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ObjectiveINGR1D (INvestigating Genetic Risk for type 1 Diabetes) was a type 1 diabetes (T1D) genetic screening study established to identify participants for a primary prevention trial (POInT, Primary Oral Insulin Trial).MethodsThe majority of participants were recruited by research midwives in antenatal clinics from 18 weeks’ gestation. Using the NHS Newborn Bloodspot Screening Programme (NBSP) infrastructure, participants enrolled in INGR1D had an extra sample taken from their day 5 bloodspot card sent for T1D genetic screening. Those at an increased risk of T1D were informed of the result, given education about T1D and the opportunity to take part in POInT.ResultsBetween April 2018 and November 2020, 66% of women approached about INGR1D chose to participate. 15 660 babies were enrolled into INGR1D and 14 731 blood samples were processed. Of the processed samples, 157 (1%) had confirmed positive results, indicating an increased risk of T1D, of whom a third (n=49) enrolled into POInT (20 families were unable to participate in POInT due to COVID-19 lockdown restrictions).ConclusionThe use of prospective consent to perform personalised genetic testing on samples obtained through the routine NBSP represents a novel mechanism for clinical genetic research in the UK and provides a model for further population-based genetic studies in the newborn.

OBJECTIVE Gestational hyperglycemia is associated with deleterious neonatal outcomes, but long-term risks for offspring obesity are less clear. We estimated the odds for offspring adolescent overweight and obesity among mothers with gestational glucose intolerance. RESEARCH DESIGN AND METHODS In a mother-offspring historical cohort, the Israel military conscription data set was linked to a large health maintenance organization. Included were women who were evaluated at adolescence and underwent two-step gestational diabetes screening (mean age, 31 years) with a 50-g glucose challenge test (GCT), followed by a 100-g oral glucose tolerance test (OGTT) if the result was abnormal. Glucose tolerance categories included gestational normoglycemia, abnormal GCT with normal OGTT, impaired glucose tolerance (IGT; one abnormal OGTT value), and gestational diabetes. The primary outcome was offspring overweight/obesity (BMI ≥85th percentile) at adolescence, measured prior to military conscription. Logistic regression models were applied. RESULTS Of 33,482 mother-offspring pairs, overweight and obesity were observed in 6,516 offspring. Across increasing categories of pregnancy glycemia, the proportions of offspring with adolescent overweight/obesity increased: normoglycemia, 19%; abnormal GCT with normal OGTT, 22%; gestational IGT, 24%; and gestational diabetes, 25% (P < 0.0001). Corresponding odds ratios after adjustment for the mother’s late adolescent characteristics (sociodemographic confounders and BMI) and pregnancy age were 1.2 (95% CI 1.1–1.4), 1.3 (1.2–1.5), and 1.4 (1.3–1.6), respectively. Further adjustment for offspring birth weight percentile and sociodemographic variables did not materially change results. Associations were more pronounced with increasing obesity severity. CONCLUSIONS Gestational glucose intolerance, including categories not meeting the gestational diabetes threshold, was associated with increased odds for offspring overweight/obesity at late adolescence.

Context The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. Objective To assess type 2 diabetes risk among adolescents with NAFLD. Design and Setting A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997–2011 and were followed until December 31, 2016. Participants A total of 1 025 796 normoglycemic adolescents were included. Interventions Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. Main Outcome Measures Type 2 diabetes incidence. Results During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47–4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). Conclusions Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.

Background: Current practice in the UK is to plot premature infant anthropometric measurements on Neonatal and Infant Close Monitoring (NICM) reference charts. These charts have several known limitations. The INTERGROWTH-21st Project has recently produced international ante- and postnatal growth standards. Exact knowledge of growth centiles allows clinicians to accurately assess infant nutritional requirements. Objective: To compare target centile measurements between INTERGROWTH-21st and UK NICM growth charts for premature infants. Method: Anthropometric measurements (weight and head circumference) of a convenience sample of neonates born between 24 and 32 weeks of gestation were analysed retrospectively. Measurements were collected across three time points and plotted on both the NICM and INTERGROWTH-21st growth charts. The respective centiles were compared and analysed by paired-sample t test, Wilcoxon rank test analysis, and multilevel mixed-effect linear regression models. Results: Centiles for weight and head circumference measurements of 96 infants plotted on INTERGROWTH-21st charts were significantly greater than their corresponding UK charts at all three time points. For weight, the average difference between the two charts varied from 9.1 to 16.4 centiles. The difference between the two charts was greater for female than male infants by up to 6.9 centiles (95% CI 10.1–3.8). Conclusion: Existing UK NICM reference charts are significantly different to the growth standards of INTERGROWTH-21st. The choice of which growth chart to adopt in the UK could have important consequences on premature infants’ future adult health and therefore requires further prospective observational studies with larger data sets including length measurements and more comprehensive population characteristics.

Immigration from one cultural milieu to another has been associated with a greater risk for incident cardio-metabolic morbidity among adults. In this nationwide, population-based, cross-sectional study of data recorded from 1992 to 2016, we assessed the association between body mass index and blood pressure levels among adolescent immigrants, aged 16 to 19 years, of Ethiopian origin, and their secular trend of overweight and obesity. Adolescents of Ethiopian origin were classified as Israeli-born (n=16 153) or immigrants (N=23 487), with stratification by age at immigration. Adolescents whose fathers were at least 3 generations in Israel (n=277 789) served as a comparative group. Hypertensive-range blood pressure values adjusted for age, sex, and height served as outcome. Among adolescents of Ethiopian origin, overweight and obesity (body mass index ≥85th percentile), increased by 2.5 and 4-fold in males and females, respectively, during the study period, compared with a 1.5-fold increase among native Israeli-born males and females. The odds for hypertensive-range measurements increased with the length of residence in Israel: 7.3%, 10.6%, and 14.4% among males who immigrated at ages 12 to 19, 6 to 11.9, and 0 to 5.9 years, respectively; and 11.5%, 16.7%, and 19.3%, respectively, among females. Israeli-born Ethiopians had a significantly higher risk for hypertensive-range measurements at any body mass index level compared with native Israeli-born examinees, after adjusting for sociodemographic factors and health status. In conclusion, among Ethiopian Israeli adolescents, abnormal blood pressure correlates directly with the time-lapse since immigration. Immigrant populations require targeted surveillance and appropriate intervention.

OBJECTIVE The relationship between acute pancreatitis and incident diabetes is unclear. We assessed whether a resolved single event of acute pancreatitis in childhood was associated with incident diabetes in adulthood. RESEARCH DESIGN AND METHODS A nationwide, population-based study of 1,802,110 Israeli adolescents (mean age 17.4 years [range 16–20]) who were examined before compulsory military service between 1979 and 2008 and whose data were linked to the Israeli National Diabetes Registry (INDR). Resolved pancreatitis was defined as a history of a single event of acute pancreatitis with normal pancreatic function at enrollment. Logistic regression analysis was applied. RESULTS Incident diabetes developed in 4.6% of subjects with resolved pancreatitis (13 of 281; none of these cases were identified as type 1 diabetes) and 2.5% among the unexposed group (44,463 of 1,801,716). Resolved acute pancreatitis was associated with incident diabetes with an odds ratio (OR) of 2.23 (95% CI 1.25–3.98) with adjustment for age, sex, and birth year. Findings persisted after further adjustments for baseline BMI and sociodemographic confounders (OR 2.10 [95% CI 1.15–3.84]). Childhood pancreatitis was associated with a diagnosis of diabetes at a younger age, with 92% of diabetes case subjects diagnosed before 40 years of age compared with 47% in the unexposed group (P = 0.002). The association accentuated when the study sample was limited to individuals of unimpaired health or normal BMI at baseline. CONCLUSIONS A history of acute pancreatitis in childhood with normal pancreatic function in late adolescence is a risk factor for incident type 2 diabetes, especially at young adulthood.

Over the last ten years, scientists have developed a method called targeted memory reactivation (TMR) for selectively strengthening memories during sleep. Prior to this, memory manipulation during sleep was at most a plot device in science fiction movies, but a large corpus of studies now demonstrates that TMR is both reliable and effective. TMR studies hypothesize that this method taps into normal consolidation mechanisms that require the repeated replay of memories during sleep. This idea has recently been supported by several new studies demonstrating that TMR upregulates the reactivation of cued memories, and that such upregulation predicts subsequent memory performance. This new body of work provides a unique window onto many properties of memory reactivation and helps to close the gap between our understanding of replay in rodents, where it has been visualised at the neural level for many years, and humans, where such studies are only just starting to become possible. We will discuss this new literature and highlight the vast potential of these new methods for future research.

Existing reviews have suggested that simulation studies of physical activity and environments are an emerging area, but none have explored findings in this area systematically. We used a scoping review framework to assess the use of simulation modeling to inform decision-making about built environment influences on physical activity. A systematic literature search was conducted in multiple databases in January 2018. Sixteen articles met the inclusion criteria. The studies evaluated interventions and features that were related to neighborhood safety (crime or traffic), active transportation, land use design, and walking and biking infrastructure. All of the studies focused on urban areas and most considered heterogeneity of outcomes based on local context. The majority of studies (70%) did not appear to have engaged or been used by practitioners or policy-makers to inform real-world decisions. There has been a growth of simulation modeling studies, but there remain gaps. The studies evaluated built environment interventions that have been recommended by expert panels, but more were of interventions related to active transportation; few considered recommended interventions to support recreational activity. Furthermore, studies have all focused on urban settings and there is a need to consider non-urban settings and how heterogeneity could reduce or exacerbate health disparities. More work to involve and evaluate practices for engaging stakeholders in model development and interpretation is also needed to overcome the translation of simulation research to practice gap, and realize its potential impact on the built environment and physical activity.

Background and Purpose: There is a continuous rise in the prevalence of adolescent obesity and incidence of stroke among young adults in many Western countries, but the association between them is unclear. Methods: A nationwide population-based study of 1 900 384 Israeli adolescents (58% men; mean age, 17.3 years) who were evaluated before mandatory military service during 1985 and 2013. Body mass index was classified according to the US Center for Disease Control and Prevention percentiles. Primary outcome was a first stroke event as recorded by the Israeli National Stroke Registry between 2014 and 2018. Cox proportional hazard models were applied. Results: There were 1088 first stroke events (921 ischemic and 167 hemorrhagic; mean diagnosis age, 41.0 years). Adolescent body mass index was significantly associated with a graded increase in the risk for any stroke, ischemic stroke, but less so with hemorrhagic stroke. The hazard ratios for the first ischemic stroke event were 1.4 (95% CI, 1.2–1.6), 2.0 (95% CI, 1.6–2.4), and 3.4 (95% CI, 2.7–4.3) for the 50th to 84th percentile, overweight and obese groups, respectively, after adjustment for sex, age, and sociodemographic confounders with the 5th to 49th body mass index percentile group as the reference. The respective hazard ratios after further adjustment for diabetes status were 1.3 (1.1–1.5), 1.6 (1.3–2.0), and 2.4 (1.9–3.1). Results persisted when the cohort was divided by diabetes status and when ischemic stroke before age 30 was the outcome. Conclusions: High adolescent body mass index was associated with ischemic stroke in young adults with or without diabetes. The rising prevalence of adolescent obesity may increase the future burden of stroke in young adults.

Context Thyroid hormones play a key role in systemic metabolism, yet the relationship between thyroid dysfunction and risk for type 2 diabetes is unclear. Objective To assess type 2 diabetes risk in adulthood among adolescents with thyroid disorders. Design and Setting A nationwide, population-based study of Israeli adolescents who were examined before military recruitment during 1988 to 2007 and were followed until December 31, 2016. Participants 1 382 560 adolescents (mean age 17.3 years). Interventions The diagnosis of thyroid disorders was based on recent thyroid function tests. Data were linked to the Israeli National Diabetes Registry. Cox proportional hazard models were applied. Main Outcome Measures Type 2 diabetes incidence. Results During a mean follow-up of 18.5 years, 1.12% (69 of 6,152) of adolescents with thyroid disorders were diagnosed with type 2 diabetes vs 0.77% of adolescents without thyroid disorders. The hazard ratio (HR) for type 2 diabetes was 2.3 (95% CI, 1.8-2.9) among those with thyroid disorders, after adjustment for sex, birth-year, body mass index, and sociodemographic confounders. The increased diabetes risk was observed in both men and women, with the presence or absence of obesity, and in the absence of other health conditions and was associated with different types of thyroid disorders. It was also similar when the outcome was defined as type 2 diabetes diagnosed at or before the age of 30 years (HR 2.3, 95% CI, 1.5-3.5). Conclusions Thyroid disorders diagnosed in adolescence are a risk factor for early-onset type 2 diabetes in both men and women.

Rapid progress in technologies such as calcium imaging and electrophysiology has seen a dramatic increase in the size and extent of neural recordings. Even so, interpretation of this data requires considerable knowledge about the nature of the representation and often depends on manual operations. Decoding provides a means to infer the information content of such recordings but typically requires highly processed data and prior knowledge of the encoding scheme. Here, we developed a deep-learning framework able to decode sensory and behavioral variables directly from wide-band neural data. The network requires little user input and generalizes across stimuli, behaviors, brain regions, and recording techniques. Once trained, it can be analyzed to determine elements of the neural code that are informative about a given variable. We validated this approach using electrophysiological and calcium-imaging data from rodent auditory cortex and hippocampus as well as human electrocorticography (ECoG) data. We show successful decoding of finger movement, auditory stimuli, and spatial behaviors – including a novel representation of head direction - from raw neural activity.

Severe obesity among children and adolescents is a significant global public health concern. The prevalence has markedly increased over the last decades, becoming common in many countries. Overwhelming rates of obesity among youth have prompted efforts to identify an evidence-based immediate- and long-term cardiometabolic risk factor profile in childhood-onset severe obesity, and to highlight gaps that require further investigation. The PubMed database was systematically searched in accordance with PRISMA guidelines. The search yielded 831 results, of which 60 fulfilled stringent criteria and were summarized in this review. The definition of severe obesity was variable, with only one half the publications using the definition BMI > 120% of the 95th percentile. Point estimates of the prevalence of at least one cardiometabolic risk factor in children with severe obesity reportedly range from 67 to 86%. Cross-sectional studies indicate that children and adolescents with severe obesity are at greater risk than those with mild obesity for type 2 diabetes, hypertension, fatty liver disease and dyslipidemia, already at childhood and adolescence. Robust epidemiological data on the long-term risk and actual point estimates in adulthood are lacking for these diseases as well as for other diseases (coronary heart disease, stroke, chronic kidney disease and cancer). Recent longitudinal studies indicate an increased risk for cardiomyopathy, heart failure, cardiovascular mortality and all-cause mortality in adulthood for adolescents with severe obesity compared to those with mild obesity. Given the alarming increase in the prevalence of severe obesity, the persistence of adiposity from childhood to adulthood and the precarious course of young adults with chronic comorbidities, the economic and clinical services burden on the healthcare system is expected to rise.

Urban development relies on many factors to remain viable, including infrastructure, services, and government provisions and subsidies. However, in situations involving federal or state level policy, development responds not just to one regulatory signal, but also to multiple signals from overlapping and competing jurisdictions. The 1982 U.S. Coastal Barrier Resources Act (CoBRA) offers an opportunity to study when and how development restrictions and economic disincentives protect natural resources by stopping or slowing urban development in management regimes with distributed authority and responsibility. CoBRA prohibits federal financial assistance for infrastructure, post-storm disaster relief, and flood insurance in designated sections (CoBRA units) of coastal barriers. How has CoBRA’s removal of these subsidies affected rates and types of urban development? Using building footprint and real estate data (n = 1,385,552 parcels), we compare density of built structures, land use types, residential house size, and land values within and outside of CoBRA units in eight Southeast and Gulf Coast states. We show that CoBRA is associated with reduced development rates in designated coastal barriers. We also demonstrate how local responses may counteract withdrawal of federal subsidies. As attention increases towards improving urban resilience in high hazard areas, this work contributes to understanding how limitations on infrastructure and insurance subsidies can affect outcomes where overlapping jurisdictions have competing goals.

OBJECTIVE Type 2 diabetes (T2D) is increasingly diagnosed at younger ages. We investigated the association of adolescent obesity with incident T2D at early adulthood. RESEARCH DESIGN AND METHODS A nationwide, population-based study evaluated 1,462,362 adolescents (59% men, mean age 17.4 years) during 1996–2016. Data were linked to the Israeli National Diabetes Registry. Weight and height were measured at study entry. Cox proportional models were applied. RESULTS During 15,810,751 person-years, 2,177 people (69% men) developed T2D (mean age at diagnosis 27 years). There was an interaction among BMI, sex, and incident T2D (Pinteraction = 0.023). In a model adjusted for sociodemographic variables, the hazard ratios for diabetes diagnosis were 1.7 (95% CI 1.4–2.0), 2.8 (2.3–3.5), 5.8 (4.9–6.9), 13.4 (11.5–15.7), and 25.8 (21.0–31.6) among men in the 50th–74th percentile, 75th–84th percentile, overweight, mild obesity, and severe obesity groups, respectively, and 2.2 (1.6–2.9), 3.4 (2.5–4.6), 10.6 (8.3–13.6), 21.1 (16.0–27.8), and 44.7 (32.4–61.5), respectively, in women. An inverse graded relationship was observed between baseline BMI and mean age of T2D diagnosis: 27.8 and 25.9 years among men and women with severe obesity, respectively, and 29.5 and 28.5 years among low-normal BMI (5th–49th percentile; reference), respectively. The projected fractions of adult-onset T2D that were attributed to high BMI (≥85th percentile) at adolescence were 56.9% (53.8–59.9%) and 61.1% (56.8–65.2%) in men and women, respectively. CONCLUSIONS Severe obesity significantly increases the risk for incidence of T2D in early adulthood in both sexes. The rise in adolescent severe obesity is likely to increase diabetes incidence in young adults in coming decades.

Including stakeholders in environmental model building and analysis is an increasingly popular approach to understanding ecological change. This is because stakeholders often hold valuable knowledge about socio-environmental dynamics and collaborative forms of modeling produce important boundary objects used to collectively reason about environmental problems. Although the number of participatory modeling (PM) case studies and the number of researchers adopting these approaches has grown in recent years, the lack of standardized reporting and limited reproducibility have prevented PM's establishment and advancement as a cohesive field of study. We suggest a four-dimensional framework (4P) that includes reporting on dimensions of (1) the Purpose for selecting a PM approach (the why); (2) the Process by which the public was involved in model building or evaluation (the how); (3) the Partnerships formed (the who); and (4) the Products that resulted from these efforts (the what). We highlight four case studies that use common PM software-based approaches (fuzzy cognitive mapping, agent-based modeling, system dynamics, and participatory geospatial modeling) to understand human–environment interactions and the consequences of ecological changes, including bushmeat hunting in Tanzania and Cameroon, agricultural production and deforestation in Zambia, and groundwater management in India. We demonstrate how standardizing communication about PM case studies can lead to innovation and new insights about model-based reasoning in support of ecological policy development. We suggest that our 4P framework and reporting approach provides a way for new hypotheses to be identified and tested in the growing field of PM.

Digital tools play an important role in supporting front-line health workers who deliver primary care. This paper explores the current state of efforts undertaken to move away from single-purpose applications of digital health towards integrated systems and solutions that align with national strategies. Through examples from health information systems, data and health worker training, this paper demonstrates how governments and stakeholders are working to integrate digital health services. We emphasize three factors as crucial for this integration: development and implementation of national digital health strategies; technical interoperability and collaborative approaches to ensure that digital health has an impact on the primary care level. Consolidation of technologies will enable an integrated, scaleable approach to the use of digital health to support health workers. PURPOSE As this edition explores a paradigm shift towards harmonization in primary healthcare systems, this paper explores complementary efforts undertaken to move away from single-purpose applications of digital health towards integrated systems and solutions that align with national strategies. It describes a paradigm shift towards integrated and interoperable systems that respond to health workers' needs in training, data and health information; and calls for the consolidation and integration of digital health tools and approaches across health areas, functions and levels of the health system. It then considers the critical factors that must be in place to support this paradigm shift. This paper aims not only to describe steps taken to move from fractured pilots to effective systems, but to propose a new perspective focused on consolidation and collaboration guided by national digital health strategies.

Summary The protein α-synuclein has a central role in the pathogenesis of Parkinson’s disease (PD). Similar to other proteins that accumulate in neurodegenerative disease, however, the function of α-synuclein remains unknown. Localization to the nerve terminal suggests a role in neurotransmitter release and over-expression inhibits regulated exocytosis, but previous work has failed to identify a clear physiological defect in mice lacking all three synuclein isoforms. Using adrenal chromaffin cells and neurons, we now find that both over-expressed and endogenous synuclein serve to accelerate the kinetics of individual exocytotic events, promoting cargo discharge and reducing pore closure (‘kiss-and-run’). Thus, synuclein exerts dose-dependent effects on dilation of the exocytotic fusion pore. Remarkably, mutations that cause PD abrogate this property of α-synuclein without impairing its ability to inhibit exocytosis when over-expressed, indicating a selective defect in normal function.

Summary The tumor suppressor p53 transcriptionally activates target genes to suppress cellular proliferation during stress. p53 has also been implicated in the repression of the proto-oncogene Myc, but the mechanism has remained unclear. Here, we identify Pvt1b, a p53-dependent isoform of the long noncoding RNA (lncRNA) Pvt1, expressed 50 kb downstream of Myc, which becomes induced by DNA damage or oncogenic signaling and accumulates near its site of transcription. We show that production of the Pvt1b RNA is necessary and sufficient to suppress Myc transcription in cis without altering the chromatin organization of the locus. Inhibition of Pvt1b increases Myc levels and transcriptional activity and promotes cellular proliferation. Furthermore, Pvt1b loss accelerates tumor growth, but not tumor progression, in an autochthonous mouse model of lung cancer. These findings demonstrate that Pvt1b acts at the intersection of the p53 and Myc transcriptional networks to reinforce the anti-proliferative activities of p53.

How is the strength of a memory determined? This review discusses three main factors that contribute to memory enhancement - 1) emotion, 2) targeted memory reactivation, and 3) neural reinstatement. Whilst the mechanisms through which memories become selectively enhanced vary, this review demonstrates that activation of the basolateral amygdala and hippocampal formation are crucial for facilitating encoding, consolidation, and retrieval. Here we suggest methodological factors to consider in future studies, and discuss several unanswered questions that should be pursued in order to clarify selective memory enhancement.

IntroductionPituitary gigantism is a rare but significant paediatric condition with complexities surrounding diagnosis and management. Transsphenoidal surgery (TSS) is the treatment of choice; however, medical treatment is often considered as adjuvant therapy.CaseA 10½ -year-old boy presented with tall stature and a height velocity of 11 cm/year. His height was 178.7 cm (+5.8 SD above mean) and insulin-like growth factor-1 (IGF-1) was elevated. An oral glucose tolerance test demonstrated non-suppression of growth hormone (GH). Initial contrast MRI was inconclusive, but C-11 methionine functional positron emission tomography CT identified a 6 mm pituitary microadenoma. A multidisciplinary team clinic held with the family allowed discussion about medical and surgical treatment options. Due to a number of factors including the patient’s young age, prepubertal status, a wish to allow him to settle into his new high school and his desire to reach a final height taller than his father’s height, it was decided to try medical therapy first with a somatostatin analogue. Pubertal induction was also commenced and bilateral epiphysiodesis surgery performed. Initial response to octreotide was positive; however, 4 months into therapy his IGF-1 was climbing and a repeat GH profile was not fully suppressed. The patient therefore proceeded to have successful TSS excision of the adenoma.ConclusionRare cases such as this require sharing of knowledge and expertise, so the best possible care is offered. It is often necessary to work across sites and disciplines. Each case requires an individual approach tailored to the patient and their family.

Decades of research have established two central roles of the hippocampus--memory consolidation and spatial navigation. Recently, a third function of the hippocampus has been proposed: simulating future events. However, claims that the neural patterns underlying simulation occur without prior experience have come under fire in light of newly published data.

Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human genetic studies have implicated the endosomal Na+/H+ exchanger NHE9 in both autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). Plasma membrane NHEs regulate cytosolic pH, but the role of intracellular isoforms has remained unclear. We now find that inactivation of NHE9 in mice reproduces behavioral features of ASD including impaired social interaction, repetitive behaviors, and altered sensory processing. Physiological characterization reveals hyperacidic endosomes, a cell-autonomous defect in glutamate receptor expression and impaired neurotransmitter release due to a defect in presynaptic Ca2+ entry. Acute inhibition of synaptic vesicle acidification rescues release but without affecting the primary defect due to loss of NHE9., The Na+/H+ exchanger NHE9 is proposed to regulate the H+ electrochemical gradient across endosomal membranes. Here, the authors find that NHE9 knockout mice show autism spectrum disorder-like behaviors and disrupted synaptic vesicle exocytosis due to impaired presynaptic calcium entry.

© 2017 by the Ecological Society of America. Including stakeholders in environmental model building and analysis is an increasingly popular approach to understanding ecological change. This is because stakeholders often hold valuable knowledge about socio-environmental dynamics and collaborative forms of modeling produce important boundary objects used to collectively reason about environmental problems. Although the number of participatory modeling (PM) case studies and the number of researchers adopting these approaches has grown in recent years, the lack of standardized reporting and limited reproducibility have prevented PM's establishment and advancement as a cohesive field of study. We suggest a four-dimensional framework (4P) that includes reporting on dimensions of (1) the Purpose for selecting a PM approach (the why); (2) the Process by which the public was involved in model building or evaluation (the how); (3) the Partnerships formed (the who); and (4) the Products that resulted from these efforts (the what). We highlight four case studies that use common PM software-based approaches (fuzzy cognitive mapping, agent-based modeling, system dynamics, and participatory geospatial modeling) to understand human-environment interactions and the consequences of ecological changes, including bushmeat hunting in Tanzania and Cameroon, agricultural production and deforestation in Zambia, and groundwater management in India. We demonstrate how standardizing communication about PM case studies can lead to innovation and new insights about model-based reasoning in support of ecological policy development. We suggest that our 4P framework and reporting approach provides a way for new hypotheses to be identified and tested in the growing field of PM.

The hippocampus is critical for the storage of new autobiographical experiences as memories. Following an initial encoding stage in the hippocampus, memories undergo a process of systems-level consolidation, which leads to greater stability through time and an increased reliance on neocortical areas for retrieval. The extent to which the retrieval of these consolidated memories still requires the hippocampus is unclear, as both spared and severely degraded remote memory recall have been reported following post-training hippocampal lesions. One difficulty in definitively addressing the role of the hippocampus in remote memory retrieval is the precision with which the entire volume of the hippocampal region can be inactivated. To address this issue, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), a chemical-genetic tool capable of highly specific neuronal manipulation over large volumes of brain tissue. We find that remote (>7 weeks after acquisition), but not recent (1–2 days after acquisition) contextual fear memories can be recalled after injection of the DREADD agonist (CNO) in animals expressing the inhibitory DREADD in the entire hippocampus. Our data demonstrate a time-dependent role of the hippocampus in memory retrieval, supporting the standard model of systems consolidation., National Institute of Mental Health (U.S.) (NIMH (5R01MH061976)), National Institute of Mental Health (U.S.) (NIMH (R01 MH084966)), United States. Defense Advanced Research Projects Agency (Grant W911NF-10-1-0059), European Research Council (ERC) (Horizon 2020: ERC starter grant-CHIME)

The two unrelated miRNAs miR-143 and miR-145, coexpressed from the miR-143/145 cluster, have been proposed to act as tumor suppressors in human cancer, and therapeutic benefits of delivering miR-143 and miR-145 to tumors have been reported. In contrast, we found that tumor-specific deletion of miR-143/145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. This was consistent with the lack of endogenous miR-143/145 expression in normal and transformed lung epithelium. Surprisingly, miR-143/145 in the tumor microenvironment dramatically promoted tumor growth by stimulating the proliferation of endothelial cells. Loss of miR-143/145 in vivo led to derepression of the miR-145 target CAMK1D, an inhibitory kinase, which when overexpressed prevents mitotic entry of endothelial cells. As a consequence, tumors in miR-143/145-deficient animals exhibited diminished neoangiogenesis, increased apoptosis, and their expansion was limited by the tumor’s ability to co-opt the alveolar vasculature. These findings demonstrate that stromal miR-143/145 promotes tumorigenesis and caution against the use of these miRNAs as agents in cancer therapeutics.SIGNIFICANCE: This study shows that miR-143/145 expressed from the tumor microenvironment stimulates neoangiogenesis and supports tumor expansion in the lung, demonstrating a surprising role for the putative tumor suppressor miRNA cluster in promoting tumorigenesis. We propose inhibition of miR-143/145 as a therapeutic avenue to modulate tumor neoangiogenesis., National Institutes of Health (U.S.) (Grant P01-CA42063-26), National Cancer Institute (U.S.) (Grant P30-CA14051)

Pitch perception is an important component of hearing, allowing us to appreciate melodies and harmonies as well as recognize prosodic cues in speech. Multiple studies over the last decade have suggested that pitch is represented by a pitch-processing center in auditory cortex. However, recent data (Barker D, Plack CJ, Hall DA. Cereb Cortex. In press; Hall DA, Plack CJ. Cereb Cortex 19: 576–585, 2009) now challenge these previous claims of a human “pitch center.”

How the brain processes temporal information embedded in sounds is a core question in auditory research. This article synthesizes recent studies from our laboratory regarding neural representations of time-varying signals in auditory cortex and thalamus in awake marmoset monkeys. Findings from these studies show that 1) the primary auditory cortex (A1) uses a temporal representation to encode slowly varying acoustic signals and a firing rate-based representation to encode rapidly changing acoustic signals, 2) the dual temporal-rate representations in A1 represent a progressive transformation from the auditory thalamus, 3) firing rate-based representations in the form of a monotonic rate-code are also found to encode slow temporal repetitions in the range of acoustic flutter in A1 and more prevalently in the cortical fields rostral to A1 in the core region of marmoset auditory cortex, suggesting further temporal-to-rate transformations in higher cortical areas. These findings indicate that the auditory cortex forms internal representations of temporal characteristics of sounds that are no longer faithful replicas of their acoustic structures. We suggest that such transformations are necessary for the auditory cortex to perform a wide range of functions including sound segmentation, object processing and multi-sensory integration. © 2008 IBRO.

Domestic public debate continues over the economic impacts of environmental regulations that require environmental restoration. This debate has occurred in the absence of broad-scale empirical research on economic output and employment resulting from environmental restoration, restoration-related conservation, and mitigation actions — the activities that are part of what we term the “restoration economy.” In this article, we provide a high-level accounting of the size and scope of the restoration economy in terms of employment, value added, and overall economic output on a national scale. We conducted a national survey of businesses that participate in restoration work in order to estimate the total sales and number of jobs directly associated with the restoration economy, and to provide a profile of this nascent sector in terms of type of restoration work, industrial classification, workforce needs, and growth potential. We use survey results as inputs into a national input-output model (IMPLAN 3.1) in order to estimate the indirect and induced economic impacts of restoration activities. Based on this analysis we conclude that the domestic ecological restoration sector directly employs ~ 126,000 workers and generates ~ $9.5 billion in economic output (sales) annually. This activity supports an additional 95,000 jobs and $15 billion in economic output through indirect (business-to-business) linkages and increased household spending.

The serotonin transporter (SERT) is a principal site of action of therapeutic antidepressants in the brain. Without exception, these inhibitors of serotonin transport contain an amine nitrogen in their structure. We previously demonstrated that novel compounds without an amine nitrogen in their structure (non-amines), blocked dopamine transport in cells transfected with the human dopamine transporter. The present study investigated whether, in the absence of an amine nitrogen, certain non-amines bind selectively to the SERT and block the transport of serotonin. At 10 μM concentration, select non-amines displayed no, or little, affinity for 9 serotonin, 5 dopamine, 7 adrenergic, 5 muscarinic cholinergic, 3 opiate and histamine receptors. The affinities of non-amines for [3H]citalopram binding sites on the SERT and their potencies for blocking [3H]serotonin transport were measured in cloned human SERT stably or transiently expressed in HEK-293. Whether oxa- or carba-based, non-amines bound to [3H]citalopram-labeled sites and blocked [3H]serotonin transport in the low nanomolar range, at values equal to or higher than those of some conventional antidepressants. A non-amine, O-1809, was 99-fold more selective for the serotonin over the dopamine transporter. As substituents on the aromatic ring of non-amines confer high affinity for the SERT, we investigated the hypothesis that aromatic–aromatic interactions may contribute significantly to non-amine/transporter association. A SERT mutant was produced in which a highly conserved aromatic amino acid, phenylalanine 548, was replaced by an alanine (F548A). Although the affinities of several non-amines were unchanged in the mutant SERT, the affinity of imipramine was decreased, revealing possible differences in amine and non-amine binding domains on the SERT. The similar affinities of non-amines and conventional antidepressant drugs for the SERT support the view that an amine nitrogen is not essential for drugs to block serotonin transport with high affinity. Non-amines open avenues for developing a new generation of antidepressants. Synapse 42:129–140, 2001. © 2001 Wiley-Liss, Inc.

Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson’s disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. α-Synuclein localizes specifically to the nerve terminal and inhibits neurotransmitter release when over-expressed, but the knockout has a modest effect on synaptic transmission, suggesting alternative presynaptic roles. Natively unstructured, synuclein adopts a helical conformation on membrane binding and recent work suggests a role in membrane remodeling. In neural degeneration, synuclein misfolds and aggregates as a β-sheet. Multiple observations now suggest propagation of the misfolded protein as a prion, providing a mechanism for the spread of degeneration through the neuraxis. However, the factors that trigger the original misfolding remain unknown.

Ecosystem service markets are popular policy tools for ecosystem protection. Advanced credit releases are an important factor affecting the supply side of ecosystem markets. Under an advanced credit release policy, regulators give ecosystem suppliers a fraction of the total ecosystem credits generated by a restoration project before it is verified that the project actually achieves the required ecological thresholds. In spite of their prominent role in ecosystem markets, there is virtually no regulatory or research literature on the proper design of advanced credit release policies. Using U.S. aquatic ecosystem markets as an example, we develop a principal–agent model of the behavior of regulators and wetland/stream mitigation bankers to determine and explore the optimal degree of advance credit release. The model highlights the tension between regulators’ desire to induce market participation, while at the same time ensuring that bankers successfully complete ecological restoration. Our findings suggest several simple guidelines for strengthening advanced credit release policy.

The threat of a chemical war has profound impacts on all layers of society. Hospitalized mental patients, as we have observed them, react in more extreme ways than staff members. They may react overanxiously, totally apathetically, or in context-related flights to partial sanity. Denial and projection were heavily used defense mechanisms together with a tendency of the more acute patients to plunge into their bizarre idiosyncratic world, lending strange meanings to what was happening in the world. Many patients were found to have strong narcissistic traits and to invest most of their libidinal energies in their private world. In times of stress this results in even greater social isolation. Different types of patients in different phases of their illness react differently to such overpowering stress, and the way they react illustrates their cognitive, behavioral, and social deficiencies. WWII literature on the reactions of mentally ill patients to "fly-bombing" seem not to take into consideration the different possible reactions of patients. This may be due to a change in emphasis in the care of mentally disturbed individuals in the last two decades. We propose to use even such an extremely stressful situation as a challenge to the mental health profession to further the well-being of their patients.

Norbin Knockout Metabotropic glutamate receptors (mGluRs) are critical neurotransmitter sensors implicated in central neuronal functions like learning and memory and in diseases of the nervous system. Wang et al. (p. 1554 ) searched for proteins that interact with mGluR5a and identified a previously unrecognized component of the receptor signaling complex. The protein Norbin directly interacted with the receptor. Loss of Norbin in mice or cultured cells showed that it is necessary for the accumulation of mGluR5a in the cell membrane, for normal modulation of synaptic plasticity, and for some behavioral responses.

The U.S. Clean Water Act requires compensatory mitigation for wetland and stream damage through restoration of damaged aquatic ecosystems. We evaluate the North Carolina’s Ecosystem Enhancement Program (EEP), a state agency responsible for compensatory mitigation. We compare communities gaining and losing aquatic resources during mitigation, finding new types of socioeconomic disparities that contradict previous studies of mitigation program behavior. We find average distances between impact and mitigation sites for streams (43.53 km) and wetlands (50.3 km) to be larger in North Carolina than in off-site mitigation programs in other regions previously studied. We also find that aquatic resources in the State are lost from urbanized areas that are more affluent, white, and highly educated, and mitigated at sites in rural areas that are less affluent, less well educated, and have a higher percentage of minorities. We also analyze the relationship between urban growth indicators and EEP accumulation of compensation sites. Growth indicators and long-term population projections are uncorrelated with both projected transportation impacts and advance mitigation acquired by the EEP, suggesting that growth considerations can be more effectively incorporated into the EEP’s planning process. We explore the possibility that spatial mismatches could develop between watersheds that are rapidly growing and those that are gaining mitigation. We make recommendations for ways that regulators incorporate growth indicators into the mitigation planning process.

This paper reports the clinical findings of a sibling group program used in an exploratory study designed to provide information about the unmet psychosocial needs of siblings of pediatric cancer patients. Two multisession groups, one for elementary school age children and one for adolescents, were held at a metropolitan teaching hospital to enable siblings to identify, express and master their feelings of anxiety and isolation in a supportive atmosphere. Eight major sources of anxiety and isolation were identified. Recommendations are made for integrating preventive intervention with siblings into standard hospital social work practice.

Background: Axillary hyperhidrosis is a chronic condition characterized by excess axillary perspiration. This results in considerable patient morbidity, with no consistently efficacious medical or surgical treatment method described in the literature. Methods: All cases of axillary hyperhidrosis over a 5-year period were reviewed retrospectively. Data were gathered by a chart review and telephone interview. Inclusion criteria included primary hyperhidrosis, failed conservative therapy, no prior surgical therapy, surgical management using a new arthroscopic shaver technique (R.L.B.-S.), and 6 months of postoperative follow-up. The technique used was consistent between surgeons. Sweating severity was assessed using a subjective numerical rating scale ranging from 1 to 10. Patient demographics, symptom history, results, and complications were analyzed. Results: Average follow-up for 50 patients meeting the inclusion criteria was 28 months. The subjective severity scale demonstrated severity of 9.8 of 10 preoperatively and 2.3 of 10 postoperatively. Three patients (6 percent) reported mild recurrence of symptoms (4.6 of 10), which was not severe enough to seek further treatment. The average follow-up of those patients was 18.5 months. An overall subjective satisfaction of 96 percent was found, with a treatment success rate of 94 percent. Complications were minimal and self-limiting. The average time away from employment was 3.9 days and the average surgical operating room time was 46 minutes. Conclusions: The authors' new arthroscopic shaver technique is efficacious, with no significant morbidity, a 96 percent satisfaction rate, a subjectively measured 75 percent reduction of sweat, and a recurrence rate of only 6 percent. For cases of primary hyperhidrosis affecting the axilla not amenable to conservative treatment, the authors recommend an arthroscopic shaver technique as the first-line treatment of choice.

The classical bordetellae are comprised of three subspecies that differ from broad to very limited host specificity. Although several lineages appear to have specialized to particular host species, most retain the ability to colonize and grow in mice, providing a powerful common experimental model to study their differences. One of the subspecies, Bordetella parapertussis, is composed of two distinct clades that have specialized to different hosts: one to humans (Bpphu), and the other to sheep (Bppov). While Bpphu and the other classical bordetellae can efficiently colonize mice, Bppov strains are severely defective in their ability to colonize the murine respiratory tract. Bppov genomic analysis did not reveal the loss of adherence genes, but substantial mutations and deletions of multiple genes involved in the production of O-antigen, which is required to prevent complement deposition on B. bronchiseptica and Bpphu strains. Bppov lacks O-antigen and, like O-antigen mutants of other bordetellae, is highly sensitive to murine complement-mediated killing in vitro. Based on these results, we hypothesized that Bppov failed to colonize mice because of its sensitivity to murine complement. Consistent with this, the Bppov defect in the colonization of wild type mice was not observed in mice lacking the central complement component C3. Furthermore, Bppov strains were highly susceptible to killing by murine complement, but not by sheep complement. These data demonstrate that the failure of Bppov to colonize mice is due to sensitivity to murine, but not sheep, complement, providing a mechanistic example of how specialization that accompanies expansion in one host can limit host range.

Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered to mediate stimulant-associated behaviors since it is low in dopamine. Yet, the primate cerebellar vermis (lobules II-III and VIII-IX) has been reported to contain axonal dopamine transporter immunoreactivity (DAT-IR). We hypothesized that DAT-IR-containing vermis areas would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands. We used BOLD fMRI to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and positron emission tomography imaging of healthy humans to determine whether the DAT-selective ligand [11C]altropane accumulated in those vermis regions. Cocaine-related cues selectively induced BOLD activation in lobules II-III and VIII-IX in cocaine users, and, at early time points after ligand administration, we found appreciable [11C]altropane accumulation in lobules VIII-IX, possibly indicating DAT presence in this region. These data suggest that parts of cerebellar vermis mediate cocaine's persisting and acute effects. In light of prior findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, we propose that the vermis be considered one of the structures involved in cocaine- and other incentive-related behaviors.

Background: The purpose of this study was to prospectively assess changes in overall health-related quality of life and breast-related symptoms in women undergoing reduction mammaplasty, and to compare preoperative and postoperative health-related quality of life with that of the normal population. Methods: Fifty-six patients were evaluated preoperatively and 6 months postoperatively with three questionnaires: the Short Form-36 Health Survey, the Symptom Inventory Questionnaire, and the Rosenberg Self-Esteem Scale. Surgeons completed preoperative patient assessment forms, operative note forms, and postoperative patient assessment forms. Results: Comparison of preoperative and postoperative health-related quality of life showed significant improvements in Short Form-36 Health Survey scores (p < 0.005), the Rosenberg Self-Esteem Scale (p < 0.001), and all symptoms on the Symptom Inventory Questionnaire (p < 0.003). Preoperative mean Short Form-36 Health Survey scores were lower than in the normal population in several areas (p < 0.005). Postoperatively, none of the mean Short Form-36 Health Survey scores were significantly lower than population norms. Conclusions: This study determined that there is a significant improvement of physical symptoms and health-related quality of life in women undergoing reduction mammaplasty at 6 months after surgery. Before surgery, these patients have a significantly worse health-related quality of life than the normal population, but they normalize postoperatively.

UNLABELLED Acetylated distarch phosphate (ADiSP) is a modified starch used in some baby foods. The bioavailability of ADiSP and a native (unmodified) starch was evaluated in 20 normal infants and 21 toddlers aged 8-24 mo with chronic non-specific diarrhea. Formulae contained 8% native or 8% modified waxy maize starch. No infant or toddler consuming Formula N (native starch) had elevated peak breath hydrogen levels (20 ppm or greater), stools clinically positive for reducing substances (0.75% or greater) or loose stools. Fourteen infants received formula M (modified starch): 2 had elevated breath hydrogen, 1 had positive stools and another had loose stools. Of the 21 toddlers fed formula M, 2 had elevated breath hydrogen, but none had positive stools or loose stools. Formula NS (native starch with 2% sorbitol) had little effect on breath hydrogen in the infants but significantly increased it in the toddlers. Formula NS produced loose stools in 2 toddlers but no clinically positive stools in any infant or toddler. Formula MS (modified starch with 2% sorbitol) elevated breath hydrogen in 3 infants and 8 toddlers, and produced positive stools in 2 infants and 2 toddlers, and loose stools in 4 infants and 7 toddlers. Formula MSF (modified starch with 2% sorbitol and 5% fructose) elevated breath hydrogen in 7 infants and 10 toddlers, positive stools in 7 infants and 6 toddlers, and loose stools or diarrhea in 7 infants and 11 toddlers. CONCLUSION ADiSP modified starch can increase breath hydrogen and produce loose stools. Sorbitol and fructose aggravate the malabsorption, in some cases leading to frank diarrhea.

Pain is the leitmotif of my life, but despite all the restrictions I'm still able to lead a self-reliant, happy existence.

Plexiform neurofibromatosis is a feature of von Recklinghausen's disease. Head and neck lesions may produce varying degrees of cosmetic and functional deformity. However, life-threatening hemorrhage into facial plexiform neurofibromas has not been previously reported.We report two patients with von Recklinghausen's disease who experienced massive hemorrhage into facial neurofibromas, one following a blunt injury and the other without a known initiating event.Conservative management did not stop the hemorrhage into facial neurofibromas in either instance. Surgical exploration was mandated for hemorrhage control and evacuation of blood clots. Hemostasis was attained by a combination of hypotensive anesthesia and chromic catgut suture ligatures.These case reports demonstrate a potentially lethal complication in patients with facial plexiform neurofibroma. Where a competent and experienced interventional neuroradiologist is not available, surgical exploration should be undertaken to control bleeding.

In this report we describe three very different and interesting complications of the Le Fort I osteotomy. The first case is of a unilateral third nerve palsy developing as a result of a carotid-cavernous fistula and false aneurysm of the internal carotid artery. The second complication to be reported is total unilateral blindness. The third case is one of total avulsion of a lateral segment of the palate in a patient with a complete bilateral cleft of the primary and secondary palates. All complications were the result of a Le Fort I osteotomy performed for correction of midface hypoplasia secondary to congenital cleft lip and palate. The literature is reviewed, and the pathomechanics of each injury are hypothesized.

A retrospective review of 146 cases with Le Fort I osteotomy performed between 1981 and 1990 is presented. A complication of 6.1% was recorded. These complications include intraoperative hemorrhage, trigeminal nerve injury, oronasal fistula and dental injury. Although the Le Fort I osteotomy has proven to be relatively safe, improvements in technique will further reduce the incidence and the severity of complications.

Polyotia is an extremely rare congenital anomaly of the external ear. Only four case reports are documented in the literature. A 13-month-old child with a mirror-image duplication of the left auricle was operated on in a one-stage corrective procedure. The duplicated portion of the affected ear was positioned anteriorly and measured approximately two-thirds the size of the posterior, normally oriented portion. There were two fully developed conchae and one fully developed and one partially developed anthelix and lobule. The entire complex had a single external auditory meatus and no tragus. There were no other congenital anomalies, and the child was developmentally normal. The technique for surgical correction is described, and a review of the literature is presented.

Deficiency of the free border of the lip is frequently encountered in secondary cleft lip deformities. The free border of the lip consists of the orbicularis oris marginalis muscle and its overlying subcutaneous tissue, vermilion, and mucosa. The pathology may involve any or all of these components. When there is an absolute shortage of subcutaneous tissue or orbicularis oris marginalis muscle, extra tissue from another source must be used for augmentation. A temporoparietal fascial graft is a simple and reliable method to increase the fullness of the free border of the lip. The tissue is soft in consistency and displays minimal resorption. Most important, more complicated procedures such as an Abbé flap or tongue flap may be avoided. From July of 1988 until June of 1992, the temporoparietal fascial graft was used successfully to correct deficiencies of the free border of the lip in 20 patients with cleft lip deformities. There were two graft exposures that healed with conservative treatment. The procedure is a useful method of augmenting both lateral lip and central lip deficiencies in secondary and tertiary cleft lip deformities.