Introduction

Lactose intolerance is characterized by gastrointestinal symptoms triggered by lactose ingestion and presumably related to bacterial metabolism of malabsorbed lactose which results in hydrogen (H₂) production. However, only a subset of individuals with lactose malabsorption (M+), as diagnosed by a positive H₂ breath test, develops symptoms (S+), while others exhibit symptoms (S+) without evidence of malabsorption (M-). In the past, the lack of validated symptom assessment tools has limited the ability to comprehensively assess symptom burden and evaluate mechanisms of symptom pathogenesis. This study used the validated aCPQ to quantify symptom burdens and correlate these with H₂-breath test parameters (see reference).

Aims & Methods

We analyzed 927 patients with functional gastrointestinal disorders who underwent a 50 g lactose H₂-breath test (180 min). Malabsorption (M+) was defined as a >20 ppm rise in breath H₂, and relevant symptoms (S+) as a >20 cm increase in VAS symptom scores. Symptom burdens (max score: 100 for pain, nausea, meteorism, flatulence, diarrhea) and total symptom burdens (max: 500) were calculated. Breath test parameters included maximal H₂, time to H₂ rise, and area under the curve of H₂ (AUC-H₂).

Results

Among 363 M+ participants (39% of the 928 patients), S+/M+ individuals (n =267) had a higher AUC-H₂ (9731 ± 7292 ppm·min) versus S-/M+ (n = 96; 5450 ± 5445 ppm·min, p<0.001), a shorter time to H₂ rise (58.8 ± 37.8 vs. 75.8 ± 50.7 min, p<0.01), and a steeper H₂-accumulation rate (1.67 ± 1.5 vs. 0.97 ± 1.1 ppm/min, p<0.001). S+/M+ individuals had significantly higher total symptom burdens (134 ± 96 mm VAS) compared to S+/M- (71 ± 68 mm VAS, p<0.001), and more frequently experienced multiple symptoms simultaneously. Pain (in 58% of patients), bloating (56%), and diarrhea (46%) were most prevalent in M+/S+ and significantly exceeded prevalences in M+/S- (p<0.01).

Conclusion

Lactose ingestion can elicit symptoms independently of malabsorption but malabsorbers are burdened by higher symptom severity. Symptoms of lactose intolerance in malabsorbers are associated with distinct H₂-breath test kinetics suggesting faster increase in bacterial H₂ production and more intestinal H₂ accumulation. These findings suggest a role for the colonic bacterial metabolism of malabsorbed lactose and the microbiome in lactose intolerance and underscore the need for objective diagnostic tools to diagnose and differentiate non-malabsorptive lactose-related symptom generation from malabsorptive lactose intolerance, allowing for more individualized approaches to managing lactose intolerance in the future, including therapeutic approaches addressing the intestinal microbiome.

References

Hammer J et al. Carbohydrate induced gastrointestinal symptoms: development and validation of a test-specific symptom questionnaire for an adult population, the adult Carbohydrate Perception Questionnaire aCPQ. Eur J Gastroenterol Hepatol 2021;32:171-177

Clinical Case Summary

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive non-Hodgkin lymphoma with poor prognosis. We present a case of colonic T-cell lymphoma diagnosed in a patient with refractory chronic diarrhoea.
A 60-year-old Chinese female with a family history of colon cancer had recurrent admissions with extensive workup for a 4-month history of chronic watery non-bloody diarrhoea and 12-kg weight loss. Initial blood tests showed normochromic normocytic anaemia and hypokalaemia. Stool studies were negative for infections but demonstrated elevated calprotectin and low elastase. Coeliac and autoimmune workup returned negative. A Computed Tomography scan showed prominent nonspecific central mesenteric abdominal nodes without pancreas or small bowel abnormalities.
Initial colonoscopy revealed a 2mm descending colon polyp and normal looking colonic mucosa. Random terminal ileum and colonic biopsies were unremarkable. Polyp histology showed focally increased intraepithelial lymphocytes insufficient to diagnose microscopic colitis.
Working differentials included pancreatic insufficiency, small intestinal bacterial overgrowth and irritable bowel syndrome. She was treated with various drugs including Rifaximin, Pancrelipase and Nortriptyline. However, her symptoms persisted with increasing stool calprotectin levels. A repeat colonoscopy performed 2 months after the initial endoscopy, showed normal colonic mucosa again. However, random colonic biopsies histology demonstrated florid intraepithelial lymphocytosis and immunohistochemistry stains confirming MEITL. Systemic chemotherapy was initiated and her diarrhoea resolved.
Though MEITL classically involves the small bowel, our case demonstrated florid colonic involvement. This patient’s indolent presentation illustrated the diagnostic pitfall of a normal looking colon during colonoscopy, raising the importance of random colonic biopsies and repeat evaluation in persistent unexplained diarrhoea.

References

Illustrative material: Endoscopic images showing normal-appearing colonic mucosa. Histological sections demonstrating intraepithelial lymphocytosis on initial colon biopsy. Subsequent biopsy on repeat colonoscopy with immunohistochemistry showing CD3, CD8, CD56, granzyme B, and TIA-1 positivity
References:
Ozaka S, Inoue K, Okajima T, et al. Monomorphic epitheliotropic intestinal T-cell lymphoma presenting as melena with long-term survival: A case report and review of literature. World J Gastroenterol. 2021;27(38):6501-6510. doi:10.3748/wjg.v27.i38.6501
Afzal A, Esmaeili A, Ibrahimi S, Farooque U, Gehrs B. Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma With Extraintestinal Areas of Peripheral T-Cell Lymphoma Involvement. Cureus. 2020;12(8):e10021. Published 2020 Aug 25. doi:10.7759/cureus.10021
Tian S, Xiao SY, Chen Q, Liu H, Ping J. Monomorphic epitheliotropic intestinal T-cell lymphoma may mimic intestinal inflammatory disorders. Int J Immunopathol Pharmacol. 2019;33:2058738419829387. doi:10.1177/2058738419829387
Shin SY. A Rare Case of Intestinal T-cell Lymphoma with Multiple Complications. JDCR 2023;11:114-118. doi.org/10.52927/jdcr.2023.11.2.114
Sun ZH, Zhou HM, Song GX, Zhou ZX, Bai L. Intestinal T-cell lymphomas: a retrospective analysis of 68 cases in China. World J Gastroenterol. 2014;20(1):296-302. doi:10.3748/wjg.v20.i1.296

Introduction

Dyspepsia is a prevalent clinical syndrome with a broad differential diagnosis. Functional dyspepsia is the most frequent aetiology, followed by peptic ulcer disease, gastro-oesophageal reflux, and biliary disorders. Less commonly, it may be due to chronic pancreatitis, malignancy, or coeliac disease.
Coeliac disease may present with dyspepsia, malabsorptive diarrhoea, and weight loss. Laboratory findings often reveal protein malnutrition, iron deficiency, and occasional hypocalcaemia due to duodenal atrophy. Thus, excluding coeliac disease is essential when such features are present. Initial assessment should include serological testing and nutritional profiling.
In routine practice, due to celiac iceberg theory, there is a growing tendency to obtain duodenal biopsies during endoscopy for dyspepsia, regardless of macroscopic findings or clinical suspicion, aiming to rule out atrophic pathology.

Aims & Methods

We hypothesised that routine duodenal biopsies in dyspepsia without pathological signs or symptoms are inefficient, both clinically and economically.
We performed a retrospective, observational, descriptive study analysing 403 duodenal biopsies taken between January 2023 and January 2024. All cases had “dyspepsia” as the endoscopic indication and were requested by gastroenterologists.
We assessed histological and macroscopic duodenal atrophy, positivity for anti-transglutaminase (tTG) and anti-DGP antibodies, and clinical and laboratory features suggestive of coeliac disease. “Clinical suspicion” was defined as symptoms or abnormal tests; “serological suspicion” as antibody positivity. A high pre-test probability was defined as the presence of either.

Results

Mean age was 48.7 ± 15.9 years, with a female predominance (77.2%). Clinical features and laboratory findings suggesting coeliac disease are detailed in Table 1. Clinical suspicion was present in 31.5% of patients. Only one patient had both clinical and serological suspicion and was the sole case (1/403) with Marsh 3A changes in relation with coeliac disease.
Although serology is recommended in low pre-test probability cases, only 67.4% (271/403) underwent antibody testing; of these, 2.2% (6/271) were positive.
Three patients (0.007%) had endoscopic signs of atrophy. Nine biopsies showed non-specific lymphocytic infiltration (Marsh 1).
In 400 macroscopically normal duodenums, 127 patients (31.7%) had a high pre-test probability. The other 273 (68.3%) had no clinical suspicion yet underwent biopsy. At our centre, each biopsy costs about €50 and requires 30 minutes of staff time. Based on our data, €20,100 and over 25 labour working days could have been saved.

Conclusion

Of 403 duodenal biopsies performed for dyspepsia, only one case of coeliac disease was detected. Routine biopsies in low pre-test probability patients appear not to be cost-effective. Notably, one third of patients underwent gastroscopy without prior antibody determination—highlighting the need to align clinical practice with diagnostic guidelines.

References

- Ebell MH. British Society of Gastroenterology Guidelines for the Evaluation and Management of Dyspepsia. Am Fam Physician. 2023 Jul;108(1):Online. PMID: 37440724.

- Ahmed YH, Mohammed RA, Alghamdi IK, Alqahtani MF, Alhelali SN, Sultan I, Badawy MI, Barakat MM, Abozeid HE, Mohammed HL. Histopathological Findings in Adult Patients With Dyspepsia and Their Association With Helicobacter pylori Infection. Cureus. 2023 Dec 23;15(12):e50981. doi: 10.7759/cureus.50981. PMID: 38259413; PMCID: PMC10801451.

- ASGE Standards of Practice Committee; Shaukat A, Wang A, Acosta RD, Bruining DH, Chandrasekhara V, Chathadi KV, Eloubeidi MA, Fanelli RD, Faulx AL, Fonkalsrud L, Gurudu SR, Kelsey LR, Khashab MA, Kothari S, Lightdale JR, Muthusamy VR, Pasha SF, Saltzman JR, Yang J, Cash BD, DeWitt JM. The role of endoscopy in dyspepsia. Gastrointest Endosc. 2015 Aug;82(2):227-32. doi: 10.1016/j.gie.2015.04.003. Epub 2015 May 29. PMID: 26032200.

- Feld L, Cifu AS. Management of Dyspepsia. JAMA. 2018 May 1;319(17):1816-1817. doi: 10.1001/jama.2018.3435. PMID: 29715342.

Introduction

PTEN Hamartoma Tumor Syndrome (PHTS) is a rare condition caused by PTEN disease-causing variants and characterized by a complex phenotype including gastrointestinal-hamartomas and an increased lifetime risk for malignancies. Current genetic testing enables carriers identification and cascade testing

Aims & Methods

To describe a large cohort of PHTS carriers including unique clinical presentation, genetic diagnosis and treatment approach.
We conducted a retrospective, comprehensive review of medical charts was conducted for individuals with PHTS who were under surveillance at specialized high-risk clinics in Israel. The diagnosis of PHTS was based on the revised diagnostic criteria, which include identification of disease-causing variants in the PTEN gene mutation and/or a combination of major and minor clinical features *.

Results

A total of 53 individuals were included in the study (43% female; median age at diagnosis: 38 years, IQR 29, range 25-75). Pathogenic or likely pathogenic variants in the PTEN gene were identified in 40 individuals (75%), (52% missense, 17% nonsense, and 25% frameshift mutations). Common clinical presentations included gastrointestinal polyps, observed in 75% (n = 40), with five patients having adenomas and one presenting with a ganglion cell polyp. Malignancies were reported in 62% (n = 33), most commonly breast cancer (20%) and thyroid cancer (9%). Macrocephaly was observed in 35% (n = 20), and developmental delay, including autism spectrum disorder, in 8 patients (15%). There were three cases of soft tissue tumors (5.6%): One individual with abdominal desmoid tumor at age 18, one individual with axillary osteosarcoma followed by bilateral chest liposarcoma and one case with a rare soft tissue sarcoma, at the base of the skull.
One case of PHTS with PTEN mosaicism was identified through sequencing of endometrial, salivary, and thyroid tissue samples, following a negative result from blood-based genetic testing. Five individuals (9.4%) received Sirolimus for severe clinical manifestations (multiple thyroid nodules, colonic polyps, gastrointestinal symptoms, and early-onset malignancies). Of them, two patients had substantial reduction in polyp burden and improvement in gastrointestinal symptoms.

Conclusion

In this substantial series we found that PTHS exhibits a wide range of phenotypic presentations, high overall cancer rates and a relatively high prevalence of soft tissue malignancies, which have been rarely described in PHTS. Constitutional mosaicism should be sought in a clinical picture suggestive of PHTS with negative germline genetic testing.

References

* Pilarski R et al: Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013
1. Hendricks LAJ et al: PTEN Study Group; Mensenkamp AR, Vos JR. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. Eur J Med Genet. 2022 Dec;65(12):104632. doi: 10.1016/j.ejmg.2022.104632. Epub 2022 Oct 18. PMID: 36270489.
2. Dhawan A et al: Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res. 2025 Feb 12;31(9):1754–65. doi: 10.1158/1078-0432.CCR-24-3819. Epub ahead of print. PMID: 39937242; PMCID: PMC12010961.
3.Dhawan A, et al: Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res. 2025 Feb 12;31(9):1754–65. doi: 10.1158/1078-0432.CCR-24-3819. Epub ahead of print. PMID: 39937242; PMCID: PMC12010961.

Introduction

Irritable bowel syndrome (IBS) pathophysiology is multifactorial, with fermentable, oligo, di- and mono-saccharides and polyols (FODMAP) playing a role in symptom induction, presumably through osmotic effects and rapid colonic fermentation. While dietary studies assessed effects on symptoms, few have investigated the direct impact on colonic motility.

Aims & Methods

Using high-resolution colonic manometry (HRCM), we examined the effects of intracolonic fructose, fructans (fructo-oligosaccharides), or mannitol infusion on colonic motility in healthy volunteers (HV).
A double-blind three-way crossover study was conducted in 15 HVs, with a ≥ 2-week wash-out period between visits. After three days of a low FODMAP and low fiber diet, subjects came fasted to the hospital's endoscopy unit. They received a 250 mL water enema before advancing a 36-sensor solid state HRCM catheter with perfusion lumen into the ascending colon via colonoscopy under conscious sedation. After a 1 h recovery period, colonic pressures were recorded 1 h in the fasted state, for 20 min during infusion of FODMAP in the ascending colon (200 mL 290 mOsm/kg fructose, fructans, or mannitol), 2 h post-infusion, and 1 h postprandially after a standardized low-calorie meal. Colonic motor patterns were manually identified and compared between the three FODMAPs, with long ones ≥12 cm and high amplitude ones with at least 3 sensors ≥100 mmHg. Gastrointestinal symptoms were recorded every 15 minutes during the 4.5 h measurement. Results are presented as median with minimum and maximum ranges.

Results

Fifteen HV, 40% male (mean age 32 years (range 19-64 y), mean BMI 22.6 kg/m² (range 19.6-33.1)), completed the three study visits. Post FODMAP infusion, a significant difference in long anterograde patterns (p=0.04) was detected (Table). Postprandially, long synchronous (p=0.001) and long anterograde (LA) (p=0.0008) were more frequently observed with fructans, while mannitol tended to induce long retrograde patterns (p=0.07). Many of the long anterograde patterns were pan-colonic interrupted pressurizations (IP; previously described as related to gas transit; Leibbrandt J Clin Med 2023), and these were significantly more frequent after fructans infusion (p=0.004). High-amplitude retrograde-propagating contractions occurred 36 times in five HV: 50% after mannitol, 25% after fructans, and 25% after fructose infusion. There was no significant difference in gastrointestinal symptoms between the three FODMAPs, although flatulence and abdominal cramps were slightly increased after infusion of fructans.

Conclusion

Fructans and mannitol alter colonic motility patterns in distinct ways. Upon fructan infusion, there is a higher frequency of anterograde and synchronous activity, including interrupted pressurizations, which are suggested to be linked to gas transit. However, the frequency of these motor patterns was not altered by mannitol. These responses to different FODMAPs may contribute to symptom generation in IBS.

References

Van den Houte et al. Gastroenterology 2024
Leibbrandt J et al. Clin Med 2023

Introduction

Low mucosal impedance has been associated with reduced mucosal integrity and is measured during ambulatory pH/impedance monitoring, defined as mean nocturnal baseline impedance (MNBI)¹. More recently, techniques to measure impedance during endoscopy are emerging². In a prospective cohort of patients with EoE (SWALLeOeW Study, ISRCTN17786884, recruitment ongoing) we assessed the technicality of comparing mucosal impedance using MNBI with impedance measured during high-resolution impedance manometry (HRIM).

Aims & Methods

Here we aim to assess the practicability of obtaining mucosal impedance measurements during HRIM and to compare this with impedance measured using MNBI in a group of patients with EoE.
Prospective participants with EoE were assessed with HRIM and MNBI and this was repeated following a treatment period (Oro-dispersible Budesonide). The pooling of repeat measures from an individual participant was deemed to be appropriate in this evaluation as the purpose was to technically validate the process of comparing MNBI with HRIM, rather than to compare individual data points.
MNBI was calculated during a quiescent nocturnal period (Laborie, Ohmega) using the average of distal impedance channels 3 and 5 cm above the proximal border of the LOS¹. Impedance data was obtained during the supine resting period during HRIM and manually exported from the software (Medtronic). Extracted frames were at least 3 respiratory cycles and up to 30 seconds, and impedance was calculated based on the sensors 2.5 and 4.5, or 3.5 and 5.5 cm above the proximal border of the LOS, depending on catheter position.

Results

22 paired HRIM and MNBI measurements were obtained to date, from 15 participants. Reasons for unsuccessful MNBI measurements were not attempting test (n=2), non-tolerance (n=10), Nickel allergy (n=1), drop-out (n=2), or unable to intubate (n=1). Reasons for unsuccessful impedance measurement during HRIM were reflux during resting pressure measurement (n=1), catheter failure (n=3), drop-out (n=2), non-tolerance (n=8) or measurement not attempted (n=2).
The mean impedance values as measured by the two methods were not significantly different: mean MNBI (95% CI): 1570 (1210-1930) ohms, HRIM (95% CI) = 1330 (920-1740) ohms, p = 0.18. The mean difference between MNBI and HRIM was 245 ohms (1380-1870) (5-95^th percentiles).
Using a normality threshold of <1500 ohms³ being suggestive of impaired mucosal integrity, the majority (19/22) of the readings showed agreement between the two methods. Of the three that did not agree, MNBI suggested impaired mucosal integrity in one, and HRIM in the other two.

Conclusion

Measuring impedance during HRIM appears to be comparably practicable to MNBI measurement in patients with EoE, with the same numbers of successful measurements achieved by the two methods. Comparison of this preliminary data also indicates good agreement between methods. Impedance measurement during HRIM could provide a faster method of assessing mucosal integrity in EoE, whilst simultaneously assessing oesophageal motility. Further work in the SWALLeOeW study will correlate mucosal impedance findings with the Eosinophilic Oesophagitis Histology Scoring System⁴ and assess impedance change in response to treatment.

References

1. Hoshikawa, Y. et al. Measurement of Esophageal Nocturnal Baseline Impedance: A Simplified Method. J Neurogastroenterol Motil 26, 241–247 (2020).
2. Lei, W.-Y., Vaezi, M. F., Naik, R. D. & Chen, C.-L. Mucosal impedance testing: A new diagnostic testing in gastroesophageal reflux disease. Journal of the Formosan Medical Association 119, 1575–1580 (2020).
3. Sifrim, D. et al. Normal values and regional differences in oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world. Gut gutjnl-2020-322627 (2020).
4. Collins, M. H. et al. Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring. Diseases of the Esophagus 30, (2016).

Introduction

The Atmo Capsule is a wireless motility capsule that senses and telemetrically transmits measurements of hydrogen (H₂) and carbon dioxide (CO₂) along the gut. In the colon, luminal concentrations of H₂ and CO₂ represent the metabolic activity of the microbial community. We hypothesized that delayed colonic transit would lead to altered gas profiles due to earlier depletion of fermentable substrates relative to transit time and/or facilitation of contact between methanogens and hydrogen (Levitt et al. CGH 2006).

Aims & Methods

The Atmo Capsule was administered to subjects with suspected upper and/or lower gut dysmotility. Colonic transit times (CTT) ≥ 59 h were considered delayed. Luminal H₂ and CO₂ concentrations (as time-normalized, area-under-the-curve [TN-AUC], [%.h]/h) were evaluated across the entire colon. Regional colonic profiles were evaluated per quartile of relative colonic transit, with quartiles 1 and 4 indicative of the proximal and distal colon, respectively. Gas measures were included if ≥ 50% of data were available for the corresponding segment. Fermentation profiles were estimated by the ratio of quartile 1:4 values, and time to peak concentrations were evaluated relative to CTT. Data were analyzed via Mann-Whitney test.

Results

The Atmo Capsule was administered to 209 subjects (median age 41; 188 female) with 170 yielding valid data on both colonic transit and colonic gas concentrations. Delayed colonic transit was identified in 60/170 (35%) subjects. In subjects with delayed CTT, H₂ concentrations tended to be higher in the proximal colon and lower in the distal colon with no overall difference across the region compared with those with normal transit (Table 1). CO₂ concentrations were higher throughout the colon except in the distal colon in subjects with delayed CTT. Peak concentrations of colonic H₂ and CO₂ were higher (H2, 8.7 h vs 5.9 %.h/h, p<0.01; CO2, 37.4 vs 29.9 %.h/h, p<0.01) and tended to occur earlier (H₂, 35.9 vs 47.0 % of colonic transit p=0.14; CO₂, 49.1 vs 86.8 % colonic transit, p<0.01) in patients with delayed compared with normal CTT.

Table 1. Gas profiles in patients with delayed colonic transit and correlation with symptom profiles. Data shown as median (interquartile range) and analyzed via Mann-Whitney test.

Conclusion

Colonic gas profiles, as measured via the Atmo Capsule, differed in patients with delayed compared with normal CTT, with patterns suggesting progressive depletion of fermentable substrates and/or conversion of H2 to methane during transit in those with delayed transit.

References

Levitt MD, Furne JK, Kuskowski M, Ruddy J. Stability of human methanogenic flora over 35 years and a review of insights obtained from breath methane measurements. Clin Gastroenterol Hepatol. 2006 Feb;4(2):123-9. doi: 10.1016/j.cgh.2005.11.006. PMID: 16469670.

Disclosure

These authors disclose the following: Braden Kuo, Anthony J. Lembo, Eammon M.M. Quigley, Satish S.C. Rao, and William D. Chey serve on the Medical Advisory Board of Atmo Biosciences. Michael Cline and Baharak Moshiree served on the Medical Advisory Board of Atmo Biosciences. Braden Kuo has received funding from NIH, Vanda, Atmo Biosciences, and Takeda and has consulted for Evoke, Takeda, Ironwood, Novo Nordisk, Cindome, and Neurogastrx. Thomas Abell has received funding from Gastric Dysrhythmias, Neurogastrx, NIH GpCRC, and Vanda and has consulted for Enterra Medical, Novo Nordisk, Nuvaira, and Vanda. Anthony J. Lembo has received funding from Ardelyx, Biomerica, GSK, Ironwood, Takeda, and Vibrant and holds stock with Allurion, Bristol Myer Squibb, and J&J. Abigail Stocker has received funding from Cindome, Enterra Medical, and Vanda. William D. Chey has received funding from Atmo Biosciences, Commonwealth Diagnostics Intl, QOL Medical, and Salix; has consulted for AbbVie, Ardelyx, Biomerica, Comvita, Gemelli, Ironwood, Nestle, QOL Medical, Phathom, Redhill, Salix, Vibrant, and Takeda; has filed patents with My Nutrition Health, Digital Manometry, and Rectal Expulsion Device; and holds stock options with Coprata, Evinature, Food Marble, Kiwi Bioscience, and Modify Health. The remaining authors disclose no conflicts.