Ultrasound as the first line investigation for midgut malrotation: a UK tertiary centre experience.

AIM: To present the first 22-months experience of transitioning to an ultrasound-first pathway for suspected midgut malrotation. MATERIALS AND METHODS: An "ultrasound-first" imaging pathway was initiated in October 2021. Twenty-two-months later, a search was undertaken of all <1-year-old patients with "bilious", "malrotation," or "volvulus" as the imaging indication. Reports and images from upper gastrointestinal fluoroscopy (UGI) and ultrasound were reviewed, and diagnoses and outcomes were documented. RESULTS: The search yielded 101 eligible cases between October 2021 and July 2023. Of the patients, 63/101 (62%) had both ultrasound and UGI: 47/63 (75%) ultrasound first, 16/63 (25%) UGI first. Thirty-one per cent (31/101) had ultrasound only and 7/70 (10%) UGI only. The pathway diagnosed 7/8 (88%) infants with midgut malrotation with or without volvulus and one infant who had an inconclusive ultrasound examination with a suspected an internal hernia and who was found to have malrotation volvulus at surgery. Twenty-one infants who had confidently normal ultrasound examinations and who also had UGI all had a normal duodenojejunal flexure position. Ultrasound detected alternative pathology in eight children. Duodenal visualisation improved with time: 6/15 (40%) in the first 6 months to 23/34 (68%) after the first year. CONCLUSION: The transition to ultrasound as the first diagnostic test for midgut malrotation can be done safely and effectively in a UK centre, which previously relied solely on UGI.

Thoracoscopic oesophageal atresia/tracheo-oesophageal fistula (OA/TOF) repair is associated with a higher stricture rate: a single institution's experience.

PURPOSE: Thoracoscopic OA/TOF repair was first described in 1999. Currently, less than 10% of surgeons routinely employ minimally access surgery. Our primary aim was to review our immediate-, early- and long-term outcomes with this technique compared with the open approach. METHODS: A retrospective review of all patients undergoing primary OA/TOF (Type C) repair at our institution from 2009 was conducted. Outcome measures included length of surgery, conversion rate from thoracoscopy, early complications such as anastomotic leak and post-operative complications such as anastomotic strictures needing dilatations. Fisher's exact and Kruskal-Wallis tests were used for statistical analysis. RESULTS: 95 patients in total underwent OA/TOF repair during the study period of which 61 (64%) were completed via an open approach. 34 were attempted thoracoscopically of which 11 (33%) were converted. There was only one clinically significant anastomotic leak in our series that took place in the thoracoscopic group. We identified a significantly higher stricture rate in our thoracoscopic cohort (72%) versus open surgery (43%, P < 0.05). However, the median number of dilations (3) performed was not significantly different between the groups. There was one recurrent fistula in the thoracoscopic converted to open group. Our median follow-up was 60 months across the groups. CONCLUSION: In our experience, the clinically significant leak rate for both open and thoracoscopic repair as well as recurrent fistula is much lower than has been reported in the literature. We do not routinely perform contrast studies and are, thus, reporting clinically significant leaks only. The use of post-operative neck flexion, ventilation and paralysis is likely to be protective towards a leak. Thoracoscopic OA/TOF repair is associated with a higher stricture rate compared with open surgery; however, these strictures respond to a similar number of dilatations and are no more refractory. Larger, multicentre studies may be useful to investigate these finding further.

One-year outcomes for congenital diaphragmatic hernia.

Background: Congenital diaphragmatic hernia (CDH) is a congenital anomaly with high mortality and long-term morbidity. The aim of this study was to benchmark trends in 1-year and hospital volume outcomes for this condition. Methods: This study included all infants born with CDH in England between 2003 and 2016. This was a retrospective analysis of the Hospital Episode Statistics database. The main outcomes were: 1-year mortality, neonatal length of hospital stay (nLOS), total bed-days at 1 year and readmission rate. The association between hospital volume and outcomes was assessed for specialist paediatric surgery centres. Results: A total of 2336 infants were included (incidence 2·5 per 10 000 live births). No significant time trends were found in incidence and main outcomes. Some 1491 infants (63·8 per cent) underwent surgical repair. The 1-year mortality rate was 31·2 per cent. Median nLOS and total bed-days were 17 and 19 days respectively. The readmission rate in specialist paediatric centres was 6·3 per cent. Higher mortality was associated with birthweight lower than 1 kg (OR 5·90, 95 per cent c.i. 1·03 to 33·75), gestational age of 36 weeks or less (OR 1·75, 1·12 to 2·75) and black ethnicity (OR 2·13, 1·03 to 4·48). Only 4·0 per cent had extracorporeal membrane oxygenation, which was associated with higher mortality (OR 5·34, 3·01 to 9·46), longer nLOS (OR 3·70, 2·14 to 6·14) and longer total bed-days (OR 3·87, 2·19 to 6·83). Specialist paediatric centres showed variation in 30-day mortality (4·6 per cent with 84 per cent coefficient of variation), nLOS (median 25 (i.q.r. 15-42) days) and total bed-days (median 28 (i.q.r. 16-51) days), but no significant volume-outcome relationship. Conclusion: Key outcomes for CDH were similar to those of other developed countries. High variation among specialist paediatric centres was found and should be investigated further to explore the value of regionalization of care.

The impact of perioperative care on complications and short term outcome in ARM type rectovestibular fistula: An ARM-Net consortium study.

BACKGROUND: The impact of perioperative care interventions on postreconstructive complications and short-term colorectal outcome in patients with anorectal malformation (ARM) type rectovestibular fistula is unknown. METHODS: An ARM-Net consortium multicenter retrospective cohort study was performed including 165 patients with a rectovestibular fistula. Patient characteristics, perioperative care interventions, timing of reconstruction, postreconstructive complications and the colorectal outcome at one year of follow-up were registered. RESULTS: Overall complications were seen in 26.8% of the patients, of which 41% were regarded major. Differences in presence of enterostomy, timing of reconstruction, mechanical bowel preparation, antibiotic prophylaxis and postoperative feeding regimen had no impact on the occurrence of overall complications. However, mechanical bowel preparation, antibiotic prophylaxis ≥48 h and postoperative nil by mouth showed a significant reduction in major complications. The lowest rate of major complications was found in the group having these three interventions combined (5.9%). Multivariate analyses did not show independent significant results of any of the perioperative care interventions owing to center-specific combinations. At one year follow-up, half of the patients experienced constipation and this was significantly higher among those with preoperative mechanical bowel preparation. CONCLUSIONS: Differences in perioperative care interventions do not seem to impact the incidence of overall complications in a large cohort of European rectovestibular fistula-patients. Mechanical bowel preparation, antibiotic prophylaxis ≥48 h, and postoperative nil by mouth showed the least major complications. Independency could not be established owing to center-specific combinations of interventions. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: III.

The impact of the 1999 Mw 7.4 event in the Izmit Bay (Turkey) on anthropogenic contaminant (PCBs, PAHs and PBDEs) concentrations recorded in a deep sediment core.

The 1999 Mw 7.4 earthquake triggered a tremendous human tragedy and had a great social impact over the population of the Izmit Bay, one of the most industrialized area of Turkey. Although the successive environmental disasters were well documented, information on its sedimentary record is lacking. The present research aims at filling this gap, through the analysis of organic contaminants (PCBs, PAHs, and PBDEs) in a dated sediment core collected in the depocenter of the Karamürsel Basin in 2005. Profiles of total PCBs and total PAHs overlap the timing of industrialization in the area (starting in the 1960s) with values increasing as the population and the number of industrial plants grew larger. Profiles for PBDEs are in accordance with increasing urban inputs but are probably affected by processes of natural formation and post-depositional mixing. The continuous sedimentary record is interrupted at a level dating back to 1980 due to the erosion caused by the 1999 earthquake, having removed a 5-7cm thick sediment layer. Contaminant concentrations in the deepest 10-15cm of a 30cm thick seismo-turbidite unit, triggered by the 1999 event, increase with the progressive fining up and evidence massive transport of sediments from coastal, more polluted sites of the north-eastern Karamürsel shelves and shores. Additional inputs of PAHs are also evident, originating from a fire at the oil refinery that followed the shaking. The effects of the earthquake generated tsunami, its backwash fluxes and the following seiches are not uniquely displayed by each class of contaminants, and they could probably reflect successive inputs deriving from different parts of the basin that are subject to anthropogenic impacts of different nature. Concentrations measured at the top of the core are consistent with an unvaried input of pollutants in the period 1980-2005.

Thirty-days readmissions in pediatric surgery: The first U.K. experience.

INTRODUCTION: The aim of this study was to investigate readmissions within 30days of operation (ReAd) in the setting of a tertiary pediatric surgical practice in the UK. METHODS: Using Hospital Episode Statistics, cases that were readmitted within 30days of primary operation were identified retrospectively. Demographics including age, gender, preexisting comorbidities, diagnosis on primary admission and the treatment, length of stay, and diagnosis on readmission with treatment, including further surgical intervention, were collected from discharge summaries and hospital notes. Neonates were excluded from this study. Comorbidities, involving one or more systems, were also identified for each case of readmission. ReAds were classified into emergency and elective cohort depending on the nature of the primary operation. Outcomes were compared between these two groups. Data were quoted as median (range) unless indicated otherwise. Data were analyzed using SPSS software Desktop 22.0, using Mann-Whitney U and Chi-Squared tests, with a consideration that a P≤0.05 was significant. RESULTS: A total of 2378 procedures were performed during the study period. Elective cases, including day cases, accounted for 77% (n=1837) of all cases. The remaining 23% (n=541) were emergency cases. Total unplanned readmission rate within 30days (ReAd) was 2%. Further surgical procedures were required in 38%. Having excluded neonates, the most common primary procedure leading to readmission within 30days was appendicectomy (26%). Overall, the most common cause for readmission within 30days was postoperative infection (30%). The ReAd in emergency cohort was 3.5% in comparison to 1.5% in elective, which was significantly different (P value=0.007). CONCLUSION: Readmission within thirty days of primary procedure in pediatric surgery has little published data. An efficient discharge planning may play a vital role in preventing unwanted readmission. Elective operations had a significantly lower readmission rate than emergency operations. Having excluded neonates, appendicectomy was found to be the most common operation associated with readmission in the pediatric surgical practice. Although widely used as quality care indicator in adults, more studies are required to validate readmission rate as a quality of care indicator in pediatric surgery practice.

Length of stay and cost analysis of neonates undergoing surgery at a tertiary neonatal unit in England.

Introduction There is a lack of knowledge on the average length of stay (LOS) in neonatal units after surgical repair of common congenital anomalies. There are few if any publications reporting the activity performed by units undertaking neonatal surgery. Such activity is important for contracting arrangements, commissioning specialist services and counselling parents. The aim of this study was to describe postnatal LOS for infants admitted to a single tertiary referral neonatal unit with congenital malformations requiring surgery. Methods Data on nine conditions were collected prospectively for babies on the neonatal unit over a five-year period (2006-2011). For those transferred back to their local unit following surgery, the local unit was contacted to determine the total LOS. Only those babies who had surgery during their first admission to our unit and who survived to discharge were included in the study. Cost estimates were based on the tariffs agreed for neonatal care between our trust and the London specialised commissioning group in 2011-2012. Results The median LOS for the conditions studied was: gastroschisis 35 days (range: 19-154 days), oesophageal atresia 33 days (range: 9-133 days), congenital diaphragmatic hernia 28 days (range: 7-99 days), intestinal atresia 24 days (range: 6-168 days), Hirschsprung's disease 21 days (range: 15-36 days), sacrococcygeal teratoma 17 days (range: 12-55 days), myelomeningocoele 15.5 days (range: 8-24 days), anorectal malformation 15 days (range: 6-90 days) and exomphalos 12 days (range: 3-228 days). The total neonatal bed day costs for the median LOS ranged from £8,701 (myelomeningocoele) to £23,874 (gastroschisis). The cost of surgery was not included. Conclusions There is wide variation in LOS for the same conditions in a single neonatal unit. This can be explained by different types and severity within the same congenital anomalies, different surgeons and other clinical confounders (eg sepsis, surgical complications, associated anomalies). These data will enable us to give more detailed information to families following prenatal or postnatal diagnosis. They also allow more detailed planning of resource allocation for neonatal admissions.

Exploring the possibility to detect recent temporal changes in highly disturbed sedimentary records through sampling repetitions and core comparisons of porosity and sand content.

Dating of sediment cores in dynamic environments (such as tropical coastal lagoons) is often impossible to achieve, due to the difficulty to recover continuous and undisturbed records. Detailed temporal definition of environmental changes cannot be assured, but there is the possibility that information retained in such sediments can still provide useful insights on local or large-scale sedimentary dynamics, when a specific strategy is adopted. This latter consists in repeated core samplings at the same location and in the comparison of core profiles for basic and easily measurable parameters (porosity and sand content). This approach was tested on sediment cores, collected repeatedly during the period 2005-2010, at the same site of the Thi Nai Lagoon (central Vietnam). The proposed procedure was able to evidence the impact on lagoon sediments of activities linked to the construction of industrial settlements in the area, with dredging removing a consistent sediment layer from 2005 to 2008 and waste dumping providing additional sediment input in the following period. Simple statistic confirmed this scenario, together with core profiles of PCBs, As, Cd, Pb, and Zn. The procedure represents a simple tool to study coastal dynamics in places where the level of accuracy of traditional sediment radiodating cannot be reached. Several ameliorations are suggested in order to help developing the monitoring of sedimentary processes in poorly studied areas.

Towards the perfect ARM center: the European Union's criteria for centers of expertise and their implementation in the member states. A report from the ARM-Net.

BACKGROUND: Pediatric surgeons and patient organisations agree that fewer centers for anorectal malformations with larger patient numbers are essential to reach better treatment. The European Union transacts a political process which aims to realize such centers of expertise for a multitude of rare diseases. All the centers on a specific rare disease should constitute an ERN on that disease. ARM-Net members in different countries report on first experiences with the implementation of national directives, identifying opportunities and risks of this process. METHODS: Relevant details from the official European legislation were analyzed. A survey among the pediatric surgeons of the multidisciplinary ARM-Net consortium about national implementation was conducted. RESULTS: European legislation calls for multidisciplinary centers treating children with rare diseases, and proposes a multitude of quality criteria. The member states are called to allocate sufficient funding and to execute robust governance and oversight, applying clear methods for evaluation. Participation of the patient organisations is mandatory. The national implementations all over Europe differ a lot in respect of extent and timeframe. CONCLUSIONS: Establishing Centers of Expertise and a ERN for anorectal malformations offers great opportunities for patient care and research. Pediatric surgeons should be actively engaged in this process.

European consensus meeting of ARM-Net members concerning diagnosis and early management of newborns with anorectal malformations.

The ARM-Net (anorectal malformation network) consortium held a consensus meeting in which the classification of ARM and preoperative workup were evaluated with the aim of improving monitoring of treatment and outcome. The Krickenbeck classification of ARM and preoperative workup suggested by Levitt and Peña, used as a template, were discussed, and a collaborative consensus was achieved. The Krickenbeck classification is appropriate in describing ARM for clinical use. The preoperative workup was slightly modified. In males with a visible fistula, no cross-table lateral X-ray is needed and an anoplasty or (mini-) posterior sagittal anorectoplasty can directly be performed. In females with a small vestibular fistula (Hegar size <5 mm), a primary repair or colostomy is recommended; the repair may be delayed if the fistula admits a Hegar size >5 mm, and in the meantime, gentle painless dilatations can be performed. In both male and female perineal fistula and either a low birth weight (<2,000 g) or severe associated congenital anomalies, prolonged preoperative painless dilatations might be indicated to decrease perioperative morbidity caused by general anesthesia. The Krickenbeck classification is appropriate in describing ARM for clinical use. Some minor modifications to the preoperative workup by Levitt and Peña have been introduced in order to refine terminology and establish a comprehensive preoperative workup.

Accuracy of prenatal ultrasound in detecting jejunal and ileal atresia: systematic review and meta-analysis.

OBJECTIVE: The accuracy of prenatal ultrasound examination in detecting jejunal and ileal atresia has been reported in the literature to be highly variable, at 25-90%. The aim of this systematic review was to evaluate the accuracy of prenatal ultrasound in detecting non-duodenal small bowel atresia (ND-SBA). METHODS: MEDLINE, EMBASE and The Cochrane Library, including The Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and The Cochrane Central Register of Controlled Trials (CENTRAL), were searched electronically. The overall detection rate of jejunal or ileal atresia using ultrasound was reported. The accuracy of using polyhydramnios and dilated loops of bowel as diagnostic signs was also explored. RESULTS: Sixteen studies involving 640 fetuses were included in this review. The detection rate of ND-SBA by prenatal ultrasound was highly variable, with values ranging from 10 to 100%, with an overall prediction of 50.6% (95% CI, 38.0-63.2%). When analyzed separately, the detection rates of jejunal and ileal atresia were 66.3%, (95% CI, 33.9-91.8%) and 25.9% (95% CI, 4.0-58.0%), respectively. Both dilated loops of bowel and polyhydramnios as diagnostic signs for ND-SBA provided a low overall detection rate. CONCLUSIONS: The diagnostic performance of prenatal ultrasound in identifying ND-SBA is extremely variable. Large studies are needed in order to identify objective and combined criteria for the diagnosis of these anomalies.

Blockade of nociceptive sensory afferent activity of the rat knee joint by the bradykinin B2 receptor antagonist fasitibant.

OBJECTIVE: The aim of this study was to determine in intact and inflamed knee joints of the rat, the effect of the bradykinin (BK) B2 receptor antagonist fasitibant (MEN16132) on nociceptor mechanosensitivity and hyperalgesia. METHODS: Joint afferent sensory fibers of the medial articular nerve of anesthetized animals were electrophysiologically recorded, measuring nerve impulse activity evoked by passive innocuous and noxious movements of the joint, in intact and kaolin and carrageenan-injected joints. Knee joints of rats were also acutely inflamed by intra-articular injection of carrageenan alone. Long term duration of fasitibant antinociceptive effects were behaviorally evaluated using the incapacitance test. RESULTS: BK (100 µM) injected into the saphenous artery, induced excitation and sensitization of multi- and single unit recordings. Fasitibant (300 µM) injected prior to BK, reduced its excitatory effects as well as the overall increase of movement-evoked activity resulting from repeated injections of BK. Fasitibant did not affect movement-evoked activity of sensory fibers of intact, non-inflamed knee joints. Intra-articular fasitibant (100 µg/knee) significantly reduced the carrageenan-induced inflammatory hyperalgesia measured with the incapacitance test up to four days after treatment. This antinociceptive effect was not obtained with systemic endovenous injection of the drug. CONCLUSIONS: Fasitibant prevents B2 receptor-mediated activation and sensitization of peripheral joint afferents and the ensuing inflammatory hyperalgesia, and may be a useful, novel drug for arthritis pain treatment.

Frequency of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from Trentino, North East Italy.

OBJECTIVE: Triple negative breast carcinomas (TNT) are infiltrating breast carcinomas (BC) with negative oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER-2) expression, and are associated with frequent BRCA1/BRCA2 mutations. The aim of the present study is to analyze the frequency and distribution of TNT in our population where a breast cancer screening program for women aged between 50 and 69 years is effective since 2001 with 85% accrual. METHODS: We investigated the records of 2112 consecutive BC and 153 interval BC (i.e. BC detected in the screened negative women in the interval between screening rounds). Tumours with complete negative expression of ER, PgR and Her2 were considered TNT; tumours with negative ER and PgR status and faint Her2 expression (score 1) were considered as possible TNT (pTNT). RESULTS: We identified 82 (3.8%) TNT and 20 (0.9%) pTNT in the series of 2112 consecutive BC and 7 TNT and 1 pTNT (5.2%) in the series of 153 interval BC. In the consecutive series, TNT/ pTNT were observed in 6.5% patients below 50 years and in 4.3% of patients above 50 years. A high proliferation rate (Ki-67 labelling > 36%) was observed in 87.8% of TNT (median labelling 56.3%) and in 60% of pTNT (median labelling 48.4%). CONCLUSIONS: Since TNT/pTNT occurring in women < 50 years is a criterion for selecting patients whom genetic counselling and BRCA1 testing should be offered, our study is of help in foreseeing the workload of the Unit of Medical Genetics and the Laboratory of Molecular Pathology.

Control of odour emission in wastewater treatment plants by direct and undirected measurement of odour emission capacity.

Odour emissions from wastewater treatment plants (WWTPs) are considered to be the main causes of disturbance noticed by the exposed population and have relevant impacts on both tourism economy and land costs. Odour impact from WWTPs is generated by primary and secondary odour emissions. Primary odour emissions are related especially to the wastewater type and variability discharged into the sewer and directed to the WWTP, and to the wastewater collection and sewage system. Secondary odours are related to the treatment units of the plant. Several studies describe the key role of primary odour emissions and how they are strongly related to odour impacts of WWTPs. In this way, a opportune characterization of the emission capacity of primary odour could be an effective way to control odour emission in the WWTPs. In this study the odour emission capacity (OEC) of different domestic sewers was described and investigated; a correlation between the OEC and the main physical-chemical parameters of wastewater quality was also carried out. Results of this study identify the optimum conditions for sampling and measuring OEC in wastewaters and define its dependence by wastewater quality. These results can contribute to setting the standards for the maximum odourant content of wastewater that are discharged into the publicly owned sewage system.

Bradykinin and B2 receptor antagonism in rat and human articular chondrocytes.

BACKGROUND AND PURPOSE: In osteoarthritis (OA), bradykinin (BK) is known to contribute to pain and synovitis, but not to cartilage degradation. Here, we investigated effects of BK and its antagonists on chondrocytes, cells involved in cartilage homeostasis. EXPERIMENTAL APPROACH: BK receptor density and affinities of BK, its analogues and antagonists were measured in cultured human and rat chondrocytes by radioligand binding. Effects of BK were assessed by accumulation of inositol phosphates (IP) and release of interleukin (IL)-6 and IL-8. KEY RESULTS: Density of [³H]-BK binding sites was higher (13-30-fold) and BK evoked a greater (48-fold) IP production, in human than in rat chondrocytes. The BK B2 receptor antagonists MEN16132 and icatibant displayed similar binding affinity. MEN16132 was 40-fold more potent than icatibant in the IP assay. In human chondrocytes, BK increased release (over 24 h) of IL-6 and IL-8, effects blocked by MEN16132 but not by the B1 receptor antagonist Lys-[Leu8][desArg9]BK. BK-induced release of IL-6, but not of IL-8, was partially inhibited by indomethacin (10 µM) and nordihydroguaiaretic acid (10 µM). Antagonists for the prostanoid EP receptors (AH6809 10 µM; L-798,196, 200 nM; L-161,982, 1 µM) were ineffective. Dexamethasone (100 nM) partially inhibited release of both IL-6 and IL-8. Inhibitors of intracellular downstream signalling pathways (SB203580 10 µM; PD98059, 30 µM; SP600125, 30 µM; BAY-117085, 5 µM) indicated the involvement of p38 MAPK and the activation of NF-κB. CONCLUSION AND IMPLICATIONS: BK mediated inflammatory changes and cartilage degradation and B2 receptor blockade would, therefore, be a potential treatment for OA.

Intestinal epithelial barrier dysfunction in disease and possible therapeutical interventions.

The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens. Epithelial cells are linked together at the apical junctional complex by tight junctions that reduce the extracellular space and the passage of charge entities while forming a physical barrier to lipophilic molecules. Cultured intestinal epithelial cells have been extensively used to study intestinal absorption of newly synthesized drugs and the regulation of tight junctions structure and function. In vitro mild irritants, proinflammatory cytokines, toxins and pathogens, and adverse environmental conditions open tight junctions and increase paracellular permeability, an effect often accompanied by immune activation of the enterocytes. Conversely, inhibition of proinflammatory cytokines, exposure to growth factors and probiotics, among others, exert a protective effect. Impaired barrier function results from activation of signalling pathways that lead to alteration of junctional proteins expression and/or distribution. In vivo, intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection. This review will describe the current knowledge of the mechanisms regulating tight junctions and intestinal permeability, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are.