Towards equitable surgical systems: development and outcomes of a national surgical, obstetric and anaesthesia plan in Tanzania.

Despite emergency and essential surgery and anaesthesia care being recognised as a part of Universal Health Coverage, 5 billion people worldwide lack access to safe, timely and affordable surgery and anaesthesia care. In Tanzania, 19% of all deaths and 17 % of disability-adjusted life years are attributable to conditions amenable to surgery. It is recommended that countries develop and implement National Surgical, Obstetric and Anesthesia Plans (NSOAPs) to systematically improve quality and access to surgical, obstetric and anaesthesia (SOA) care across six domains of the health system including (1) service delivery, (2) infrastructure, including equipment and supplies, (3) workforce, (4) information management, (5) finance and (6) Governance. This paper describes the NSOAP development, recommendations and lessons learnt from undertaking NSOAP development in Tanzania. The NSOAP development driven by the Ministry of Health Community Development Gender Elderly and Children involved broad consultation with over 200 stakeholders from across government, professional associations, clinicians, ancillary staff, civil society and patient organisations. The NSOAP describes time-bound, costed strategic objectives, outputs, activities and targets to improve each domain of the SOA system. The final NSOAP is ambitious but attainable, reflects on-the-ground priorities, aligns with existing health policy and costs an additional 3% of current healthcare expenditure. Tanzania is the third country to complete such a plan and the first to report on the NSOAP development in such detail. The NSOAP development in Tanzania provides a roadmap for other countries wishing to undertake a similar NSOAP development to strengthen their SOA system.

Patients' perspective of the effectiveness and acceptability of pharmacological and non-pharmacological treatments of fibromyalgia.

Background and aims Fibromyalgia is a complex condition characterised by widespread pain, sleep disturbance, fatigue and cognitive impairment, with a global mean prevalence estimated at 2.7%. There are inconsistencies in guidelines on the treatment of fibromyalgia leading to dissatisfaction from patients and healthcare professionals. This study investigated patient-reported outcomes of pharmacological and non-pharmacological treatment usage and effectiveness with an assessment of acceptability. Methods Nine hundred and forty-one participants completed a self-administered anonymous questionnaire giving quantitative data of demographics, treatment usage and treatment outcomes. Participant-reported effectiveness and side effects were compared in the following treatment classes: analgesics, antidepressants, gabapentinoids, gastrointestinal treatments, activity interventions, dietary-based treatments, and psychological, physical and alternative therapies. Participants also reported whether they knew about or had tried different treatments. Results The results from the online survey indicated that the range of mean effectiveness ratings were similar for pharmacological and non-pharmacological treatments, whereas non-pharmacological treatments had lower side effects ratings and higher acceptability relative to pharmacological treatments. Participants were not aware of some treatment options. Conclusions The results show lower side effects ratings and higher acceptability for non-pharmacological treatments compared to pharmacological treatments despite similar effectiveness ratings. Implications This article presents results from a large online survey on fibromyalgia patient perspectives of pharmacological and non-pharmacological treatments. Results will inform healthcare professionals and patients about optimal treatments based on ratings of effectiveness, side effects and acceptability that are tailored to patient symptom profiles. Some participants were unaware of treatment options highlighting the importance of patient education allowing collaboration between patients and healthcare professionals to find optimal treatments.

Surgical quality indicators in low-resource settings: A new evidence-based tool.

BACKGROUND: Worldwide efforts to improve access to surgical care must be accompanied by improvements in the quality of surgical care; however, these efforts are contingent on the ability to measure quality. This report describes a novel, evidence-based tool to measure quality of surgical care in low-resource settings. METHODS: We defined a widely applicable, multidimensional conceptual framework for quality. The suitability of currently available quality metrics to low-resource settings was evaluated. Then we developed new indicators with sufficient supportive evidence to complete the framework. The complete set of metrics was condensed into four collection sources and tools. RESULTS: The following 15 final evidence-based indicators were defined: (1) Safe structure: morbidity and mortality conference; (2) safe process: use of the safe surgery checklist; (3) (4) safe outcomes: perioperative mortality rate and proportion of cases with complications graded >2 on the Clavien-Dindo scale; (5) effective structure: provider density; (6) effective process: procedure rate; (7) effective outcome: rate of caesarean sections; (8) patient-centered process: use of informed consent; (9) patient-centered outcome: patient hospital satisfaction questionnaire; (10) timely structure: travel time to hospital; (11) timely process: time from emergency department presentation to non-elective abdominal surgery; (12) timely outcome: patient follow-up plan; (13) efficient process: daily operating room usage; (14) equitable outcome: comparative income of patients compared with population; and (15) proportion of patients facing catastrophic expenditure because of surgical care. CONCLUSION: This tool provides an evidence-based conceptual tool to assess the quality of surgical care in diverse low-resource settings.

Necroptosis Is an Important Severity Determinant and Potential Therapeutic Target in Experimental Severe Pancreatitis.

BACKGROUND AND AIMS: Severe acute pancreatitis is characterized by acinar cell death and inflammation. Necroptosis is an aggressive and pro-inflammatory mode of cell death that can be prevented by necrostatin-1 administration or RIP3 deletion. METHODS: Mouse pancreatic acinar cells were incubated with supramaximally stimulating concentrations of caerulein or sub-micellar concentrations of TLCS and necroptosis was inhibited by either addition of necrostatin or by RIP3 deletion. Cell death was quantitated using either LDH leakage from acini or PI staining of nuclei. Necrosome formation was tracked and quantitated using cell fractionation or immunoprecipitation. Pancreatitis was induced in mice by retrograde intraductal infusion of TLCS or by repetitive supramaximal stimulation with caerulein. RESULTS: Necroptosis was found to be the most prevalent mode of acinar cell in vitro death and little or no apoptosis was observed. Acinar cell death was associated with necrosome formation and prevented by either necrostatin administration or RIP3 deletion. Both of these interventions reduced the severity of TLCS- or caerulein-induced pancreatitis. Delaying necrostatin administration until after pancreatitis had already been established could still reduce the severity of TLCS-induced pancreatitis. CONCLUSIONS: Necroptosis is the predominant mode of acinar cell death in severe experimental mouse pancreatitis. The severity of pancreatitis can be reduced by administration of necrostatin and that necrostatin can still reduce the cell injury of pancreatitis even if it is administered after the disease has already been established. Inhibition of necroptosis may be an effective strategy for the treatment of severe clinical pancreatitis.

Global proliferation of cephalopods.

Human activities have substantially changed the world's oceans in recent decades, altering marine food webs, habitats and biogeochemical processes [1]. Cephalopods (squid, cuttlefish and octopuses) have a unique set of biological traits, including rapid growth, short lifespans and strong life-history plasticity, allowing them to adapt quickly to changing environmental conditions [2-4]. There has been growing speculation that cephalopod populations are proliferating in response to a changing environment, a perception fuelled by increasing trends in cephalopod fisheries catch [4,5]. To investigate long-term trends in cephalopod abundance, we assembled global time-series of cephalopod catch rates (catch per unit of fishing or sampling effort). We show that cephalopod populations have increased over the last six decades, a result that was remarkably consistent across a highly diverse set of cephalopod taxa. Positive trends were also evident for both fisheries-dependent and fisheries-independent time-series, suggesting that trends are not solely due to factors associated with developing fisheries. Our results suggest that large-scale, directional processes, common to a range of coastal and oceanic environments, are responsible. This study presents the first evidence that cephalopod populations have increased globally, indicating that these ecologically and commercially important invertebrates may have benefited from a changing ocean environment.

An acoustic filter based on layered structure.

Acoustic filters (AFs) are key components to control wave propagation in multi-frequency systems. We present a design which selectively achieves acoustic filtering with a stop band and passive amplification at the high- and low-frequencies, respectively. Measurement results from the prototypes closely match the design predictions. The AF suppresses the high frequency aliasing echo by 14.5 dB and amplifies the low frequency transmission by 8.0 dB, increasing an axial resolution from 416 to 86 µm in imaging. The AF design approach is proved to be effective in multi-frequency systems.

An efficient approach to computing third- order scattering of sound by sound with application to parametric arrays.

A mathematical description of third-order scattered sound fields is derived using a multi-Gaussian beam (MGB) model that describes the sound field of any arbitrary axially symmetric beam as a series of Gaussian base functions. The third-order intermodulation (IM3) frequency components are produced by considering the cascaded nonlinear secondorder effects when analyzing the interaction between the firstand second-order frequency components during the nonlinear scattering of sound by sound from two noncollinear ultrasonic baffled piston sources. The theory is extended to the modeling of the sound beams generated by parametric transducer arrays, showing that the MGB model can be efficiently used to calculate both the second- and third-order sound fields of the array. Measurements are presented for the IM3 frequency components and parametric array sound fields and comparisons of the model are made with traditional simulation results from direct numerical integration.

Third-order parametric array generated by distantly spaced primary ultrasonic tones.

Traditional parametric arrays are produced by a second-order nonlinear interaction between two primary ultrasonic tones that are close in frequency, resulting in a difference tone that is in the audio band. This article presents a parametric array produced by a third-order nonlinear interaction between two primary ultrasonic tones that are distantly spaced in frequency such that one tone is approximately the second harmonic of the other. The result is a third-order lower intermodulation (IM3) tone in the audio band with greater directivity and lower side lobe amplitude than comparable second-order fields. Measurements are presented that compare the directivity of 1-, 2-, and 4-kHz difference tones to that of 1-, 2-, and 4-kHz IM3 lower tones. Furthermore, a cascaded second-order approach for N-element transducer arrays is used to model third-order scattering with good agreement between measurement and theory.

Scaling issues in ferroelectric barium strontium titanate tunable planar capacitors.

We report on the geometric limits associated with tunability of interdigitated capacitors, specifically regarding the impact of a parasitic non-tunable component that necessarily accompanies a ferroelectric surface capacitor, and can dominate the voltage-dependent response as capacitor dimensions are reduced to achieve the small capacitance values required for impedance matching in the X band. We present a case study of simple gap capacitors prepared and characterized as a function of gap width (i.e., the distance between electrodes) and gap length (i.e., the edge-to-edge gap distance). Our series of measurements reveals that for gap widths in the micrometer range, as gap lengths are reduced to meet sub-picofarad capacitance values, the non-tunable parasitic elements limit the effective tunability. These experimental measurements are supported by a companion set of microwave models that clarify the existence of parallel parasitic elements.

TNF-alpha-dependent regulation of acute pancreatitis severity by Ly-6C(hi) monocytes in mice.

The roles of monocytes/macrophages and their mechanisms of action in the regulation of pancreatitis are poorly understood. To address these issues, we have employed genetically altered mouse strains that either express the human diphtheria toxin receptor (DTR) coupled to the CD11b promoter or have global deletion of TNF-α. Targeted, conditional depletion of monocytes/macrophages was achieved by administration of diphtheria toxin (DT) to CD11b-DTR mice. We show that in the absence of DT administration, pancreatitis is associated with an increase in pancreatic content of Ly-6C(hi) monocytes/macrophages but that this response is prevented by prior administration of DT to CD11b-DTR mice. DT administration also reduces pancreatic edema and acinar cell injury/necrosis in two dissimilar experimental models of acute pancreatitis (a secretagogue-induced model and a model elicited by retrograde pancreatic duct infusion of sodium taurocholate). In the secretagogue-elicited model, the DT-induced decrease in pancreatitis severity is reversed by adoptive transfer of purified Ly-6C(hi) monocytes harvested from non-DT-treated CD11b-DTR mice or by the transfer of purified Ly-6C(hi) monocytes harvested from TNF-α(+/+) donor mice, but it is not reversed by the transfer of Ly-6C(hi) monocytes harvested from TNF-α(-/-) donors. Our studies indicate that the Ly-6C(hi) monocyte subset regulates the severity of pancreatitis by promoting pancreatic edema and acinar cell injury/necrosis and that this phenomenon is dependent upon the expression of TNF-α by those cells. They suggest that therapies targeting Ly-6C(hi) monocytes and/or TNF-α expression by Ly-6C(hi) monocytes might prove beneficial in the prevention or treatment of acute pancreatitis.

Experimental acute biliary pancreatitis induced by retrograde infusion of bile acids into the mouse pancreatic duct.

Mechanistic studies of acute pancreatitis require animal models because clinical material is generally not available during the early phases of the disease. Here we describe a protocol to induce biliary pancreatitis by retrogradely infusing bile acids into the pancreatic duct of anesthetized mice. The resulting model replicates events believed to be responsible for the onset of clinical biliary (i.e., gallstone) pancreatitis and creates highly reproducible pancreatitis with a severity that depends on the concentration of infused bile acid. Pancreatitis reaches its maximal level of severity within 24 h of induction, and it resolves over the subsequent week. This protocol enables the investigator to use genetically modified strains of mice, and it requires only relatively simple and easily learned techniques of small animal surgery. With practice and gentle technique, the surgery (from induction of anesthesia to completion of the infusion) can be completed within 25 min per animal.

Biliary acute pancreatitis in mice is mediated by the G-protein-coupled cell surface bile acid receptor Gpbar1.

BACKGROUND & AIMS: The mechanisms by which reflux of bile acids into the pancreas induces pancreatitis are unknown. We reasoned that key events responsible for this phenomenon might be mediated by Gpbar1, a recently identified and widely expressed G-protein-coupled, cell surface bile acid receptor. METHODS: Acute pancreatitis was induced in wild-type and Gpbar1(-/-) mice by either retrograde ductal infusion of taurolithocholic acid-3-sulfate (TLCS) or supramaximal secretagogue stimulation with caerulein. In vitro experiments were performed in which acini obtained from wild-type and Gpbar1(-/-) mice were exposed to either submicellar concentrations of TLCS (200-500 microM) or a supramaximally stimulating concentration of caerulein (10 nM). RESULTS: Gpbar1 is expressed at the apical pole of acinar cells and its genetic deletion is associated with reduced hyperamylasemia, edema, inflammation, and acinar cell injury in TLCS-induced, but not caerulein-induced, pancreatitis. In vitro, genetic deletion of Gpbar1 is associated with markedly reduced generation of pathological calcium transients, intracellular activation of digestive zymogens, and cell injury when these responses are induced by exposure to TLCS, but not when they are induced by exposure to caerulein. CONCLUSIONS: Gpbar1 may play a critical role in the evolution of bile-acid-induced pancreatitis by coupling exposure to bile acids with generation of pathological intracellular calcium transients, intra-acinar cell zymogen activation, and acinar cell injury. Acute biliary pancreatitis may be a "receptor-mediated" disease and interventions that interfere with Gpbar1 function might prove beneficial in the treatment and/or prevention of biliary acute pancreatitis.

The impact of metallization thickness and geometry for X-band tunable microwave filters.

The impact of dc resistance on the performance of X-band filters with ferroelectric varactors was investigated. Two series of combline bandpass filters with specific geometries to isolate sources of conductor losses were designed and synthesized. Combining the changes in filter geometry with microwave measurements and planar filter solver (Sonnet software) simulations quantitatively identified the dependency of insertion loss on overall metallization thickness and local regions of thin metallization. The optimized 8-GHz bandpass filters exhibited insertion losses of 6.8 dB. These filters required 2.5 microm of metal thickness (or 3 effective skin depths) to achieve this loss. The trend of loss with thickness indicates diminishing return with additional metal. The integration scheme requires thin regions of metal in the immediate vicinity of the varactors. It is shown through experiment and simulation that short distances (i.e., 15 microm) of thin metallization can be tolerated provided that they are located in regions where the resonant microwave current is low.

Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis.

Protease-activated receptor-2 (PAR2) is a 7-transmembrane G-protein-coupled tethered ligand receptor that is expressed by pancreatic acinar and ductal cells. It can be physiologically activated by trypsin. Previously reported studies (Namkung, W., Han, W., Luo, X., Muallem, S., Cho, K. H., Kim, K. H., and Lee, M. G. (2004) Gastroenterology 126, 1844-1859; Sharma, A., Tao, X., Gopal, A., Ligon, B., Andrade-Gordon, P., Steer, M. L., and Perides, G. (2005) Am. J. Physiol. 288, G388-G395) have shown that PAR2 activation exerts a protective effect on the experimental model of pancreatitis induced by supramaximal secretagogue (caerulein) stimulation. We now show that PAR2 exerts a worsening effect on a different model of experimental pancreatitis, i.e. one induced by retrograde pancreatic ductal infusion of bile salts. In vitro studies using freshly prepared pancreatic acini show that genetic deletion of PAR2 reduces bile salt-induced pathological calcium transients, acinar cell injury, and activation of c-Jun N-terminal kinase, whereas genetic deletion of PAR2 has the opposite or no effect on these pancreatitis-related events when they are elicited, in vitro, by caerulein stimulation. Studies employing a combination of trypsin inhibition and activation of PAR2 with the activating peptide SLIGRL show that all these differences indeed depend on the activation of PAR2. These studies are the first to report that a single perturbation can have model-specific and opposite effects on pancreatitis, and they underscore the importance of performing mechanistic pancreatitis studies using two dissimilar models of the disease to detect idiosyncratic, model-specific events. We suggest PAR2 activation exerts a worsening effect on the severity of clinical pancreatitis and that interventions interfering with PAR2 activation may be of benefit in the treatment of patients with severe pancreatitis.

Acute pancreatitis.

Acute pancreatitis is an inflammatory disease of the pancreas. Acute abdominal pain is the most common symptom, and increased concentrations of serum amylase and lipase confirm the diagnosis. Pancreatic injury is mild in 80% of patients, who recover without complications. The remaining patients have a severe disease with local and systemic complications. Gallstone migration into the common bile duct and alcohol abuse are the most frequent causes of pancreatitis in adults. About 15-25% of pancreatitis episodes are of unknown origin. Treatment of mild disease is supportive, but severe episodes need management by a multidisciplinary team including gastroenterologists, interventional radiologists, intensivists, and surgeons. Improved understanding of pathophysiology and better assessments of disease severity should ameliorate the management and outcome of this complex disease.

Tumor progression locus-2 is a critical regulator of pancreatic and lung inflammation during acute pancreatitis.

Pancreatic and lung inflammation during acute pancreatitis is a poorly understood, but clinically important, phenomenon. The proto-oncogene Tpl2 (tumor progression locus-2) has recently been shown to have important immunomodulatory effects on some inflammatory processes, but its importance to pancreatitis has not been previously examined. Our studies were designed to (a) define the effects of Tpl2 on pancreatic and lung inflammation during pancreatitis and (b) identify mechanisms and cell types responsible for those effects. We examined pancreatitis-associated Tpl2 effects in wild type and Tpl2(-/-) mice subjected to either secretagogue-induced or bile salt-induced pancreatitis. To determine the myeloid or non-myeloid lineage of cells responsible for the Tpl2 effects, we used Tpl2(-/-) chimeric mice generated by lethal irradiation followed by bone marrow transplantation. Mechanisms responsible for the effects of Tpl2 ablation on caerulein-induced proinflammatory events were evaluated under in vivo and in vitro conditions using the techniques of electrophoretic mobility shift assay, immunoblot analysis, and quantitative reverse transcription-PCR. We found that Tpl2 ablation markedly reduced pancreatic and lung inflammation in these two dissimilar models of pancreatitis, but it did not alter pancreatic injury/necrosis in either model. The reduction in caerulein-induced pancreatic inflammation is dependent upon Tpl2 ablation in non-myeloid cells and is associated with both in vivo and in vitro inhibition of MEK, JNK, and AP-1 activation and the expression of MCP-1, MIP-2, and interleukin-6. Non-myeloid cell expression of Tpl2 regulates pancreatic inflammation during pancreatitis by mediating proinflammatory signals and the generation of neutrophil chemoattracting factors.

A mouse model of acute biliary pancreatitis induced by retrograde pancreatic duct infusion of Na-taurocholate.

OBJECTIVE: Most mechanistic studies of pancreatitis in mice employ the secretagogue-induced model. The currently reported studies were designed to develop an alternative, and possibly more clinically relevant, mouse model of pancreatitis. DESIGN: Na-taurocholate (10-50 microl, 1-5%) in saline, or saline alone, was retrogradely infused into the mouse pancreatic duct. The animals were killed 6-24 hours later and the severity of pancreatitis in the pancreatic head and tail was examined by quantitating hyperamylasemia, pancreatic edema, acinar cell necrosis, and pancreatic inflammation. In addition, intrapancreatic activation of trypsinogen, generation of IL-6, intrapulmonary sequestration of neutrophils, and alterations in lung compliance were evaluated. The effects of Na-taurocholate on in-vitro acinar cell calcium transients, viability, and trypsinogen activation were examined. RESULTS: Little or no evidence of pancreatitis was observed in mice infused with saline alone or in the tail of pancreata removed from animals infused with Na-taurocholate. In the head of the pancreas, evidence of pancreatitis was observed 12-24 hours after infusion of 20-50 microl 2-5% Na-taurocholate and the earliest morphological changes involved terminal duct and acinar cells. Intrapancreatic trypsin activity was transiently elevated within 5 minutes of Na-taurocholate infusion and pancreatic IL-6 levels were elevated 24 hours later. Under in-vitro conditions, Na-taurocholate triggered pathological acinar cell calcium transients, cell death, and calcium-dependent trypsinogen activation. CONCLUSION: This clinically relevant model of acute biliary pancreatitis yields reproducible results and its severity can be easily manipulated. It is ideally suited for use in mechanistic studies employing genetically modified mouse strains.

Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis.

We have hypothesized that the colocalization of digestive zymogens with lysosomal hydrolases, which occurs during the early stages of every experimental pancreatitis model, facilitates activation of those zymogens by lysosomal hydrolases such as cathepsin B and that this activation triggers acute pancreatitis by leading to acinar cell injury. Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. To resolve this controversy and explore the causal relationships between zymogen activation and other early pancreatitis events, we induced pancreatitis in mice by repeated supramaximal secretagogue stimulation with caerulein. Some animals were pretreated with the cathepsin B inhibitor CA-074 me to inhibit cathepsin B, prevent intrapancreatic activation of digestive zymogens, and reduce the severity of pancreatitis. We show that inhibition of cathepsin B by pretreatment with CA-074 me prevents intrapancreatic zymogen activation and reduces organellar fragility, but it does not alter the caerulein-induced colocalization phenomenon or subcellular F-actin redistribution or prevent caerulein-induced activation of NF-kappaB, ERK1/2, and JNK or upregulated expression of cytochemokines. We conclude 1) that the colocalization phenomenon, F-actin redistribution, activation of proinflammatory transcription factors, and upregulated expression of cytochemokines are not the results of zymogen activation, and 2) that these early events in pancreatitis are not dependent on cathepsin B activity. In contrast, zymogen activation and increased subcellular organellar fragility during caerulein-induced pancreatitis are dependent on cathepsin B activity.