Genetic crosses within and between species of Cryptosporidium.

Parasites and their hosts are engaged in reciprocal coevolution that balances competing mechanisms of virulence, resistance, and evasion. This often leads to host specificity, but genomic reassortment between different strains can enable parasites to jump host barriers and conquer new niches. In the apicomplexan parasite Cryptosporidium, genetic exchange has been hypothesized to play a prominent role in adaptation to humans. The sexual lifecycle of the parasite provides a potential mechanism for such exchange; however, the boundaries of Cryptosporidium sex are currently undefined. To explore this experimentally, we established a model for genetic crosses. Drug resistance was engineered using a mutated phenylalanyl tRNA synthetase gene and marking strains with this and the previously used Neo transgene enabled selection of recombinant progeny. This is highly efficient, and genomic recombination is evident and can be continuously monitored in real time by drug resistance, flow cytometry, and PCR mapping. Using this approach, multiple loci can now be modified with ease. We demonstrate that essential genes can be ablated by crossing a Cre recombinase driver strain with floxed strains. We further find that genetic crosses are also feasible between species. Crossing Cryptosporidium parvum, a parasite of cattle and humans, and Cryptosporidium tyzzeri a mouse parasite resulted in progeny with a recombinant genome derived from both species that continues to vigorously replicate sexually. These experiments have important fundamental and translational implications for the evolution of Cryptosporidium and open the door to reverse- and forward-genetic analysis of parasite biology and host specificity.

Intestinal cDC1s provide IL-12 dependent and independent functions required for CD4+ T cell-mediated resistance to Cryptosporidium.

Cryptosporidium is an enteric pathogen that is a prominent cause of diarrheal disease. Control of this infection requires CD4+ T cells, though the processes that lead to T cell-mediated resistance have been difficult to assess. Here, Cryptosporidium parasites that express MHCII-restricted model antigens were generated to dissect the early events that influence CD4+ T cell priming and effector function. These studies highlight that parasite-specific CD4+ T cells are primed in the draining mesenteric lymph node (mesLN) and differentiate into Th1 cells in the gut, where they mediate IFN-γ-dependent control of the infection. Although type 1 conventional dendritic cells (cDC1s) were not required for initial priming of CD4+ T cells, cDC1s were required for CD4+ T cell expansion and gut homing. cDC1s were also a major source of IL-12 that was not required for priming but promoted full differentiation of CD4+ T cells and local production of IFN-γ. Together, these studies reveal distinct roles for cDC1s in shaping CD4+ T cell responses to enteric infection: first to drive early expansion in the mesLN and second to drive effector responses in the gut.

Barriers to healthcare and a 'triple empathy problem' may lead to adverse outcomes for autistic adults: A qualitative study.

LAY ABSTRACT: Autistic people live with more mental and physical health conditions and, on average, die younger than non-autistic people. Despite widespread commitments to tackling these issues, autistic people still report various barriers to accessing healthcare. This article aims to explore the area in depth, from the perspective of autistic people. This research benefits from being led by autistic people, for autistic people - all of the researchers are autistic, and most of us are also medical doctors. Data, in the form of written comments and stories, were collected as part of a large survey. Here, we explored these for common themes and possible deeper meaning within the experiences. People who took part reported a variety of barriers. Here, our article gives voice to their stories, in their own words. Themes included: early barriers; communication mismatch; doubt - in oneself and from doctors; helplessness and fear; and healthcare avoidance and adverse health outcomes. Our findings allowed us to create a model that aimed to understand and explain the reported barriers in the context of the previously known consequences. We also built on wider autism theories to explain our findings in more depth.

Genetic crosses within and between species of Cryptosporidium.

Parasites and their hosts are engaged in rapid coevolution that balances competing mechanisms of virulence, resistance, and evasion. This often leads to host specificity, but genomic reassortment between different strains can enable parasites to jump host barriers and conquer new niches. In the apicomplexan parasite Cryptosporidium genetic exchange has been hypothesized to play a prominent role in adaptation to humans. The sexual lifecycle of the parasite provides a potential mechanism for such exchange; however, the boundaries of Cryptosporidium sex are currently undefined. To explore this experimentally, we established a model for genetic crosses. Drug resistance was engineered using a mutated phenylalanyl tRNA synthetase gene and marking strains with this and the previously used Neo transgene enabled selection of recombinant progeny. This is highly efficient, and genomic recombination is evident and can be continuously monitored in real time by drug resistance, flow cytometry, and PCR mapping. Using this approach multiple loci can now be modified with ease. We demonstrate that essential genes can be ablated by crossing a Cre recombinase driver strain with floxed strains. We further find that genetic crosses are also feasible between species. Crossing C. parvum, a parasite of cattle and humans, and C. tyzzeri a mouse parasite resulted in progeny with a recombinant genome derived from both species that continues to vigorously replicate sexually. These experiments have important fundamental and translational implications for the evolution of Cryptosporidium and open the door to reverse- and forward- genetic analysis of parasite biology and host specificity.

The experiences of autistic doctors: a cross-sectional study.

Introduction: Medicine may select for autistic characteristics. As awareness and diagnosis of autism are growing, more medical students and doctors may be discovering they are autistic. No studies have explored the experiences of autistic doctors. This study aimed to fill that gap. Methods: This is a cross-sectional study. A participatory approach was used to identify the need for the project and to modify a pre-existing survey for use exploring the experiences of autistic doctors. Results: We received 225 responses. 64% had a formal diagnosis of autism. The mean age of receiving a formal diagnosis was 36 (range 3-61). Most were currently working as doctors (82%). The most common specialties were general practice / family medicine (31%), psychiatry (18%), and anesthesia (11%). Almost half of those working had completed specialty training (46%) and 40% were current trainees. 29% had not disclosed being autistic to anyone at work. 46% had requested adjustments in the workplace but of these, only half had them implemented.Three quarters had considered suicide (77%), one quarter had attempted suicide (24%) and half had engaged in self-harm (49%). 80% reported having worked with another doctor they suspected was autistic, but only 22% reported having worked with another doctor they knew was autistic. Having never worked with a potentially autistic colleague was associated with having considered suicide.Most preferred to be called "autistic doctors" (64%). Most considered autism to be a difference (83%). Considering autism to be a disorder was associated with preference for the term "doctors with autism," and with having attempted suicide. Conclusion: Autistic doctors reported many challenges in the workplace. This may have contributed to a culture of nondisclosure. Mental health was poor with high rates of suicidal ideation, self-harm, and prior suicide attempts. Despite inhospitable environments, most were persevering and working successfully. Viewing autism as a disorder was associated with prior suicide attempts and a preference for person-first language. A neurodiversity-affirmative approach to autism may lead to a more positive self-identity and improved mental health. Furthermore, providing adequate supports and improving awareness of autistic medical professionals may promote inclusion in the medical workforce.

The experiences of medical students with ADHD: A phenomenological study.

Attention Deficit/Hyperactivity 'Disorder' (ADHD) is a form of neurodivergence, characterised by lifelong differences in attention, impulsivity, and hyperactivity. University students with ADHD underachieve academically and tend to have lower levels of self-esteem. Medical schools have an obligation to minimise barriers for students with ADHD. Understanding the experiences of medical students with ADHD is vital to promote inclusive approaches. Our exploratory research question was: "What are the experiences of medical students with ADHD?" This was an interpretive phenomenological study. Loosely structured interviews were conducted with participants (medical students with ADHD) over Zoom. Subsequent transcripts were analysed using interpretive phenomenological analysis. Six people participated. Our analysis identified the following themes: Identity and diagnosis; ADHD profile; system issues; conflict, competition and compensation; improving the experience. Participants reported experiences of bullying and isolation at medical school, perpetrated by doctors and peers, as well as feelings of alienation when unable to conform on placement and in exams. From this, participants adopted survival strategies, such as masking, to avoid being ostracised. All recognised their ADHD status when their mental health deteriorated during their medical studies. Of those who disclosed their diagnosis, none were offered personalised support. Participants feared disclosure, largely due to weaponised professionalism and the effects of toxic competitiveness in medicine. They yearned for a sense of belonging. Participants reported strengths associated with ADHD such as empathy and working well under pressure, which are highly desirable aptitudes for doctors. This study has highlighted areas where medical schools can be instrumental in cultivating an environment where medical students with ADHD can thrive, not just survive. This may take the form of peer support groups, alongside reasonable adjustments throughout medical school-particularly for Objective Structured Clinical Examinations, for example. Enabling these students to thrive may help to prevent early burnout and subsequent attrition from medicine.

Applying to medical school with undiagnosed dyslexia: a collaborative autoethnography.

Recent statistics found the prevalence of dyslexia in UK medical schools to be 7%, sitting below the national prevalence of 10%. The factors contributing to this discrepancy are currently unknown, but may result from an interplay of individual and systemic barriers to entering medicine. This collaborative, analytic autoethnography aimed to use the experiences of 'Meg', a fourth-year medical student who was diagnosed as dyslexic whilst at medical school, to explore how the lack of a diagnosis during the admissions process may have impacted her journey into medicine. The data were collected using reflective writing and an interview before conducting a thematic analysis. Our analysis resulted in the construction of two meta-themes, relating to the negative emotional impact of not having a diagnosis and feelings of inferiority. Seven themes were also constructed. Some explored how Meg's personal experience of undiagnosed dyslexia acted as a barrier to entering medicine. Others explored the impact of external factors, such as socio-economic background and the provision of support, on an individual's chance of successfully applying to medical school. Finally, we explored the inadvertent impact undiagnosed (and unrecognised) dyslexia had on Meg's life course, including how medicine-specific aptitude tests, such as the BMAT and UKCAT, may have contributed to this. These results provide a unique window into the culture of applying to medical school as an undiagnosed dyslexic person, whilst discussing the need for medical schools to consider how their admissions processes may inadvertently disadvantage undiagnosed dyslexic applicants.

The experiences of autistic medical students: A phenomenological study.

BACKGROUND: Increasing recognition of autism is reflected in the growing awareness of autistic health care providers. Regulatory bodies including the UK General Medical Council and the UK Medical Schools Council have published guidance fostering inclusion. Whilst many autistic doctors and students are thriving, many may not disclose their diagnosis unless difficulties arise, which perpetuates stereotypes. No studies have explored the experiences of autistic medical students. We aimed to do this. METHODS: This was an interpretive phenomenological study. Autistic medical students were recruited using Facebook announcements. Participants underwent audio-recorded, loosely structured interviews. Recordings were transcribed verbatim and underwent an interpretive phenomenological analysis. RESULTS: Five participated from five different UK medical schools. Constructed themes included: Autistic profiles and stereotypes-'I'm a lot better with patients than I am with my peers, with staff, which is hard for a lot of people to understand'; sensory processing and the learning environment-'noises really hurt my ears … It actually hurts'; me, myself and masking-'so, medicine's hard. But I'm also studying myself and I'm figuring myself out and that degree is harder'; the social world-'I always feel like I'm watching my back'; and navigating the system-'[they say] "but you're going to be a doctor one day, so you need to get used to it"'. CONCLUSION: Participants longed for understanding and support from their medical schools. They reported experiences of isolation, bullying and anxiety. Most felt themselves to be victims of the system, whereby they were expected to adapt themselves in order to appear non-autistic. When participants reported not coping due to being autistic, most were advised to 'take time out'. None were offered personalised adjustments to their learning environment. All reported strengths associated with being autistic. This supports the assertion that autistic people can be safe, effective and skilled doctors.

Autistic SPACE: a novel framework for meeting the needs of autistic people in healthcare settings.

Autistic people experience significant health disparities and reduced life expectancy. Barriers to accessing healthcare are associated with adverse health outcomes. Autism training and healthcare professionals' knowledge about autism is variable, and heterogeneity among autistic people leads to additional educational and clinical complexities. Autism remains nebulous for many practitioners, who are unclear about communication differences, access needs or life experiences common to autistic people. Healthcare environments can be challenging for all patients but autistic people may require specific accommodations to allow equitable access. The authors have developed a simple framework which may facilitate equitable clinical services at all points of access and care, using the acronym 'SPACE'. This encompasses five core autistic needs: Sensory needs, Predictability, Acceptance, Communication and Empathy. Three additional domains are represented by physical space, processing space and emotional space. This simple yet memorable framework encompasses commonalities shared by autistic people.

The sweet and sour sides of trypanosome social motility.

Recent studies showed that the formation of elegant geometric patterns by communities of Trypanosoma brucei on semi-solid surfaces, dubbed social motility (SoMo) by its discoverers, is a manifestation of pH taxis. This is caused by procyclic forms generating and responding to pH gradients through glucose metabolism and cAMP signalling. These findings established that trypanosomes can sense and manipulate gradients, potentially helping them to navigate through host tissues. At the same time, the host itself and bystanders such as endosymbionts have the potential to shape the environment and influence the chances of successful transmission. We postulate that the ability to sense and contribute to the gradient landscape may also underlie the tissue tropism and migration of other parasites in their hosts.

Barriers to healthcare and self-reported adverse outcomes for autistic adults: a cross-sectional study.

OBJECTIVES: Autistic people experience poor physical and mental health along with reduced life expectancy compared with non-autistic people. Our aim was to identify self-reported barriers to primary care access by autistic adults compared with non-autistic adults and to link these barriers to self-reported adverse health consequences. DESIGN: Following consultation with the autistic community at an autistic conference, Autscape, we developed a self-report survey, which we administered online through social media platforms. SETTING: A 52-item, international, online survey. PARTICIPANTS: 507 autistic adults and 157 non-autistic adults. PRIMARY AND SECONDARY OUTCOME MEASURES: Self-reported barriers to accessing healthcare and associated adverse health outcomes. RESULTS: Eighty per cent of autistic adults and 37% of non-autistic respondents reported difficulty visiting a general practitioner (GP). The highest-rated barriers by autistic adults were deciding if symptoms warrant a GP visit (72%), difficulty making appointments by telephone (62%), not feeling understood (56%), difficulty communicating with their doctor (53%) and the waiting room environment (51%). Autistic adults reported a preference for online or text-based appointment booking, facility to email in advance the reason for consultation, the first or last clinic appointment and a quiet place to wait. Self-reported adverse health outcomes experienced by autistic adults were associated with barriers to accessing healthcare. Adverse outcomes included untreated physical and mental health conditions, not attending specialist referral or screening programmes, requiring more extensive treatment or surgery due to late presentations and untreated potentially life-threatening conditions. There were no significant differences in difficulty attending, barriers experienced or adverse outcomes between formally diagnosed and self-identified autistic respondents. CONCLUSIONS: Reduction of healthcare inequalities for autistic people requires that healthcare providers understand autistic perspectives, communication needs and sensory sensitivities. Adjustments for autism-specific needs are as necessary as ramps for wheelchair users.

Cyclic AMP signalling and glucose metabolism mediate pH taxis by African trypanosomes.

The collective movement of African trypanosomes on semi-solid surfaces, known as social motility, is presumed to be due to migration factors and repellents released by the parasites. Here we show that procyclic (insect midgut) forms acidify their environment as a consequence of glucose metabolism, generating pH gradients by diffusion. Early and late procyclic forms exhibit self-organising properties on agarose plates. While early procyclic forms are repelled by acid and migrate outwards, late procyclic forms remain at the inoculation site. Furthermore, trypanosomes respond to exogenously formed pH gradients, with both early and late procyclic forms being attracted to alkali. pH taxis is mediated by multiple cyclic AMP effectors: deletion of one copy of adenylate cyclase ACP5, or both copies of the cyclic AMP response protein CARP3, abrogates the response to acid, while deletion of phosphodiesterase PDEB1 completely abolishes pH taxis. The ability to sense pH is biologically relevant as trypanosomes experience large changes as they migrate through their tsetse host. Supporting this, a CARP3 null mutant is severely compromised in its ability to establish infections in flies. Based on these findings, we propose that the expanded family of adenylate cyclases in trypanosomes might govern other chemotactic responses in their two hosts.

A full CIRCLE: inclusion of autistic doctors in the Royal College Of Psychiatrists' values and Equality Action Plan.

Autistic psychiatrists bring strengths and values to the workforce and ask to be acknowledged and supported as part of the Royal College of Psychiatrists' CIRCLE values and Equality Action Plan. Courage and collaboration are required to jointly learn and innovate, promoting well-being, resilience and excellence for autistic doctors.