Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?

Members of the phosphodiesterase 4 (PDE4) enzyme family regulate the availability of the secondary messenger cyclic adenosine monophosphate (cAMP) and, by doing so, control cellular processes in health and disease. In particular, PDE4D has been associated with Alzheimer's disease and the intellectual disability seen in fragile X syndrome. Furthermore, single point mutations in critical PDE4D regions cause acrodysostosis type 2(ACRDYS2, also referred to as inactivating PTH/PTHrP signalling disorder 5 or iPPSD5), where intellectual disability is seen in ∼90% of patients alongside the skeletal dysmorphologies that are characteristic of acrodysostosis type 1 (ACRDYS1/iPPSD4) and ACRDYS2. Two contrasting mechanisms have been proposed to explain how mutations in PDE4D cause iPPSD5. The first mechanism, the 'over-activation hypothesis', suggests that cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) signalling is reduced by the overactivity of mutant PDE4D, whilst the second, the 'over-compensation hypothesis' suggests that mutations reduce PDE4D activity. That reduction in activity is proposed to cause an increase in cellular cAMP, triggering the overexpression of other PDE isoforms. The resulting over-compensation then reduces cellular cAMP and the levels of cAMP/PKA signalling. However, neither of these proposed mechanisms accounts for the fine control of PDE activation and localization, which are likely to play a role in the development of iPPSD5. This review will draw together our understanding of the role of PDE4D in iPPSD5 and present a novel perspective on possible mechanisms of disease.

Association between telehealth use and general practitioner characteristics during COVID-19: findings from a nationally representative survey of Australian doctors.

OBJECTIVE: To investigate factors associated with the use of telehealth by general practitioners (GPs) during COVID-19. DESIGN: A nationally representative longitudinal survey study of Australian doctors analysed using regression analysis. SETTING: General practice in Australia during the COVID-19 pandemic. PARTICIPANTS: 448 GPs who completed both the 11th wave (2018-2019) of the Medicine in Australia: Balancing Employment and Life (MABEL) Survey and the MABEL COVID-19 Special Online Survey (May 2020). OUTCOME MEASURES: Proportion of all consultations delivered via telephone (audio) or video (audiovisual); proportion of telehealth consultations delivered via video. RESULTS: 46.1% of GP services were provided using telehealth in early May 2020, with 6.4% of all telehealth consultations delivered via video. Higher proportions of telehealth consultations were observed in GPs in larger practices compared with solo GPs: between +0.21 (95% CI +0.07 to +0.35) and +0.28 (95% CI +0.13 to +0.44). Greater proportions of telehealth consultations were delivered through video for GPs with appropriate infrastructure and for GPs with more complex patients: +0.10 (95% CI +0.04 to +0.16) and +0.04 (95% CI +0.00 to +0.08), respectively. Lower proportions of telehealth consultations were delivered via video for GPs over 55 years old compared with GPs under 35 years old: between -0.08 (95% CI -0.02 to -0.15) and -0.15 (95% CI -0.07 to -0.22), and for GPs in postcodes with a higher proportion of patients over 65 years old: -0.005 (95% CI -0.001 to -0.008) for each percentage point increase in the population over 65 years old. CONCLUSIONS: GP characteristics are strongly associated with patterns of telehealth use in clinical work. Infrastructure support and relative pricing of different consultation modes may be useful policy instruments to encourage GPs to deliver care by the most appropriate method.