Vaccine hesitancy and HPV vaccine uptake among male and female youth in Switzerland: a cross-sectional study

OBJECTIVES: Identifying factors associated with human papillomavirus (HPV) vaccine uptake is essential for designing successful vaccination programmes. We aimed to examine the association between vaccine hesitancy (VH) and HPV vaccine uptake among male and female youth in Switzerland. DESIGN: With a cross-sectional study, an interview-based questionnaire was used to collect information on sociodemographic factors, vaccination records and to measure the prevalence of VH using the Youth Attitudes about Vaccines scale (YAV-5), a modified version of the Parent Attitudes about Childhood Vaccinations survey instrument. SETTING AND PARTICIPANTS: Eligible male and female participants, 15-26 years of age, were recruited through physicians' offices and military enlistment in all three language regions of Switzerland. Of 1001 participants, we included 674 participants with a vaccination record available (415 males and 259 females) in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome was uptake for HPV vaccine (having received >/=1 dose of HPV vaccine). Covariates were VH, sex, age and other sociodemographics. RESULTS: 151 (58%) female and 64 (15%) male participants received >/=1 dose of HPV vaccine. 81 (31%) female and 92 (22%) male participants were VH (YAV-5-Score >50). The odds for being unvaccinated were higher for VH women than non-VH women, adjusted OR=4.90 (95% CI 2.53 to 9.50), but similar among VH and non-VH men, OR=1.90 (95% CI 0.84 to 4.31). The odds for being unvaccinated were lower for younger men (born on or after 1 July 2002) than older men (born before 1 July 2002), OR=0.34 (95% CI 0.14 to 0.81), but we found no association between age and vaccine uptake for female youth, OR=0.97 (95% CI 0.48 to 1.97). CONCLUSIONS: VH was associated with lower HPV vaccine uptake in female youth but not male youth in our study population in Switzerland. Our findings suggest that issues other than VH contribute to HPV underimmunisation in male youth in Switzerland

Isolated adult hypoganglionosis presenting as sigmoid volvulus: a case report

<p>Abstract</p> <p>Introduction</p> <p>Isolated hypoganglionosis is a rare cause of intestinal innervation defects. It is characterized by sparse and small myenteric ganglia, absent or low acetylcholinesterase activity in the lamina propria and hypertrophy of the muscularis mucosae, principally in the region of the colon and rectum. It accounts for 5% of all intestinal neuronal malformations. To the best of our knowledge, only 92 cases of isolated hypoganglionosis were reported from 1978 to 2009. Isolated hypoganglionosis usually manifests as enterocolitis or poor bowel function, and is diagnosed in infancy or childhood. We report the first case of isolated hypoganglionosis presenting with sigmoid volvulus in a 34-year-old woman.</p> <p>Case presentation</p> <p>A 34-year-old Asian woman had progressively increasing abdominal pain and had not passed stool or flatus for two days. A physical examination revealed a distended abdomen with sluggish gut sounds. A computerized tomography (CT) scan demonstrated gross dilatation of the sigmoid colon (maximal diameter 14.3 cm) suggestive of sigmoid volvulus. During emergency laparotomy, sigmoidectomy with a side-to-side colorectal anastomosis was performed. Histopathology of the resected specimen showed occasional ganglion cells and hypertrophied nerve bundles in the muscle layers, suggesting hypoganglionosis. Colonoscopy was performed, and multiple full-thickness biopsies were taken that showed hypoganglionosis of the entire large bowel. Our patient underwent total colectomy with an ileorectal anastomosis. Subsequently our patient reported a dramatic improvement in her bowel function.</p> <p>Conclusions</p> <p>Isolated hypoganglionosis is a rare cause of intestinal dysganglionosis and cannot be differentiated from Hirschsprung's disease based on clinical presentation. This case report describes an atypical presentation of the disease. A definitive diagnosis requires histopathological analysis of full-thickness intestinal biopsies. Treatment should be tailored to the extent of hypoganglionosis.</p

Titanium-45 as a candidate for PET imaging: production, processing & applications

Introduction The 80kD glycoprotein transferrin (TF) and its related receptor (TFR1) play a major role in the recruitment by cancer cells of factors for their multiplication, adhesion, invasion and metastatic potential. Though primarily designed to bind iron and then be internalised into cells with its receptor, TF can also bind most transition metals such as Co, Cr, Mn, Zr, Ni, Cu, V, In & Ga. Under certain conditions TF binds Ti (IV) even more tightly than it does Fe and that this occurs at the N-lobe (as distinct from C) of apoTF. Further, under physiological conditions the species Fe(C)Ti(N)-TF may provide the route for Ti entry into cells via TFR1 (1). Thus, the radiometal PET reporter isotope 45Ti with an ‘intermediate’ (~hrs) half-life suited to tracking cell-focused biological mechanisms is an attractive option for elucidating cellular mechanisms involving TF binding and internalisation, at least in (preclinical) animal models. 45Ti (T½ = 3.08 hr; + branching ratio = 85 %; mean β+ energy = 439keV, no significant dose-conferring non-511keV γ-emissions) was produced using the reaction 45Sc(p,n)45Ti by irradiating (monoisotopic) scandium discs with an energy-degraded proton beam produced by an 18MeV isochronous medical cyclotron. Separation and purification was achieved with an hydroxylamine hydrochloride functionalised resin. Comparative microPET imaging was performed in an immunodeficient mouse model, measuring biodistributions of the radiolabels 45Ti-oxalate and 45Ti-human-TF (45Ti-h-TF), out to 6hr post-injection. Materials and Methods High purity 15mm diameter scandium disc foils (99.5%, Goodfellow, UK) each thickness 0.100 ± 0.005 mm (55 mg) were loaded into an in-house constructed solid-targetry system mounted on a 300mm external beam line utilising helium-gas and chilled water to cool the target body (2). The proton beam was degraded to 11.7 MeV using a graphite disc integrated into the graphite collimator. This energy abolishes the competing ‘contaminant’ reactions 45Sc(p,n+p)44Sc and 45Sc(p,2n)44Ti. Beam current was measured using the well documented 65Cu(p,n)65Zn reaction. Calculations showed that the chosen energy is close to the optimal primary energy (~12 MeV) for maximising the (thin-target) yield from a 0.100 mm thick target. For separation of Ti from the Sc target two methods were examined; (i) ion exchange column separation using 2000 mg AG 50W-X8 resin conditioned with 10mL 9M HCl. Disc is dissolved in 1 mL of 9M HCl, which at completion of reaction is pipetted into column. Successive 1 mL volumes of 9M HCl are added, and subsequent elutions collected. (ii) Following Gagnon et al., (3) a method employing hydroxylamine hydro-chloride functionalised resin (’hydroxamate method’) was applied, similar to its use in our hands for purification and separation of 89Zr (2) following its original description for 89Zr by Holland et al., (4). Disc dissolved in 2mL 6M HCl, then diluted to 2M. Elute through column to waste fraction 1 (w1 – see FIG. 1). Then elute 6 mL of 2M HCl through column to w2, followed by 6 mL of traceSELECT H2O to w3. Finally, elute Ti into successive 1 mL product fractions (p1, 2 etc.) using 5 mL of 1M oxalic acid. This procedure takes approximate 1 hr. 45Ti in elution vials was measured using γ-spectroscopy. Sc in the same vials was determined later using ICP-MS. Results A typical production run using a beam current of 40 μA for 60min on a 0.100mm-thick disc produced an activity of 1.83 GBq. Radionuclidic analysis of an irradiated disc using calibrated cryo-HPGe γ-spectroscopy revealed T½ = 2.97–3.19 hr (95% CI) for 45Ti, and with contaminant 44Sc < 0.19 %, with no other isotopes detected. Despite systematic adjustments to column conditions satisfactory chemical separation was not achieved using the ion exchange column method (i), despite previous reports of its success (5). Typical results of separation using the successful hydroxamate method (ii) are shown on the FIGURE 1. It is seen that significant portion of 45Ti is lost in the initial washing steps leading to waste collection. N = 4 replicate experiments showed a variation (SD) of 10 % of the mean in each elu-tion fraction. Subsequent ICP-MS of the same elutions for (cold) Sc showed approximately 80 % by mass appeared in w1 and 20 % in w2, with negligible total mass (total fraction ~1/6000) of Sc in product (p1–4) vials. However, the FIG. 1 shows that a total of only 30% of the original activity of 45Ti (corrected to EOB) is available in the product vials, with the vial of highest specific activity (p1) containing 14 %. However, using a stack of 2×0.100mm thick Sc discs as a target yields isotope of adequate specific activity with-out need for concentration, for subsequent labelling and small-animal imaging purposes. In a ‘proof-of-principle’ experiment, two groups of healthy Balb/c-nu/nu female adult mice were administered with 45Ti radiotracers. The first group (N = 3) received approximately 20 MBq IP of 45Ti-oxalate buffered to pH = 7.0, and under-went microPET/CT imaging (Super Argus PET, Sedecal, Spain) out to 6hr post-injection, plus biodistribution analysis of radioactivity by dis-section at sacrifice (6hr). The second group (N = 3) received approximately 20 MBq IP of 45Ti-h-TF and were also studied to 6hr post-injection, followed by radioactive analysis after dissection at sacrifice. Organ and tissue biodistributions of the two groups at 6hr were similar but with 45Ti-oxalate showing slightly greater affinity for bone. Biodistribution by dissection results broadly confirmed the findings from PET images. However, TLC results suggested that similarity of radiolabel biodistributions of the two groups may be due to contamination of the TF radiolabel with non-conjugated Ti at time of injection. An alternative explanation is dechelation in vivo of 45Ti from 45Ti-h-TF. Conclusion Despite significant loss of 45Ti to the waste fractions of the separation process (total 53 %, corrected to EOB), 45Ti of acceptable specific activity and high radionuclidic purity has been produced from the reaction 45Sc(p,n)45Ti, with separation and purification of the product by hydroxamate column chemistry, confirming an earlier report. Though microPET in vivo imaging using 45Ti-based radiolabels was shown to be feasible, the similarity in the results for the label 45Ti-h-TF compared with ‘raw’ 45Ti-oxalate suggests further investigations. These may include a direct comparison of in vivo 45Ti-h-TF small-animal imaging plus post-dissection biodistribution with the same procedures using 89Zr labelled h-apotransferrin (6)

Large Language Models Encode Clinical Knowledge

Large language models (LLMs) have demonstrated impressive capabilities in natural language understanding and generation, but the quality bar for medical and clinical applications is high. Today, attempts to assess models' clinical knowledge typically rely on automated evaluations on limited benchmarks. There is no standard to evaluate model predictions and reasoning across a breadth of tasks. To address this, we present MultiMedQA, a benchmark combining six existing open question answering datasets spanning professional medical exams, research, and consumer queries; and HealthSearchQA, a new free-response dataset of medical questions searched online. We propose a framework for human evaluation of model answers along multiple axes including factuality, precision, possible harm, and bias. In addition, we evaluate PaLM (a 540-billion parameter LLM) and its instruction-tuned variant, Flan-PaLM, on MultiMedQA. Using a combination of prompting strategies, Flan-PaLM achieves state-of-the-art accuracy on every MultiMedQA multiple-choice dataset (MedQA, MedMCQA, PubMedQA, MMLU clinical topics), including 67.6% accuracy on MedQA (US Medical License Exam questions), surpassing prior state-of-the-art by over 17%. However, human evaluation reveals key gaps in Flan-PaLM responses. To resolve this we introduce instruction prompt tuning, a parameter-efficient approach for aligning LLMs to new domains using a few exemplars. The resulting model, Med-PaLM, performs encouragingly, but remains inferior to clinicians. We show that comprehension, recall of knowledge, and medical reasoning improve with model scale and instruction prompt tuning, suggesting the potential utility of LLMs in medicine. Our human evaluations reveal important limitations of today's models, reinforcing the importance of both evaluation frameworks and method development in creating safe, helpful LLM models for clinical applications