Developing a core outcome set for clinical trials in olfactory disorders: a COMET initiative.

STATEMENT OF PROBLEM: Evaluating the effectiveness of the management of Olfactory Dysfunction (OD) has been limited by a paucity of high-quality randomised and/or controlled trials. A major barrier is heterogeneity of outcomes in such studies. Core outcome sets (COS) - standardized sets of outcomes that should be measured/reported as determined by consensus-would help overcome this problem and facilitate future meta-analyses and/or systematic reviews (SRs). We set out to develop a COS for interventions for patients with OD. METHODS: A long-list of potential outcomes was identified by a steering group utilising a literature review, thematic analysis of a wide range of stakeholders' views and systematic analysis of currently available Patient Reported Outcome Measures (PROMs). A subsequent e-Delphi process allowed patients and healthcare practitioners to individually rate the outcomes in terms of importance on a 9-point Likert scale. RESULTS: After 2 rounds of the iterative eDelphi process, the initial outcomes were distilled down to a final COS including subjective questions (visual analogue scores, quantitative and qualitative), quality of life measures, psychophysical testing of smell, baseline psychophysical testing of taste, and presence of side effects along with the investigational medicine/device and patient's symptom log. CONCLUSIONS: Inclusion of these core outcomes in future trials will increase the value of research on clinical interventions for OD. We include recommendations regarding the outcomes that should be measured, although future work will be required to further develop and revalidate existing outcome measures.

Position paper on olfactory dysfunction: 2023

BACKGROUND: Since publication of the original Position Paper on Olfactory Dysfunction in 2017 (PPOD-17), the personal and societal burden of olfactory disorders has come sharply into focus through the lens of the COVID-19 pandemic. Clinicians, scientists and the public are now more aware of the importance of olfaction, and the impact of its dysfunction on quality of life, nutrition, social relationships and mental health. Accordingly, new basic, translational and clinical research has resulted in significant progress since the PPOD-17. In this updated document, we present and discuss currently available evidence for the diagnosis and management of olfactory dysfunction. Major updates to the current version include, amongst others: new recommendations on olfactory related terminology; new imaging recommendations; new sections on qualitative OD and COVID-19 OD; updated management section. Recommendations were agreed by all co-authors using a modified Delphi process. CONCLUSIONS: We have provided an overview of current evidence and expert-agreed recommendations for the definition, investigation, and management of OD. As for our original Position Paper, we hope that this updated document will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency, and generalisability of work in this field.

The COVANOS trial - insight into post-COVID olfactory dysfunction and the role of smell training.

BACKGROUND: Olfactory dysfunction is a cardinal symptom of COVID-19 infection, however, studies assessing long-term olfactory dysfunction are limited and no randomised-controlled trials (RCTs) of early olfactory training have been conducted. METHODOLOGY: We conducted a prospective, multi-centre study consisting of baseline psychophysical measurements of smell and taste function. Eligible participants were further recruited into a 12-week RCT of olfactory training versus control (safety information). Patient-reported outcomes were measured using an electronic survey and BSIT at baseline and 12 weeks. An additional 1-year follow-up was open to all participants. RESULTS: 218 individuals with a sudden loss of sense of smell of at least 4-weeks were recruited. Psychophysical smell loss was observed in only 32.1%; 63 participants were recruited into the RCT. The absolute difference in BSIT improvement after 12 weeks was 0.45 higher in the intervention arm. 76 participants completed 1-year follow-up; 10/19 (52.6%) of participants with an abnormal baseline BSIT test scored below the normal threshold at 1-year, and 24/29 (82.8%) had persistent parosmia. CONCLUSIONS: Early olfactory training may be helpful, although our findings are inconclusive. Notably, a number of individuals who completed the 1-year assessment had persistent smell loss and parosmia at 1-year. As such, both should be considered important entities of long-Covid and further studies to improve management are highly warranted.

Are immunosuppressive conditions and preoperative corticosteroid treatment risk factors in inguinal hernia repair?

INTRODUCTION: Immunosuppressive conditions and/or preoperative corticosteroid treatment have a negative influence on wound healing and can, therefore, lead to higher rates of surgical site infections (SSIs) and seromas. For inguinal hernia, no such studies have been carried out to date. METHODS: In an analysis of data from the Herniamed Registry, 2312 of 142,488 (1.6%) patients with primary unilateral inguinal hernia repair had an anamnestic history of an immunosuppressive condition and/or preoperative corticosteroid treatment. Using propensity score matching, 2297 (99.4%) pairs with comparative patient characteristics were formed. These were then compared using the following primary outcome criteria: intra- and postoperative complications, complication-related reoperations, recurrence at one-year follow-up, pain on exertion, pain at rest, and chronic pain requiring treatment at one-year follow-up. Of the 2297 matched pairs with primary unilateral inguinal hernia repair, 82.76% were male patients. 1010 (44.0%) were operated in laparo-endoscopic techniques (TEP, TAPP), 1225 (53.3%) in open techniques (Bassini, Shouldice, Lichtenstein, Plug, TIP, Gilbert, Desarda), and 62 (2.7%) in other techniques. RESULTS: The matched pair analysis results did not identify any disadvantage in terms of the outcome criteria for patients with an anamnestic history of immunosuppressive condition and/or preoperative corticosteroid treatment (yes vs no). In particular, no disadvantage was noted in the rate of surgical site infections (0.65% vs 0.70%; ns) or seromas (1.22% vs 1.57%; ns). The overall rates of postoperative complications were 3.40% vs 4.31% (p = ns) (plus 0.22% concordant events in five matched pairs). CONCLUSION: In primary unilateral inguinal hernia surgery, an immunosuppressive condition and/or preoperative corticosteroid treatment does not appear to have a negative influence on wound complications.

Anosmia as a presenting symptom of SARS-CoV-2 infection in healthcare workers - A systematic review of the literature, case series, and recommendations for clinical assessment and management.

BACKGROUND: Healthcare workers are at the forefront of the ongoing COVID-19 pandemic and are at high risk for both the contraction and subsequent spread of virus. Understanding the role of anosmia as an early symptom of infection may improve monitoring and management of SARS-CoV2 infection. METHODOLOGY: We conducted a systematic review of the literature of SARS-CoV2 infection/COVID-19 and anosmia to help inform management of anosmia in healthcare works. We report a case series of healthcare workers, who presented with a loss of sense of smell secondary to COVID-19 infection to demonstrate management principles. RT-PCR was used to confirm COVID-19 positivity and psychophysical testing of olfaction was performed using the British version of the University of Pennsylvania Smell Identification Test, UPSIT. RESULTS: The systematic literature search returned 31 articles eligible for inclusion in the study and informed our recommendations for clinical assessment and management. All three healthcare professionals who presented with loss of sense of smell subsequently tested positive for SARS-CoV-2. Psychophysical testing of olfaction using the UPSIT confirmed mild and moderate microsmia in two, respectively, and normosmia at day 17 in one. CONCLUSIONS: Olfactory (± gustatory) dysfunction is indicative of COVID-19 infection and thus has important implications in the context of healthcare workers, or key workers in general, who work in close contact with others if not recognised as suffering from COVID. This leads to a potentially higher likelihood of spreading the virus. In conjunction with our literature review these findings have helped with creating recommendations on the assessment and management of olfactory dysfunction during the ongoing COVID-19 pandemic, both for healthcare workers and patients.

What are the influencing factors for chronic pain following TAPP inguinal hernia repair: an analysis of 20,004 patients from the Herniamed Registry.

BACKGROUND: In inguinal hernia repair, chronic pain must be expected in 10-12% of cases. Around one-quarter of patients (2-4%) experience severe pain requiring treatment. The risk factors for chronic pain reported in the literature include young age, female gender, perioperative pain, postoperative pain, recurrent hernia, open hernia repair, perioperative complications, and penetrating mesh fixation. This present analysis of data from the Herniamed Hernia Registry now investigates the influencing factors for chronic pain in male patients after primary, unilateral inguinal hernia repair in TAPP technique. METHODS: In total, 20,004 patients from the Herniamed Hernia Registry were included in uni- and multivariable analyses. For all patients, 1-year follow-up data were available. RESULTS: Multivariable analysis revealed that onset of pain at rest, on exertion, and requiring treatment was highly significantly influenced, in each case, by younger age (p < 0.001), preoperative pain (p < 0.001), smaller hernia defect (p < 0.001), and higher BMI (p < 0.001). Other influencing factors were postoperative complications (pain at rest p = 0.004 and pain on exertion p = 0.023) and penetrating compared with glue mesh fixation techniques (pain on exertion p = 0.037). CONCLUSIONS: The indication for inguinal hernia surgery should be very carefully considered in a young patient with a small hernia and preoperative pain.

Intratympanic steroid use for idiopathic sudden sensorineural hearing loss: current otolaryngology practice in Germany and Austria.

AIMS: The frequency of the use of intratympanic steroids (ITS) as a treatment for idiopathic sudden sensorineural hearing loss (ISSNHL) in Europe is still unknown and remains a contentious issue amongst otolaryngologists. We undertook a survey of otolaryngologists in Germany and Austria to establish if there is any professional consensus with which to form a protocol for its use. METHODS: A survey of 21 questions was distributed electronically to otolaryngologists in Germany and Austria and data on demographics, indications for intratympanic treatment, procedure, follow-up, and outcomes were analysed. RESULTS: We received 908 responses. 49.1% of otolaryngologists used ITS for ISSNHL. Of those otolaryngologists who use ITS, 73.7% do not use it as primary treatment. 20.6% use ITS in conjunction with oral steroids for primary treatment and only 5.8% use ITS as monotherapy for primary treatment. 90.5% use ITS as salvage therapy. 81.1% do not consider the use of ITS after 2 weeks from the onset of symptoms. 8.3% used a tympanostomy tube and while the most commonly used steroid was dexamethasone at a concentration of 4 mg/ml (61%), a wide variety or other steroids and concentrations were used. CONCLUSIONS: This survey illustrates wide variation of current practice of intratympanic corticosteroid injection for ISSHL in Germany and Austria. In the absence of high-level evidence, knowing what current practice is allows clinicians to assess what they do against what their colleagues are doing, and if they do something very different, make them question their practice. Moreover, the obtained data will help to direct future clinical trials with the aim to compare the outcomes of more commonly used protocols.

Liquid antiadhesive agents for intraperitoneal hernia repair procedures: Artiss® compared to CoSeal® and Adept® in an IPOM rat model.

BACKGROUND: Adhesion formation remains an important issue in hernia surgery. Liquid agents were developed for easy and versatile application, especially in laparoscopy. The aim of this study was to compare the antiadhesive effect of fibrin sealant (FS, Artiss®), Icodextrin (ID, Adept®) and Polyethylene glycol (PEG, CoSeal®) alone and in combination and to evaluate the resulting effect on tissue integration of the mesh. METHODS: A total of 56 Sprague-Dawley rats were operated in open IPOM technique. A middleweight polypropylene mesh of 2 × 2 cm size was implanted and covered with 1: FS, 2: ID, 3: PEG, 4: FS + ID, 5: FS + PEG, 6: PEG + ID, 7: control group, uncovered mesh (n = 8 per treatment/control). Observation period was 30 days. Macroscopic and histological evaluation was performed. RESULTS: Severe adhesions were found in group 2 (ID), group 6 (PEG + ID) and the controls. Best results were achieved with FS alone or FS + ID. Mesh integration in the treatment groups was reduced in comparison with the control group. This is a new finding possibly relevant for the outcome of intraperitoneal mesh repair. Group 6 (PEG + ID) showed an impairment of tissue integration with <50 % of the mesh surface in seven samples. CONCLUSION: FS alone and in combination with ID yielded excellent adhesion prevention. ID alone did not show significant adhesion prevention after 30 days. Tissue integration of FS-covered meshes was superior to ID or PEG alone or combined. PEG did show adhesion prevention comparable to FS but evoked impaired tissue integration. So Artiss® is among the most potent antiadhesive agents in IPOM repair.

Is the age of >65 years a risk factor for endoscopic treatment of primary inguinal hernia? Analysis of 24,571 patients from the Herniamed Registry.

INTRODUCTION: Several analyses of hernia registries have demonstrated that patients older than 65 years have significantly higher perioperative complication rates compared with patients up to the age of 65. To date, no special analyses of endoscopic/laparoscopic inguinal hernia surgery or of the relevant additional influence factors have been carried out. Besides, there is no definition to determine whether 65 years should really be considered to be the age limit. METHODS: In the Herniamed Hernia Registry, it was possible to identify 24,571 patients with a primary inguinal hernia and aged at least 16 years who had been operated on between September 1, 2009, and April 15, 2013, using either the TAPP technique (n = 17,214) or TEP technique (n = 7,357). Patients in the age group up to and including 65 years (≤65 years) were compared with those older than 65 years (>65 years) in terms of their perioperative outcome. That was done first using unadjusted analysis and then multivariable analysis. RESULTS: Unadjusted analysis revealed significantly different results for the intraoperative (1.19 vs 1.60%; p = 0,010), postoperative surgical (2.72 vs 4.59%; p < 0.001) and postoperative general complications (0.85 vs 1.98%; p < 0.001) as well as for complication-related reoperations (1.07 vs 1.37%; p = 0,044), which were more favorable in the ≤65 years age group. However, in multivariable analysis, it was not possible to confirm that for the intraoperative complications or the reoperations. Reoperations were needed more often for bilateral procedures (p < 0.001; OR 2.154 [1.699; 2.730]), higher ASA classification (IV vs I: p = 0.004; OR 6.001 [1.786; 20.167]), larger hernia defect and scrotal hernias. The impact of these factors, in addition to that of age >65 years, was also reflected in the postoperative complication rates. The age limit for increased onset of perioperative complication rates tends to be more than 80 rather than 65 years. CONCLUSION: The higher perioperative complication rate associated with endoscopic/laparoscopic inguinal hernia surgery in patients older than 65 years is of multifactorial genesis and is observed in particular as from the age of 80 years.

When is mesh fixation in TAPP-repair of primary inguinal hernia repair necessary? The register-based analysis of 11,230 cases.

Whereas for TEP the guidelines do not recommend mesh fixation on the basis of meta-analyses regardless of the defect size, for TAPP mesh fixation can be omitted only up to a defect size of 3 cm because of the paucity of studies on this topic. Hence, this study now seeks to explore this subject on the basis of prospective data from the Herniamed Hernia Registry. In the period September 01, 2009, to January 31, 2014, 11,228 male patients were operated on with the TAPP technique for a primary unilateral inguinal hernia and were followed up for 1 year. Mesh fixation was used for 7422 (66.1 %) of these patients and no mesh fixation for 3806 patients (33.9 %). Unadjusted analysis did not find any significant difference in the recurrence rate (0.88 % with fixation vs. 1.1 % without fixation; p = 0.259). Multivariable analysis of all potential influence factors (age, ASA, BMI, risk factors, defect size, mesh fixation, localization of defect, mesh size) did not identify any factor that impacted recurrence on 1-year follow-up. Only for medial and combined defect localization versus lateral localization was a highly significant effect identified (p < 0.001). With mesh fixation and larger mesh size, it was possible to significantly reduce the recurrence rate for larger medial hernias in this series (p = 0.046). For TAPP repair of an inguinal hernia, mesh fixation is not necessary in a significant number of patients. Patients with a medial and combined hernia are at higher risk of recurrence. In the patient series analyzed, it was possible to significantly reduce the recurrence rate with mesh fixation and larger mesh size for medial defects.

The outcome of septorhinoplasty surgery on olfactory function.

OBJECTIVES: To assess olfactory outcomes in patients undergoing septorhinoplasty surgery in our unit. DESIGN: Prospective cohort study. SETTING: The Royal National Throat Nose and Ear Hospital, London. PARTICIPANTS: Forty-three patients undergoing functional septorhinoplasty (Males = 26; mean age = 34.1 ± 12.2) were recruited into the study. MAIN OUTCOME MEASURES: The primary outcome of olfactory function was assessed using 'Sniffin sticks'. Our secondary outcomes were assessment of patient quality of life using the disease specific Sino-nasal Outcome Test-23 questionnaire (SNOT-23) and a visual analogue scale for sense of smell. These measures were repeated at 12 weeks post operatively. RESULTS: There was a significant change in the Sniffin' sticks score post-operatively (8.3 versus 9.6; P < 0.001). The SNOT-23 score also showed a significant improvement post-operatively (53.5 versus 40.4; P < 0.001). A significant improvement was not found in the smell/taste question (question 21) of the SNOT-23 questionnaire as well as the visual analogue scale for sense of smell. A difference in olfactory outcome was not found between open versus closed approaches, primary versus revision surgery and traumatic versus non traumatic cases. CONCLUSIONS: The results show a measured significant improvement in olfaction following functional Septorhinoplasty but not a subjective improvement in the patients perception of their sense of smell and hence not a clinically significant difference. The reasons for the measured improvement are not clear and are likely to be multifactorial.

Postoperative outcomes for unilateral congenital trochlear nerve palsy: A retrospective cohort study.

PURPOSE: Congenital trochlear nerve palsy is the most common cause of vertical strabismus. The goal of this study was to investigate surgical outcomes after superior oblique tendon plication with or without inferior oblique recession in children and adults with unilateral congenital trochlear nerve palsy. METHODS: Data and outcomes were collected in patients with a diagnosis of unilateral congenital superior oblique palsy during a retrospective single-center study conducted at the University Hospital of Tours. A reproducible, standard ophthalmological and oculomotor examination was performed pre- and postoperatively at 1 year, including presence or absence of diplopia, vertical and horizontal deviations, and compensatory head posture. Surgical success, defined as an endpoint including absence of diplopia in primary position, absence of head tilt, and vertical deviation at distance fixation<5 prism diopters (PD), was analyzed. RESULTS: A total of fifty-seven patients (median [IQR] age of 11 years [5-42]) were analyzed. Patients experienced a significant reduction in vertical distance and near deviations (p<0.001), compensatory head tilt (p < 0.001), and diplopia after surgery (p < 0.001). Surgical success was higher in adults (17/24, 70.8%) than in children (15/33, 45.5%), although this did not reach statistical significance (p=0.0657). CONCLUSION: This study suggests that plication of the superior oblique muscle tendon, with or without recession of the inferior oblique muscle, can be effective in treating unilateral congenital trochlear nerve palsy. Further studies are necessary to compare surgical procedures and investigate their efficacy in adults compared to children in the short and long term.

Rethinking the 'one-stop' neck lump clinic: a novel pathway beyond coronavirus disease 2019.

OBJECTIVES: UK guidelines advocate 'one-stop' neck lump assessment for cancer referrals. This paper reports the pilot of a novel pre-clinic ultrasound pathway, presents outcomes, and discusses strengths and limitations in the context of the coronavirus disease 2019 pandemic. METHODS: Two-week-wait cancer referral patients with a neck lump were allocated a pre-clinic ultrasound scan followed by a clinic appointment. Demographic, patient journey and outcome data were collected and analysed. RESULTS: Ninety-nine patients underwent ultrasound assessment with or without biopsy on average 8 days following referral. Patients were followed up on average 14.1 days (range, 2-26 days) after initial referral. At the first clinic appointment, 45 patients were discharged, 10 were scheduled for surgery, 12 were diagnosed with cancer, 6 were referred to another specialty and cancer was excluded in 19 patients. Retrospectively, four ultrasounds were performed unnecessarily. CONCLUSION: Pre-clinic ultrasound scanning is an alternative to the one-stop neck lump pathway. This study demonstrates fewer clinic visits, faster diagnosis and a low proportion of unnecessary scans, whilst minimising face-to-face consultations and aerosol-generating procedures.

A systematic review of facial plastic surgery simulation training models.

OBJECTIVES: The coronavirus disease 2019 pandemic has led to a need for alternative teaching methods in facial plastics. This systematic review aimed to identify facial plastics simulation models, and assess their validity and efficacy as training tools. METHODS: Literature searches were performed. The Beckman scale was used for validity. The McGaghie Modified Translational Outcomes of Simulation-Based Mastery Learning score was used to evaluate effectiveness. RESULTS: Overall, 29 studies were selected. These simulated local skin flaps (n = 9), microtia frameworks (n = 5), pinnaplasty (n = 1), facial nerve anastomosis (n = 1), oculoplastic procedures (n = 5), and endoscopic septoplasty and septorhinoplasty simulators (n = 10). Of these models, 14 were deemed to be high-fidelity, 13 low-fidelity and 2 mixed-fidelity. None of the studies published common outcome measures. CONCLUSION: Simulators in facial plastic surgical training are important. These models may have some training benefits, but most could benefit from further assessment of validity.

A systematic review on diagnostics and surgical treatment of adult right-sided Bochdalek hernias and presentation of the current management pathway.

PURPOSE: Bochdalek hernia is a congenital diaphragmatic hernia. The incidence in adults is estimated around 0.17%. Right-sided hernias are much more seldom than left-sided ones because of faster closure of the right pleuroperitoneal canal and the protective effect of the liver. Due to its rarity, there have been no large prospective or retrospective studies following great need for evidence-based diagnostics and treatment strategies. In this systematic review, we evaluated the current evidence of diagnostics, treatment, and follow-up of adult right-sided Bochdalek hernias. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines a systematic literature review was conducted in PubMed and Cochrane library from 2004 to January 2021. The literature search included all studies with non-traumatic right-sided Bochdalek hernias. Literature on left- or both-sided, pregnancy-associated, pediatric, and other types of hernias were explicitly excluded. Quality assessment of the included studies was performed. RESULTS: Database search identified 401 records. After eligibility screening 41 studies describing 44 cases of right-sided non-traumatic Bochdalek hernias in adulthood were included for final analysis. Based upon the systematic literature review, the current diagnostic, therapeutic, and follow-up management pathway for this rare surgical emergency is presented. CONCLUSION: This systematic review underlined that most studies investigating management of adult non-traumatic right-sided Bochdalek hernias are of moderate to low methodological quality. Hernias tend to occur more frequently in middle-aged and older women presenting with abdominal pain and dyspnea. A rapid and accurate diagnosis following surgical repair and regular follow-up is mandatory. High-quality studies focusing on the management of this rare entity are urgently needed.

Transanal irrigation improves quality of life in patients with low anterior resection syndrome.

AIM: Transanal irrigation (TAI) has been reported to be a cheap and effective treatment for the 'anterior resection syndrome (ARS)'. This study aimed to evaluate its effect on the quality of life (QOL) of patients suffering from ARS. METHOD: In a prospective study involving two colorectal centres, 14 patients (11 male; median age 68 (45-80) years) were included in the study. The median duration of ARS was 19 (9-48) months. The median number of defaecations was 8 (4-12)/day and 3 (2-5)/night. All patients were trained to perform TAI using the Peristeen™ System under the guidance of a stoma nurse. Anal physiology was performed, quality of life (QOL) was estimated by the SF-36 and Rockwood (ASCRS) questionnaires and continence by the Cleveland Incontinence Score. RESULTS: At the last follow up the median time of using TAI was 29 (15-46) months. The median volume of water used for the irrigation was 900 (500-1500) ml. There was a significant decrease in the number of defaecations during the day (baseline, 8 [4-12]; last follow up, 1 [1-2]) and at night (baseline, 3 [2-5]; last follow up, 0 [0-0]). The Cleveland Incontinence Score fell from 17 [15-20] (baseline) to 5 [4-9] (last follow up) and the mental component of the SF-36 and all domains of the Rockwood QOL instrument improved. CONCLUSION: Transanal irrigation is an effective treatment of anterior resection syndrome and results in a marked improvement of the continence score and QOL.

An in-depth diagnostic exploration of an inflammation and necrosis syndrome in a population of newborn piglets.

Inflammation and loss of tail integrity can be reasons for serious impairment of animal welfare and one of the major challenges facing modern pig farming. Evidence from practice increasingly suggests that tail lesions might be caused not only by tail biting but also by inflammation and necrosis, which can occur without any action from other pigs. Such changes are not limited to the tail but can also be observed in the ears, heels and soles, claw coronary bands, teats, navel, vulva and face. To describe inflammatory and necrotic manifestations in newborn piglets, all 146 piglets from 11 sows were clinically examined not later than 2 h after birth. In addition, the tail base of 30 randomly selected piglets out of the 146 was histo-pathologically examined as one of the most conspicuously affected body parts. Over 80% of the newborns showed affections in the tail base, claw wall and heels. In 65-87% of the animals, the coronary bands, teats, the face and the ears were affected. None of the 146 piglets was completely free from pathological manifestations. On average, the piglets were affected in six out of nine body parts simultaneously. Histological examinations showed that clear alterations in the skin were already manifested around the time of birth in all examined piglets. Alterations were characterised by the occurrence of numerous lymphocytes and granulocytes throughout the entire subepithelial connective tissue, predominantly in perivascular and perifollicular localisation but also within directly subepithelial glandular ducts and diffusely within the subepithelial connective tissue. In the majority of individuals, the epithelial structure was intact. This concurrence of symptoms in the newborns indicates a primarily endogenous aetiology of an inflammation and necrosis syndrome. Further studies in diverse herd contexts are necessary to establish the conditions for the emergence of such a syndrome and develop welfare indicators.