Artificial intelligence for human gunshot wound classification.

Certain features are helpful in the identification of gunshot entrance and exit wounds, such as the presence of muzzle imprints, peripheral tears, stippling, bone beveling, and wound border irregularity. Some cases are less straightforward and wounds can thus pose challenges to an emergency room doctor or forensic pathologist. In recent years, deep learning has shown promise in various automated medical image classification tasks. This study explores the feasibility of using a deep learning model to classify entry and exit gunshot wounds in digital color images. A collection of 2418 images of entrance and exit gunshot wounds were procured. Of these, 2028 entrance and 1314 exit wounds were cropped, focusing on the area around each gunshot wound. A ConvNext Tiny deep learning model was trained using the Fastai deep learning library, with a train/validation split ratio of 70/30, until a maximum validation accuracy of 92.6% was achieved. An additional 415 entrance and 293 exit wound images were collected for the test (holdout) set. The model achieved an accuracy of 87.99%, precision of 83.99%, recall of 87.71%, and F1-score 85.81% on the holdout set. Correctly classified were 88.19% of entrance wounds and 87.71% of exit wounds. The results are comparable to what a forensic pathologist can achieve without other morphologic cues. This study represents one of the first applications of artificial intelligence to the field of forensic pathology. This work demonstrates that deep learning models can discern entrance and exit gunshot wounds in digital images with high accuracy.

Factors that influence compliance for referral from primary care to hospital for maternal and neonatal complications in Bosaso, Somalia: a qualitative study.

OBJECTIVES: To estimate referral compliance and examine factors that influence decisions to comply with referral for newborn and maternal complications in Bosaso, Somalia. SETTING: Bosaso, Somalia, is a large port city that hosts a large proportion of internally displaced persons. The study was conducted at the only four primary health centres offering 24/7 delivery services and the only public referral hospital in Bosaso. PARTICIPANTS: All pregnant women who sought care at four primary centres and were referred to the hospital for maternal complications or mothers whose newborns were referred for neonatal complications were approached for enrolment from September to December 2019. In-depth interviews (IDIs) of 54 women and 14 healthcare workers (HCWs) were conducted. OUTCOME MEASURES: This study examined timely referral compliance from the primary centre to the hospital. IDIs were analysed for a priori themes investigating the decision-making process and experience of care for maternal and newborn referrals. RESULTS: Overall, 94% (n=51/54) of those who were referred, 39 maternal and 12 newborns, complied with the referral and arrived at the hospital within 24 hours. Of the three that did not comply, two delivered on the way, and one cited lack of money as the reason for noncompliance. Four themes emerged: trust in medical authority, cost of transportation and care, quality of care, and communications. The factors that facilitated compliance were the availability of transportation, family support, concern for health, and trust in medical authority. HCWs raised the importance of considering the maternal-newborn dyad throughout the referral process, and the need for official standard operating procedures for referrals including communications between the primary care and the hospital. CONCLUSIONS: High compliance for referral from primary to hospital care for maternal and newborn complications was observed in Bosaso, Somalia. Costs associated with transportation and care at the hospital need attention to motivate compliance.

Anomalous papillary muscles-Implications in the surgical treatment of hypertrophic obstructive cardiomyopathy.

OBJECTIVES: To categorize and assess the functional significance of anomalous papillary muscles in patients undergoing surgical management of obstructive hypertrophic cardiomyopathy. METHODS: We reviewed the records of operations for obstructive hypertrophic cardiomyopathy and identified 73 patients with an anomalous papillary muscle. Anomalous papillary muscles inserting directly into the body of the anterior mitral valve leaflet were classified as type I, those with both direct insertion into the body of the leaflet and attachment to the free edge of the anterior leaflet were categorized as type II, and anomalous papillary muscles inserting into the free edge of the anterior leaflet were grouped as type III. Additionally, we investigated detection rates by preoperative transthoracic echocardiography, intraoperative transesophageal echocardiography, and cardiac magnetic resonance imaging. RESULTS: The mean age of patients was 51.9 ± 12.3 years, and 49.3% were male. The anomalous papillary muscle was classified as type I in 31.5% of patients, type II in 35.6%, and type III in 32.9%. Only type I and type II anomalous papillary muscles contributed to left ventricular outflow tract obstruction. The anomalous papillary muscle was detected on preoperative transthoracic echocardiography in 11% of patients and by intraoperative transesophageal echocardiography in 27.4% of patients. No anomalous papillary muscles were identified on cardiac magnetic resonance imaging. All patients underwent septal myectomy with or without (n = 34) associated excision of the anomalous papillary muscle. Excision of the papillary muscles was more common in patients with type I and II (76.4% and 80.8%, respectively) when compared with type III (4.2%). Ten patients underwent mitral valve repair, and 1 patient had mitral valve replacement. CONCLUSIONS: Papillary muscle abnormalities are important findings in patients with obstructive hypertrophic cardiomyopathy but are not identified preoperatively in the majority of patients. Recognition of anomalous papillary muscles intraoperatively and understanding of the morphologic subtypes are critical to adequate gradient relief and preservation of mitral valve function. The optimum approach involves a transaortic extended septal myectomy associated with the resection of the anomalous papillary muscles in patients with type I and II anatomy.

The Donnan-dominated resting state of skeletal muscle fibers contributes to resilience and longevity in dystrophic fibers.

Duchenne muscular dystrophy (DMD) is an X-linked dystrophin-minus muscle-wasting disease. Ion homeostasis in skeletal muscle fibers underperforms as DMD progresses. But though DMD renders these excitable cells intolerant of exertion, sodium overloaded, depolarized, and spontaneously contractile, they can survive for several decades. We show computationally that underpinning this longevity is a strikingly frugal, robust Pump-Leak/Donnan (P-L/D) ion homeostatic process. Unlike neurons, which operate with a costly "Pump-Leak-dominated" ion homeostatic steady state, skeletal muscle fibers operate with a low-cost "Donnan-dominated" ion homeostatic steady state that combines a large chloride permeability with an exceptionally small sodium permeability. Simultaneously, this combination keeps fiber excitability low and minimizes pump expenditures. As mechanically active, long-lived multinucleate cells, skeletal muscle fibers have evolved to handle overexertion, sarcolemmal tears, ischemic bouts, etc.; the frugality of their Donnan dominated steady state lets them maintain the outsized pump reserves that make them resilient during these inevitable transient emergencies. Here, P-L/D model variants challenged with DMD-type insult/injury (low pump-strength, overstimulation, leaky Nav and cation channels) show how chronic "nonosmotic" sodium overload (observed in DMD patients) develops. Profoundly severe DMD ion homeostatic insult/injury causes spontaneous firing (and, consequently, unwanted excitation-contraction coupling) that elicits cytotoxic swelling. Therefore, boosting operational pump-strength and/or diminishing sodium and cation channel leaks should help extend DMD fiber longevity.

Immediate Postpartum Long-Acting Reversible Contraception: A Comparison Across Six Humanitarian Country Contexts.

Postpartum family planning (FP) could prevent more than 30% of maternal deaths by effectively spacing births; this is particularly relevant in humanitarian contexts given that disproportionate maternal death occurs in countries affected by crises. In humanitarian settings, where accessing functional facilities is challenging with security risks that constrain movement, many women are unable to return for their 6-week postpartum visits and thus unable to receive FP counseling and adopt a method that suits their fertility intentions. Thus, immediate postpartum family planning (IPPFP) interventions, focused on long-acting reversible contraception (LARC) and tailored toward humanitarian contexts, could contribute to healthy timing and spacing of pregnancy, particularly among postpartum women, and improve maternal and newborn health. In 2014, Save the Children integrated postpartum intrauterine device (IUD) services into its FP package in emergency settings. In 2017, this expanded to include postpartum implant uptake as well, given updated World Health Organization guidelines. Three countries (Democratic Republic of Congo, Somalia, and Pakistan) opted for higher-intensity programming for IPPFP with a specific focus on LARC. This involved training delivery-room providers on counseling and provision of IPPFP, as well as training antenatal care nurses in counseling pregnant women on IPPFP options. Three countries (Rwanda, Syria, and Yemen) did not implement notable IPPFP interventions, although they provided the standard of care and monitored provision via monthly service delivery data. Using data from 2016 to 2019, we examined trends in immediate postpartum LARC (IPP LARC) uptake and compared countries with higher-intensity IPP LARC interventions to countries providing standard care. Tests of association were performed to assess the significance of these differences. In the country programs with higher-intensity IPPFP interventions, IPP LARC as a percentage of all deliveries was much higher overall during the July 2016-December 2019 period. The IPP LARC intervention had a significant impact on the overall proportion of women and girls who adopted an IUD or implant within the first 48 h of delivery, F (1, 250) = 523.16, p < 0.001. The mean percentage of IPP LARC among all deliveries in intervention country programs was 10.01% as compared to 0.77% in countries providing standard care. Results suggest that there is demand for IPP LARC in humanitarian contexts and that uptake increases when multipronged solutions focusing on provider training, community outreach, and service integration are applied.

Strengthening Health Systems in Humanitarian Settings: Multi-Stakeholder Insights on Contraception and Postabortion Care Programs in the Democratic Republic of Congo and Somalia.

Background: In humanitarian settings, strengthening health systems while responding to the health needs of crisis-affected populations is challenging and marked with evidence gaps. Drawing from a decade of family planning and postabortion care programming in humanitarian settings, this paper aims to identify strategic components that contribute to health system strengthening in such contexts. Materials and Methods: A diverse range of key informants from North Kivu (Democratic Republic of Congo, DRC) and Puntland (Somalia), including female and male community members, adolescents and adults, healthcare providers, government and community leaders, participated in qualitative interviews, which applied the World Health Organization health system building blocks framework. Data were thematically analyzed according to this framework. Results: Findings from the focus group discussions (11 in DRC, 7 in Somalia) and key informant interviews (seven in DRC, four in Somalia) involving in total 54 female and 72 male participants across both countries indicate that health programs in humanitarian settings, such as Save the Children's initiative on family planning and postabortion care, could contribute to strengthening health systems by positively influencing national policies and guidance, strengthening local coordination mechanisms, capacitating the healthcare workforce with competency-based training and supportive supervision (benefiting facilities supported by the project and beyond), developing the capacity of Ministry of Health staff in the effective management of the supply chain, actively and creatively mobilizing the community to raise awareness and create demand, and providing quality and affordable services. Financial sustainability is challenged by the chronically limited healthcare expenditure experienced in both humanitarian contexts. Conclusions: In humanitarian settings, carefully designed healthcare interventions, such as those that address the family planning and postabortion care needs of crisis-affected populations, have the potential not only to increase access to essential services but also contribute to strengthening several components of the health system while increasing the government capacity, ownership, and accountability.

HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow.

Normal growth and development of lymphatic structures depends on mechanical forces created by accumulating interstitial fluid. However, prolonged exposure to pathologic mechanical stimuli generated by chronically elevated lymph flow results in lymphatic dysfunction. The mechanisms that transduce these mechanical forces are not fully understood. Our objective was to investigate molecular mechanisms that alter the growth and metabolism of isolated lymphatic endothelial cells (LECs) exposed to prolonged pathologically elevated lymph flow in vivo within the anatomic and physiologic context of a large animal model of congenital heart disease with increased pulmonary blood flow using in vitro approaches. To this end, late gestation fetal lambs underwent in utero placement of an aortopulmonary graft (shunt). Four weeks after birth, LECs were isolated and cultured from control and shunt lambs. Redox status and proliferation were quantified, and transcriptional profiling and metabolomic analyses were performed. Shunt LECs exhibited hyperproliferative growth driven by increased levels of Hypoxia Inducible Factor 1α (HIF-1α), along with upregulated expression of known HIF-1α target genes in response to mechanical stimuli and shear stress. Compared to control LECs, shunt LECs exhibited abnormal metabolism including abnormalities of glycolysis, the TCA cycle and aerobic respiration. In conclusion, LECs from lambs exposed in vivo to chronically increased pulmonary lymph flow are hyperproliferative, have enhanced expression of HIF-1α and its target genes, and demonstrate altered central carbon metabolism in vitro. Importantly, these findings suggest provocative therapeutic targets for patients with lymphatic abnormalities.

Lessons Learned From Helping Babies Survive in Humanitarian Settings.

Humanitarian crises, driven by disasters, conflict, and disease epidemics, have profound effects on society, including on people's health and well-being. Occurrences of conflict by state and nonstate actors have increased in the last 2 decades: by the end of 2018, an estimated 41.3 million internally displaced persons and 20.4 million refugees were reported worldwide, representing a 70% increase from 2010. Although public health response for people affected by humanitarian crisis has improved in the last 2 decades, health actors have made insufficient progress in the use of evidence-based interventions to reduce neonatal mortality. Indeed, on average, conflict-affected countries report higher neonatal mortality rates and lower coverage of key maternal and newborn health interventions compared with non-conflict-affected countries. As of 2018, 55.6% of countries with the highest neonatal mortality rate (≥30 per 1000 live births) were affected by conflict and displacement. Systematic use of new evidence-based interventions requires the availability of a skilled health workforce and resources as well as commitment of health actors to implement interventions at scale. A review of the implementation of the Helping Babies Survive training program in 3 refugee responses and protracted conflict settings identify that this training is feasible, acceptable, and effective in improving health worker knowledge and competency and in changing newborn care practices at the primary care and hospital level. Ultimately, to improve neonatal survival, in addition to a trained health workforce, reliable supply and health information system, community engagement, financial support, and leadership with effective coordination, policy, and guidance are required.

Effectiveness of clinical training on improving essential newborn care practices in Bossaso, Somalia: a pre and postintervention study.

BACKGROUND: Increasingly, neonatal mortality is concentrated in settings of conflict and political instability. To promote evidence-based practices, an interagency collaboration developed the Newborn Health in Humanitarian Settings: Field Guide. The essential newborn care component of the Field Guide was operationalized with the use of an intervention package encompassing the training of health workers, newborn kit provisions and the installation of a newborn register. METHODS: We conducted a quasi-experimental prepost study to test the effectiveness of the intervention package on the composite outcome of essential newborn care from August 2016 to December 2018 in Bossaso, Somalia. Data from the observation of essential newborn care practices, evaluation of providers' knowledge and skills, postnatal interviews, and qualitative information were analyzed. Differences in two-proportion z-tests were used to estimate change in essential newborn care practices. A generalized estimating equation was applied to account for clustering of practice at the health facility level. RESULTS: Among the 690 pregnant women in labor who sought care at the health facilities, 89.9% (n = 620) were eligible for inclusion, 84.7% (n = 525) were enrolled, and newborn outcomes were ascertained in 79.8% (n = 419). Providers' knowledge improved from pre to posttraining, with a mean difference in score of + 11.9% (95% CI: 7.2, 16.6, p-value < 0.001) and from posttraining to 18-months after training with a mean difference of + 10.9% (95% CI: 4.7, 17.0, p-value < 0.001). The proportion of newborns who received two or more essential newborn care practices (skin-to-skin contact, early breastfeeding, and dry cord care) improved from 19.9% (95% CI: 4.9, 39.7) to 94.7% (95% CI: 87.7, 100.0). In the adjusted model that accounted for clustering at health facilities, the odds of receiving two or more essential newborn practices was 64.5 (95% CI: 15.8, 262.6, p-value < 0.001) postintervention compared to preintervention. Predischarge education offered to mothers on breastfeeding 16.5% (95% CI: 11.8, 21.1) vs 44.2% (95% CI: 38.2, 50.3) and newborn illness danger signs 9.1% (95% CI: 5.4, 12.7) vs 5.0% (95% CI: 2.4, 7.7) remained suboptimal. CONCLUSIONS: The intervention package was feasible and effective in improving essential newborn care. Knowledge and skills gained after training were mostly retained at the 18-month follow-up.

"You must first save her life": community perceptions towards induced abortion and post-abortion care in North and South Kivu, Democratic Republic of the Congo.

Structural barriers such as a restrictive legal environment, limited medical resources, and high-costs inhibit access to safe abortion in the Democratic Republic of the Congo (DRC); these barriers are exacerbated by two decades of conflict. Socio-normative barriers further complicate access to safe abortion and post-abortion care (PAC) in DRC, where fear of abortion-related stigma may lead women to avoid PAC services. Programme partners support the Ministry of Health to provide good quality contraceptive and PAC services in North and South Kivu, DRC. This paper presents results from focus group discussions that explored community members' attitudes towards women who induce abortion and their care-seeking behaviour in programme areas. Results indicate that while abortion stigma was widespread, community members' attitudes towards women who induced abortions were not one-dimensional. Although they initially expressed negative opinions regarding women who induced abortion, beliefs became more nuanced as discussion shifted to the specific situations that could motivate a woman to do so. For example, many considered it understandable that a woman would induce abortion after rape: perhaps unsurprising, given the prevalence of conflict-related sexual violence in this area. While community members believed that fear of stigma or associated negative social consequences dissuaded women from seeking PAC, a majority believed that all women should have access to life-saving PAC. This commitment to ensuring that women who induced abortion have access to PAC, in addition to the professed acceptability of induced abortion in certain situations, indicates that there could be an opening to destigmatise abortion access in this context.

When political solutions for acute conflict in Yemen seem distant, demand for reproductive health services is immediate: a programme model for resilient family planning and post-abortion care services.

The political situation in Yemen has been precarious since 2011 when popular protest broke out amid the Arab Spring, calling for President Saleh to step down. In March 2015, a Houthi insurgency took control of the capital, Sana'a and ignited a civil conflict that is now characterised by foreign political and military involvement. Since 2015, health facilities have been a primary target for airstrikes and bombing. Seaports have been blockaded barring the delivery of essential medicines and supplies, contributing to the near collapse of an already fragile health system. Since 2012, Save the Children (SC) has been implementing a Family Planning (FP) and Post-abortion Care (PAC) programme in two governorates heavily affected by the conflict. Despite the risks associated with the conflict, there remains a strong demand for SC's FP and PAC services. Ongoing programmatic support and capacity strengthening have allowed quality FP and PAC services to continue for Yemenis even when humanitarian access is impeded. Since the onset of conflict in March 2015, 16 facilities provided services to 43,218 new FP clients (with 23% accepting a long-acting method) and treated 3627 women with PAC. Over 93% of FP clients would recommend FP services at the facility to a friend or family member. Findings support growing evidence that women affected by conflict require family planning services, and that demand does not decline as long as quality services remain accessible. An adaptable reproductive health programme model that embraces innovative approaches is necessary for establishing services and maintaining quality during acute conflict.

Postabortion Care in Humanitarian Emergencies: Improving Treatment and Reducing Recurrence.

BACKGROUND: Unsafe abortion contributes to maternal mortality worldwide and disproportionately affects the most disadvantaged women and girls; thus, improving the treatment of complications of abortion is essential. Shifting PAC treatment from sharp dilation and curettage (D&C) to the use of aspiration techniques, notably manual vacuum aspiration (MVA), and medical treatment with misoprostol improves health outcomes. Equally critical is ensuring that women have access to voluntary contraception after an abortion to prevent future unintended pregnancies. In humanitarian settings, access to voluntary family planning to disrupt the cycle of unsafe abortion is even more critical because access to quality services cannot be guaranteed due to security risks, migration, and devastation of infrastructure. Save the Children applied a multipronged postabortion care (PAC) approach in the Democratic Republic of the Congo (DRC), Somalia, and Yemen that focused on capacity building; assurance of supplies and infrastructure; community collaboration and mobilization; and monitoring and evaluation. METHODS: Program-level data were extracted for each of the 3 countries from the inception of their program through 2017. The sources of information included monthly service delivery reports that tracked key PAC indicators as well as qualitative data from evaluations of community mobilization activities. RESULTS: The number of PAC clients increased in all countries. In the DRC in 2012, 19% of PAC clients requiring treatment received D&C; in 2017 the percentage was reduced to 3%. In 2013, 25% of all PAC clients in Yemen were treated with D&C; this percentage was reduced to 3% in 2017. The proportion of women choosing contraception after an abortion increased. In 2012, only 42% of all PAC clients in the DRC chose a contraceptive method; by 2017, the proportion had increased to 70%. Somalia had substantial increases in PAC demand, with the percentage of all PAC clients electing contraception increasing from 64% in 2012 to 82% in 2017. In Yemen, where the health system has been constrained due to severe conflict, the percentage of PAC clients choosing voluntary contraception rose from 17% in 2013 to 38% in 2017. Uptake and demand for PAC was mobilized through targeted community outreach in each context. CONCLUSION: These data demonstrate that providers can effectively shift away from D&C as treatment for PAC and that contraceptive uptake by PAC clients can increase substantially, even in settings where the use of contraception after abortion is often stigmatized.

Intravascular cardiac lipoproteinosis: extrarenal manifestation of lipoprotein glomerulopathy.

Intracapillary lipoprotein thrombi are a distinct histopathologic finding described in the setting of lipoprotein glomerulopathy. The disease is associated with mutations in the apolipoprotein E gene and responds well to lipid-lowering treatments. Lipoprotein glomerulopathy is thought to primarily affect the kidneys, and lipoprotein thrombi have never been described in any other organ. Herein we present the first recognized case with extrarenal manifestations in the form of intravascular cardiac lipoprotein deposition.

Essential newborn care practice at four primary health facilities in conflict affected areas of Bossaso, Somalia: a cross-sectional study.

BACKGROUND: Newborn mortality is increasingly concentrated in contexts of conflict and political instability. However, there are limited guidelines and data on the availability and quality of newborn care in conflict settings. In 2016, an interagency collaboration developed the Newborn Health in Humanitarian Settings Field Guide- Interim version (Field Guide). In this study, we sought to understand the baseline availability and quality of essential newborn care in Bossaso, Somalia as part of an investigation to determine the feasibility and effectiveness of the Field Guide in improving newborn care in humanitarian settings. METHODS: A cross-sectional study was conducted at four purposely selected health facilities serving internally displaced persons affected by conflict in Bossaso. Essential newborn care practice and patient experience with childbirth care received at the facilities were assessed via observation of clinical practice during childbirth and the immediate postnatal period, and through postnatal interviews of mothers. Descriptive statistics and logistic regression were employed to summarize and examine variation by health facility. RESULTS: Of the 332 pregnant women approached, 253 (76.2%) consented and were enrolled. 97.2% (95% CI: 94.4, 98.9) had livebirths and 2.8% (95% CI: 1.1, 5.6) had stillbirths. The early newborn mortality was 1.7% (95% CI: 0.3, 4.8). Nearly all [95.7%, (95% CI: 92.4, 97.8)] births were attended by skilled health worker. Similarly, 98.0% (95% CI: 95.3, 99.3) of newborns received immediate drying, and 99.2% (95% CI: 97.1, 99.9) had delayed bathing. Few [8.6%, (95% CI: 5.4, 12.9)] received immediate skin-to-skin contact and the practice varied significantly by facility (p < 0.001). One-third of newborns [30.1%, (95% CI: 24.4, 36.2)] received early initiation of breastfeeding and there was significant variation by facility (p < 0.001). While almost all [99.2%, (95% CI: 97.2, 100)] service providers wore gloves while attending births, handwashing was not as common [20.2%, (95% CI: 15.4, 25.6)] and varied by facility (p < 0.001). Nearly all [92%, (95% CI: 86.9, 95.5)] mothers were either very happy or happy with the childbirth care received at the facility. CONCLUSION: Essential newborn care interventions were not universally available. Quality of care varied by health facility and type of intervention. Training and supervision using the Field Guide could improve newborn outcomes.

Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling.

The natural history of pulmonary vascular disease associated with congenital heart disease (CHD) depends on associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop pulmonary vascular disease more commonly than patients exposed to increased PBF alone. To investigate the effects of these differing mechanical forces on physiologic and molecular responses, we developed two models of CHD using fetal surgical techniques: 1) left pulmonary artery (LPA) ligation primarily resulting in increased PBF and 2) aortopulmonary shunt placement resulting in increased PBF and PAP. Hemodynamic, histologic, and molecular studies were performed on control, LPA, and shunt lambs as well as pulmonary artery endothelial cells (PAECs) derived from each. Physiologically, LPA, and to a greater extent shunt, lambs demonstrated an exaggerated increase in PAP in response to vasoconstricting stimuli compared with controls. These physiologic findings correlated with a pathologic increase in medial thickening in pulmonary arteries in shunt lambs but not in control or LPA lambs. Furthermore, in the setting of acutely increased afterload, the right ventricle of control and LPA but not shunt lambs demonstrates ventricular-vascular uncoupling and adverse ventricular-ventricular interactions. RNA sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchical clustering. In addition, we found hyperproliferation of PAECs from LPA lambs, and to a greater extent shunt lambs, with associated increased angiogenesis and decreased apoptosis in PAECs derived from shunt lambs. A further understanding of mechanical force-specific drivers of pulmonary artery pathology will enable development of precision therapeutics for pulmonary hypertension associated with CHD.

Cytotoxic Swelling of Sick Excitable Cells - Impaired Ion Homeostasis and Membrane Tension Homeostasis in Muscle and Neuron.

When they become simultaneously leaky to both Na+ and Cl-, excitable cells are vulnerable to potentially lethal cytotoxic swelling. Swelling ensues in spite of an isosmotic milieu because the entering ions add osmolytes to the cytoplasm's high concentration of impermeant anionic osmolytes. An influx of osmotically-obliged water is unavoidable. A cell that cannot stanch at least one the leaks will succumb to death by Donnan effect. "Sick excitable cells" are those injured through ischemia, trauma, inflammation, hyperactivity, genetically-impaired membrane skeletons and other insults, all of which foster bleb-damage to regions of the plasma membrane. Nav channels resident in damaged membrane exhibit left-shifted kinetics; the corresponding Nav window conductance constitutes a Na+-leak. In cortical neurons, sustained depolarization to ∼-20mV elicits a sustained lethal gCl. Underlying Vrest in skeletal muscle is a constitutively active gCl; not surprisingly therefore, dystrophic muscle fibers, which are prone to bleb damage and which exhibit Nav-leak and Na+-overload, are prone to cytotoxic swelling. To restore viability in cytotoxically swelling neurons and muscle, the imperative of fully functional ion homeostasis is well-recognized. However, as emphasized here, in a healthy excitable cell, fully functional membrane tension homeostasis is also imperative. ATPase-pumps keep plasma membrane batteries charged, and ATPase-motor proteins maintain membrane tone. In sick excitable cells, neither condition prevails.

A model for studying the energetics of sustained high frequency firing.

Regulating membrane potential and synaptic function contributes significantly to the energetic costs of brain signaling, but the relative costs of action potentials (APs) and synaptic transmission during high-frequency firing are unknown. The continuous high-frequency (200-600Hz) electric organ discharge (EOD) of Eigenmannia, a weakly electric fish, underlies its electrosensing and communication. EODs reflect APs fired by the muscle-derived electrocytes of the electric organ (EO). Cholinergic synapses at the excitable posterior membranes of the elongated electrocytes control AP frequency. Based on whole-fish O2 consumption, ATP demand per EOD-linked AP increases exponentially with AP frequency. Continual EOD-AP generation implies first, that ion homeostatic processes reliably counteract any dissipation of posterior membrane ENa and EK and second that high frequency synaptic activation is reliably supported. Both of these processes require energy. To facilitate an exploration of the expected energy demands of each, we modify a previous excitability model and include synaptic currents able to drive APs at frequencies as high as 600 Hz. Synaptic stimuli are modeled as pulsatile cation conductance changes, with or without a small (sustained) background conductance. Over the full species range of EOD frequencies (200-600 Hz) we calculate frequency-dependent "Na+-entry budgets" for an electrocyte AP as a surrogate for required 3Na+/2K+-ATPase activity. We find that the cost per AP of maintaining constant-amplitude APs increases nonlinearly with frequency, whereas the cost per AP for synaptic input current is essentially constant. This predicts that Na+ channel density should correlate positively with EOD frequency, whereas AChR density should be the same across fish. Importantly, calculated costs (inferred from Na+-entry through Nav and ACh channels) for electrocyte APs as frequencies rise are much less than expected from published whole-fish EOD-linked O2 consumption. For APs at increasingly high frequencies, we suggest that EOD-related costs external to electrocytes (including packaging of synaptic transmitter) substantially exceed the direct cost of electrocyte ion homeostasis.

KLF2-mediated disruption of PPAR-γ signaling in lymphatic endothelial cells exposed to chronically increased pulmonary lymph flow.

Lymphatic abnormalities associated with congenital heart disease are well described, yet the underlying mechanisms remain poorly understood. Using a clinically relevant ovine model of congenital heart disease with increased pulmonary blood flow, we have previously demonstrated that lymphatic endothelial cells (LECs) exposed in vivo to chronically increased pulmonary lymph flow accumulate ROS and have decreased bioavailable nitric oxide (NO). Peroxisome proliferator-activated receptor-γ (PPAR-γ), which abrogates production of cellular ROS by NADPH oxidase, is inhibited by Krüppel-like factor 2 (KLF2), a flow-induced transcription factor. We hypothesized that chronically increased pulmonary lymph flow induces a KLF2-mediated decrease in PPAR-γ and an accumulation of cellular ROS, contributing to decreased bioavailable NO in LECs. To better understand the mechanisms that transduce the abnormal mechanical forces associated with chronically increased pulmonary lymph flow, LECs were isolated from the efferent vessel of the caudal mediastinal lymph node of control ( n = 5) and shunt ( n = 5) lambs. KLF2 mRNA and protein were significantly increased in shunt compared with control LECs, and PPAR-γ mRNA and protein were significantly decreased. In control LECs exposed to shear forces in vitro, we found similar alterations to KLF2 and PPAR-γ expression. In shunt LECs, NADPH oxidase subunit expression was increased, and bioavailable NO was significantly lower. Transfection of shunt LECs with KLF2 siRNA normalized PPAR-γ, ROS, and bioavailable NO. Conversely, pharmacological inhibition of PPAR-γ in control LECs increased ROS equivalent to levels in shunt LECs at baseline. Taken together, these data suggest that one mechanism by which NO-mediated lymphatic function is disrupted after chronic exposure to increased pulmonary lymph flow is through altered KLF2-dependent PPAR-γ signaling, resulting in increased NADPH oxidase activity, accumulation of ROS, and decreased bioavailable NO. NEW & NOTEWORTHY Lymphatic endothelial cells, when exposed in vivo to chronically elevated pulmonary lymph flow in a model of congenital heart disease with increased pulmonary blood flow, demonstrate Krüppel-like factor 2-dependent disrupted peroxisome proliferator-activated receptor-γ signaling that results in the accumulation of reactive oxygen species and decreased bioavailable nitric oxide.

Circles of care for people with intellectual and developmental disabilities: Communication, collaboration, and coordination.

OBJECTIVE: To review health information exchange (HIE) processes that affect the health of people with intellectual and developmental disabilities (IDD) and to suggest practical tips and strategies for communicating, collaborating, and coordinating in the primary care setting. SOURCES OF INFORMATION: The "Primary care of adults with intellectual and developmental disabilities. 2018 Canadian consensus guidelines" literature review and interdisciplinary input. MAIN MESSAGE: Disparities exist between the provision of health care for the general population and that for people with IDD. These disparities are due in part to gaps in HIE. Health information exchange involves documenting, collecting, and disseminating a patient's health information. In exploring ways to improve HIE for people with IDD, the communication skills of the family physician are considered in the context of the triad that includes the patient, his or her caregivers, and the family physician. The framework of the Patient's Medical Home is used in exploring these processes, and various strategies are offered for communicating, collaborating, and coordinating health care that can be implemented by family physicians in order to narrow the gaps in care that exist for people with IDD. CONCLUSION: Improvements in HIE by communicating, collaborating, and coordinating health care better will improve health outcomes for people with IDD.

Calculating the Consequences of Left-Shifted Nav Channel Activity in Sick Excitable Cells.

Two features common to diverse sick excitable cells are "leaky" Nav channels and bleb damage-damaged membranes. The bleb damage, we have argued, causes a channel kinetics based "leakiness." Recombinant (node of Ranvier type) Nav1.6 channels voltage-clamped in mechanically-blebbed cell-attached patches undergo a damage intensity dependent kinetic change. Specifically, they experience a coupled hyperpolarizing (left) shift of the activation and inactivation processes. The biophysical observations on Nav1.6 currents formed the basis of Nav-Coupled Left Shift (Nav-CLS) theory. Node of Ranvier excitability can be modeled with Nav-CLS imposed at varying LS intensities and with varying fractions of total nodal membrane affected. Mild damage from which sick excitable cells might recover is of most interest pathologically. Accordingly, Na+/K+ ATPase (pump) activity was included in the modeling. As we described more fully in our other recent reviews, Nav-CLS in nodes with pumps proves sufficient to predict many of the pathological excitability phenomena reported for sick excitable cells. This review explains how the model came about and outlines how we have used it. Briefly, we direct the reader to studies in which Nav-CLS is being implemented in larger scale models of damaged excitable tissue. For those who might find it useful for teaching or research purposes, we coded the Nav-CLS/node of Ranvier model (with pumps) in NEURON. We include, here, the resulting "Regimes" plot of classes of excitability dysfunction.