparison to YOLOv3 and YOLOv4, this current YOLOv5 model had better precision, recall, and average precision (AP), which were 98.10%, 100%, and 99.60%, respectively. The YOLOv5 algorithm was used for the first time in this study to detect mold on food surfaces. In conclusion, the proposed model successfully recognizes any kind of mold present on the food surface. Using YOLOv5, we are currently conducting research to identify the specific species of the detected mold.

Single-cell transcriptome identifies FCGR3B upregulated subtype of alveolar macrophages in patients with critical COVID-19.

Understanding host cell heterogeneity is critical for unraveling disease mechanism. Utilizing large-scale single-cell transcriptomics, we analyzed multiple tissue specimens from patients with life-threatening COVID-19 pneumonia, compared with healthy controls. We identified a subtype of monocyte-derived alveolar macrophages (MoAMs) where genes associated with severe COVID-19 comorbidities are significantly upregulated in bronchoalveolar lavage fluid of critical cases. FCGR3B consistently demarcated MoAM subset in different samples from severe COVID-19 cohorts and in CCL3L1-upregulated cells from nasopharyngeal swabs. In silico findings were validated by upregulation of FCGR3B in nasopharyngeal swabs of severe ICU COVID-19 cases, particularly in older patients and those with comorbidities. Additional lines of evidence from transcriptomic data and in vivo of severe COVID-19 cases suggest that FCGR3B may identify a specific subtype of MoAM in patients with severe COVID-19 that may present a novel biomarker for screening and prognosis, as well as a potential therapeutic target.

Sciatica Presentations and Predictors of Poor Outcomes Following Surgical Decompression of Herniated Lumbar Discs: A Review Article.

Pain associated with sciatica is one of the most common indications for surgery. The annual rate of discectomy has increased over recent years, with a significant number of patients reporting a poor outcome or symptom recurrence after surgery. This study aims to evaluate the predictors of poor outcome for patients undergoing lumbar discectomy for sciatica. A comprehensive search was conducted to find relevant literature published between 1985 and 2019. All literature with a clear methodology were included. Many factors that affect postoperative recovery after lumbar discectomy have been reported. Some evidence suggests that sociodemographic factors, including female gender, smoking, increased age, low socioeconomic status, and low education level may be associated with less favorable outcomes after surgery. Symptom duration does not appear to be associated with a significant difference in long-term outcomes; however, early surgery (within one year) may result in a faster postoperative recovery with better early results. Furthermore, patients who had discectomy for predominant leg pain had better outcomes compared to those who had the surgery for back pain as the main presentation. There was no evidence to suggest a correlation between the size of the herniated disc and long-term outcomes of sciatica; however, a higher anatomical level of herniation (L1-2, L2-3) was associated with poorer outcomes compared to the lower level of herniation (L3-4, L4-5). A few studies suggested slow postoperative recovery correlates with unemployment and depression. We recommend that the predictors of postoperative outcomes should be taken into consideration when selecting or counseling patients for lumbar disc decompression.

Management of Displaced Intra-Articular Calcaneal Fractures: A Comparative Study of Open and Minimally Invasive Surgery.

Objectives The ideal treatment of displaced intra-articular calcaneal fractures continues to be a subject of debate. The aim of the study was to compare the radiological outcome, cumulative radiation exposure, surgical time, time to surgery, wound healing times and cost involved in minimally invasive surgery (MIS) and open reduction internal fixation (ORIF) for calcaneal fractures. Methods This was a retrospective study of 39 calcaneum operated in our unit during 2012 to 2019, of which 20 had undergone ORIF and 19 had been operated upon following MIS. Results A total of 39 calcanea (37 patients) were operated, of which 20 had open procedure and 19 had MIS procedure, including one bilateral surgery in each group. Mean age of the patients in the MIS group was 42.18 years (range: 15-68 years) and that of the patients in the open group was 43 years (range: 21-75 years). Of the fractures, 53.84% (n = 21) was Sanders type III, 28.20% (n = 11) was type II and 17.94% (n = 7) was type IV. There was no statistically significant difference in the mean correction of Bohler's angle and Gissane's angle between the groups. The mean cost for implant used for each open procedure was £882.79, and the implant cost for each MIS procedure was £142.89. Mean utilisation of cumulative X-ray dose was significantly higher in MIS (0.764 mGy) in comparison to open surgery (0.392 mGy). The average surgical time for MIS was 64.9 minutes and that of open surgery was 106.3 minutes. Average waiting time for MIS was 6.6 days and that for ORIF was 9.8 days. Wound healing was quicker (average 13.4 days) in MIS than ORIF (average 17.2 days). All these differences were statistically significant. Conclusions Minimally invasive calcaneal fracture surgery is quicker and cheaper and can be performed earlier. It is associated with early wound healing, although it requires higher cumulative radiation dose.

Current Management of Paediatric Supracondylar Fractures of the Humerus.

Supracondylar fractures of the humerus in children are common and can be distressing injuries to the child, the parents and to the surgical team. Type 1 fractures are managed non-operatively, however displaced fractures (Types 2, 3 and 4) are usually managed surgically. Accurate and repetitive neuromuscular assessment is critical not just for medicolegal reasons but also to expedite management with different specialists if needed. The Rock, paper, scissor, OK technique is simple which is easily understood by most children. We discuss the current evidence with regards to pin diameter, number, pin configuration along with a simple algorithm on how to manage a child with a displaced supracondylar fracture with no pulse focussing mainly on the extension-type fracture.

Adjuvant Local Antibiotic Hydroxyapatite Bio-Composite in the management of open Gustilo Anderson IIIB fractures. Prospective Review of 80 Patients from the Manchester Ortho-Plastic Unit.

BACKGROUND: This study aims to evaluate outcomes of using Adjuvant Local Antibiotic Hydroxyapatite Bio-Composite in management of Open Gustilo-Anderson IIIB Fractures. METHODS AND RESULTS: 80 patients were managed with single-stage "Fix and Flap" along with intra-operative Adjuvant Local Antibiotic Bio-Composite. Successful fracture union was achieved in 96.1% of patients, with a limb salvage rate of 96.25%. Infection rate was only 1.25%. CONCLUSION: High union rate and very low deep infection rate can be predictably achieved in complex Open Gustilo-Anderson IIIB fractures by meticulous technique, use of local adjunctive antibiotics bio-composite and a combined ortho-plastic approach.

Characteristics of Carbapenemase-Producing Klebsiella pneumoniae Isolated in the Intensive Care Unit of the Largest Tertiary Hospital in Bangladesh.

For addressing the issue of antimicrobial drug resistance in developing countries, it is important to investigate the characteristics of carbapenemase-producing organisms. We aimed to genetically characterize a carbapenemase-producing Klebsiella pneumoniae (CPKP) isolated in the intensive care unit of a tertiary hospital in Bangladesh. The number of CPKP isolates were 43/145 (30%), of which pandrug-resistant (PDR) strains were 14%. These carbapenemases were New Delhi metallo-beta-lactamase (NDM)-1 (53%), NDM-5 (14%), oxacillinase (OXA)-181 (12%), OXA-232 (10%), NDM-5 + OXA-181 (5%), and NDM-5 + OXA-232 (2%). Many CPKP isolates harbored a variety of resistance genes, and the prevalence of 16S rRNA methyltransferase was particularly high (91%). The 43 CPKP isolates were classified into 14 different sequence types (STs), and the common STs were ST34 (26%), ST147 (16%), ST11 (9%), ST14 (9%), ST25 (7%), and ST231 (7%). In this study, PDR strains were of three types, ST147, ST231, and ST14, and their PDR rates were 57, 33, and 25%, respectively. The spread of the antimicrobial drug resistance of CPKP in Bangladesh was identified. In particular, the emergence of PDR is problem, and there may be its spread as a superbug of antimicrobial treatment.

Protective and therapeutic potential of ginger (Zingiber officinale) extract and [6]-gingerol in cancer: A comprehensive review.

Natural dietary agents have attracted considerable attention due to their role in promoting health and reducing the risk of diseases including cancer. Ginger, one of the most ancient known spices, contains bioactive compounds with several health benefits. [6]-Gingerol constitutes the most pharmacologically active among such compounds. The aim of the present work was to review the literature pertaining to the use of ginger extract and [6]-gingerol against tumorigenic and oxidative and inflammatory processes associated with cancer, along with the underlying mechanisms of action involved in signaling pathways. This will shed some light on the protective or therapeutic role of ginger derivatives in oxidative and inflammatory regulations during metabolic disturbance and on the antiproliferative and anticancer properties. Data collected from experimental (in vitro or in vivo) and clinical studies discussed in this review indicate that ginger extract and [6]-gingerol exert their action through important mediators and pathways of cell signaling, including Bax/Bcl2, p38/MAPK, Nrf2, p65/NF-κB, TNF-α, ERK1/2, SAPK/JNK, ROS/NF-κB/COX-2, caspases-3, -9, and p53. This suggests that ginger derivatives, in the form of an extract or isolated compounds, exhibit relevant antiproliferative, antitumor, invasive, and anti-inflammatory activities.

Management of Patients Aged ≥85 Years With ST-Elevation Myocardial Infarction.

Guidelines mandate urgent revascularization in patients presenting with ST-elevation myocardial infarction (STEMI) irrespective of age. Whether this strategy is optimal in patients aged ≥85 years remains uncertain. We aimed to assess the clinical characteristics and outcomes of patients aged ≥85 years with STEMI stratified by their management strategy. We analyzed baseline clinical characteristics of 101 consecutive patients aged ≥85 years who presented with STEMI to a tertiary Australian hospital. Patients were stratified based on whether they underwent invasive management with urgent coronary angiography ± percutaneous coronary intervention or conservative management. Our primary outcome was long-term mortality. Independent predictors of conservative management and long-term mortality were assessed by multivariate logistic regression and Cox proportional hazard modeling respectively. Of the 101 patients included, 45 underwent invasive management. Independent predictors of having conservative management were older age, anterior STEMI, and cognitive impairment (all p <0.01). Patients managed invasively had lower in-hospital (13.3% vs 32.1%, p = 0.03), 30-day (13.3% vs 37.5%, p <0.01), 12-month (22.2% vs 57.1%, p <0.01), and long-term (40.0% vs 75.0%, p <0.01) mortality. Invasive management was an independent predictor of lower long-term mortality (hazard ratio 0.29, 95% CI 0.11 to 0.76, p <0.01). In conclusion, patients aged ≥85 years with STEMI who were older, had cognitive impairment or presented with anterior ST-elevation were more likely to be managed conservatively. Those who underwent invasive management had reasonable short- and long-term outcomes.

Anti-VEGF treatment in neovascular age-related macular degeneration: a treat-and-extend protocol over 2 years.

PURPOSE: To evaluate 2-year visual acuity outcome of a treat-and-extend protocol of anti-vascular endothelial growth factor treatment in age-related macular degeneration. METHODS: In this prospective cohort study, 120 age-related macular degeneration patients with choroidal neovascularization received 3 initial monthly ranibizumab or bevacizumab injections; monthly injections were continued until there was no choroidal neovascularization activity (subretinal/intraretinal fluid, loss of >5 letters, or persistent/recurrent retinal hemorrhage). When there was no choroidal neovascularization activity, the interval to the next visit/injection was extended by 2 weeks to a maximum of 12 weeks. In the presence of choroidal neovascularization activity, this interval was shortened by 2 weeks. Main outcome measures included the percentage losing <15 letters and the mean visual acuity change after 12 months and 24 months. RESULTS: Mean baseline visual acuity was 51.2 ± 12.1 Early Treatment Diabetic Retinopathy Study scores. Mean visual acuity change from baseline was +9.5 ± 10.9 and +8.0 ± 12.9 letters after 12 months and 24 months, respectively, with, on average, 8.6 ± 1.1 visits/injections in the first year and 5.6 ± 2.0 in the second year. After 12 months and 24 months, 97.5% and 95.0% of patients, respectively, lost <15 letters. CONCLUSION: The "inject-and-extend" protocol-with fewer injections and visits-delivered outcomes comparable to those of the pivotal clinical trials of monthly ranibizumab.

Genetic influences on the outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration.

PURPOSE: To determine the association of genetic variants in known age-related macular degeneration (AMD) risk-associated genes with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular AMD. DESIGN: Prospective cohort study. PARTICIPANTS: We enrolled 224 consecutive patients with neovascular AMD at the Royal Victorian Eye and Ear Hospital, Australia. METHODS: Patients were treated with 3 initial monthly ranibizumab or bevacizumab injections followed by 9 months of "as required" injections based on clinician's decision at each follow-up visit according to retreatment criteria. Seventeen single nucleotide polymorphisms (SNPs) in known AMD risk-associated genes including CFH (rs800292, rs3766404, rs1061170, rs2274700 and rs393955), HTRA1 (rs11200638), CFHR1-5 (rs10922153, rs16840639, rs6667243, and rs1853883), LOC387715/ARMS2 (rs3793917 and rs10490924), C3 (rs2230199 and rs1047286), C2 (rs547154), CFB (rs641153) and F13B (rs6003) were examined. Multivariate analysis was used to determine the role of each SNP in treatment outcome. MAIN OUTCOME MEASURES: The influence of selected SNPs on mean change in visual acuity (VA) at 12 months. RESULTS: Mean baseline VA was 51 ± 16.8 Early Treatment Diabetic Retinopathy Study letters. Overall, the mean change in VA from baseline was +3.2 ± 14.9 letters at 12 months. The AA (homozygote risk) genotype at rs11200638 - HTRA1 promoter SNP (P = 0.001) and GG (homozygote risk) genotype at rs10490924 (A69S) in LOC387715/ARMS2 (P = 0.002) were each significantly associated with poorer VA outcome at 12 months after multiple correction. Mean ± standard deviation change in VA from baseline in patients with AA genotype at rs11200638 was -2.9 ± 15.2 letters after 12 months compared with +5.1 ± 14.1 letters in patients with AG or GG genotypes at this SNP. Patients with either of these genotypes were also significantly more likely to lose >15 letters after 12 months. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (r(2) = 0.92). None of the other examined SNPs was associated with outcome. CONCLUSIONS: The HTRA1 promoter SNP (rs11200638) and A69S at LOC387715/ARMS2 were associated with a poorer visual outcome for ranibizumab or bevacizumab treatment in neovascular AMD, suggesting strong pharmacogenetic associations with anti-VEGF treatment. This finding could aid in applying more individualized treatment regimens based on patients' genotype to achieve optimal treatment response in AMD. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Comparison of in vitro heat and cold tolerances of the new invasive species Bactrocera invadens (Diptera: Tephritidae) with three known tephritids.

Bactrocera invadens Drew, Tsuruta & White (Diptera: Tephritidae) is spreading throughout central Africa attacking a variety of fruit; quarantines are placed on fruit from this region that are considered hosts. The only phytosanitary treatment that is commercially available is an ionizing irradiation treatment for all Tephritidae at 150 Gy. The development of other treatments, such as heat, cold, or fumigation, usually requires testing tens of thousands of insects at a dose that provides efficacy and may take several years. It may be possible to shorten the time required to develop treatments by comparing tolerance of a new quarantine pest to tolerances of pests with similar behaviors and modes of infestation for which treatment schedules are available. Cold and heat tolerance ofB. invadens was compared with tolerance of Anastrepha ludens (Loew), Bactrocera dorsalis (Hendel), and Ceratitis capitata (Wiedemann) in vitro. Third-instar B. invadens was no more cold tolerant than the other species when treated in diet at 0.94 +/- 0.65 degrees C and no more heat tolerant than C. capitata when immersed in vials in water at 44.7 +/- 0.1 degrees C. The data at 0.94 +/- 0.65 degrees C was used to include B. invadens in a USDA cold treatment schedule for citrus fruit from Africa so that trade would not be interrupted while protecting U.S. agriculture from this invasive pest.

Prevalence and risk factors for epiretinal membranes in a multi-ethnic United States population.

PURPOSE: To describe the prevalence of and risk factors for epiretinal membrane (ERM) in a multi-ethnic population and to evaluate possible racial or ethnic differences. DESIGN: Cross-sectional study. PARTICIPANTS: Participants of the Multi-Ethnic Study of Atherosclerosis (MESA), examined at the second visit of the MESA when retinal photography was performed. METHODS: Data on 5960 participants aged 45 to 84 years from MESA, including white, black, Hispanic, and Chinese persons from 6 United States communities, were analyzed. Epiretinal membrane was assessed from digital nonstereoscopic fundus photographs and was defined as cellophane macular reflex (CMR) without retinal folds or preretinal macular fibrosis (PMF) with retinal folds. Risk factors were assessed from standardized interviews, clinical examinations, and laboratory investigations. MAIN OUTCOME MEASURES: Epiretinal membrane prevalence by ethnic or racial group and risk factors associated with ERM. RESULTS: The prevalence of any ERM was 28.9%, of which 25.1% were CMR cases and 3.8% were PMF cases. The prevalence of ERM was significantly higher in Chinese persons (39.0%), compared with Hispanic (29.3%), white (27.5%), or black (26.2%; P<0.001) persons. In multivariate models, increasing age (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.06-1.34, per year increase in age), diabetes (OR, 1.92; 95% CI, 1.39-2.65), and hypercholesterolemia (OR, 1.33; 95% CI, 1.04-1.69) were significantly associated with CMR. CONCLUSIONS: This study showed that ERM was significantly more common in Chinese persons compared with whites, blacks, and Hispanics. Risk factors for ERM were increasing age, presence of diabetes, and hypercholesterolemia.